Martindale

The Complete Drug Reference

Thirty-sixth edition

Edited by
Sean C Sweetman
BPharm, FRPharmS

London • Chicago
Published by the Pharmaceutical Press
An imprint of RPS Publishing

1 Lambeth High Street, London SEl 7JN, UK

100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA

© Pharmaceutical Press 2009

is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the Royal Pharmaceutical

Society of Great Britain

First edition of Martindale: The Extra Pharmacopoeia was published in 1883.

Squire’s Companion was incorporated in the twenty-third edition in 1952.

Thirty-sixth edition published 2009

Printed in China by Everbest Printing Co. Ltd

ISBN 978 0 85369 840 1

ISSN 0263-5364

All rights reserved. No part of this publication may be

reproduced, stored in a retrieval system, or transmitted in any
form or by any means, without the prior written permission
of the copyright holder.
The publisher makes no representation, express or implied,
with regard to the accuracy of the information contained in
this book and cannot accept any legal responsibility or
liability for any errors or omissions that may be made.

A catalogue record for this book is available from the British Library
 Martindale: The Complete Drug Reference
Editor: Sean C Sweetman, BPharm, FRPharmS

Senior Assistant Editor: Paul S Blake, BPharm, GradDipHealthInformatics, FRPharmS

Assistant Editors: Alison Brayfield, BPharm, MRPharmS

Julie M McGlashan, BPharm, DipInfSc, MRPharmS
Gail C Neathercoat, BSc, MRPharmS
Anne V Parsons, BPharm, MRPharmS

Staff Editors: Catherine RM Cadart, BPharm, GradDipHospPharm, MRPharmS

Kathleen Eager, BPharm, MRPharmS
Susan L Handy, BPharm, DipClinPharm, MRPharmS
Fauziah T Hashmi, BSc, Msc, MRPharmS
Sue W Ho, BPharm, MRPharmS
Joanna A Humm, MPharm, MRPharmS
Jean Macpherson, BSc, PgCert, MRPharmS, MCPP
Melissa TA Siew, BPharm, CertPharmPractice, Cert Hum (Open), MRPharmS
Sandra Sutton, BPharm, MSc Med, Cert Proj Mngt, SAPC (SA)
Gerda W Viedge, BPharm, MRPharmS

Senior Editorial Assistant: Chloë SAJ Hatwal, BSc, MRes

Editorial Assistants: Elizabeth D King, DipBTECPharmSc

James O’Reilly, BSc, MSc
Elen R Shute, BA, MPhil

Clerical Assistant: Christine L Iskandar

Knowledge Systems: Michael C Evans, BSc

Contents
Preface v
Abbreviations viii
Contracted Names for Ions and Groups xi
Atomic Weights of the Elements xiii

Volume 1
• Monographs on drugs and ancillary substances

Analgesics Anti-inflammatory Drugs and Antipyretics 1 Dermatological Drugs and Sunscreens 1576
Anthelmintics 134 Disinfectants and Preservatives 1622
Antibacterials 158 Electrolytes 1667
Antidementia Drugs 362 Gases 1688
Antidepressants 372 Gastrointestinal Drugs 1692
Antidiabetics 431 General Anaesthetics 1779
Antiepileptics 465 Growth Hormone and its Modulators 1798
Antifungals 517 Immunosuppressants 1810
Antigout Drugs 552 Local Anaesthetics 1850
Antihistamines 561 Miotics Mydriatics and Antiglaucoma Drugs 1873
Antimalarials 594 Muscle Relaxants 1887
Antimigraine Drugs 616 Neuromuscular Blockers 1900
Antimyasthenics 629 Nonionic Surfactants 1914
Antineoplastics 635 Nutritional Agents and Vitamins 1922
Antiparkinsonian Drugs 791 Obstetric Drugs 2002
Antiprotozoals 822 Organic Solvents 2019
Antivirals 850 Paraffins and Similar Bases 2028
Anxiolytic Sedatives Hypnotics and Antipsychotics 952 Pesticides and Repellents 2034
Blood Products Plasma Expanders and Haemostatics 1042 Radiopharmaceuticals 2052
Bone Modulating Drugs 1083 Sex Hormones and their Modulators 2058
Bronchodilators and Anti-asthma Drugs 1108 Soaps and Other Anionic Surfactants 2138
Cardiovascular Drugs 1152 Stabilising and Suspending Agents 2140
Chelators Antidotes and Antagonists 1435 Stimulants and Anorectics 2148
Colouring Agents 1469 Thyroid and Antithyroid Drugs 2165
Contrast Media 1474 Urological Drugs 2178
Corticosteroids 1490 Vaccines Immunoglobulins and Antisera 2201
Cough Suppressants Expectorants Mucolytics and Nasal Decongestants 1547 Supplementary Drugs and Other Substances 2244

Volume 2

• Preparations 2419

• Directory of Manufacturers 3205

• General Index 3275

iv
Preface
The aim of Martindale is to provide healthcare professionals with unbiased compiling the text of a Martindale monograph extensive use is made of the
evaluated information on drugs and medicines used throughout the world. It drug's licensed product information as published in various countries and
therefore has to develop as the body of knowledge on existing drugs grows, new approved by the relevant regulatory health bodies. Acknowledgement is also
drugs emerge, new preparations are launched, and old preparations are given to information referenced from a number of authoritative sources
abandoned, reformulated, or redefined. It also has to reflect the changing needs including the British National Formulary, the British National Formulary for
of those practising pharmacy and medicine. We try to ensure that each new Children, the British Pharmacopoeia, the European Pharmacopoeia, the United
edition continues to meet all these needs. States National Formulary, and the United States Pharmacopeia.
In order to provide more up-to-date information the interval between the Martindale is not a book of standards. Inclusion of a substance or a preparation
publication of the printed versions of Martindale has been reduced over is not to be considered as a recommendation for use, nor does it confer any status
successive editions and the book is now produced about every 2 years. For those on the substance or preparation. While considerable efforts have been made to
who require even more up-to-date information from Martindale there are various check the material in Martindale, the publisher cannot accept any responsibility
electronic versions, sections of which are updated more frequently. for errors and omissions. Also the reader is assumed to possess the necessary
The year 2008 saw the publication of the third Spanish edition of Martindale, knowledge to interpret the information that Martindale provides.
the translation having again been undertaken by our colleagues at Grupo Ars
XXI, and also saw the appearance of the first edition of a Chinese language Philosophy and methodology
version of Martindale. Martindale’s uses are as varied as its users. However, our primary aims are:
Martindale has been continuously expanded since it was first published in • to summarise clinically useful information on all drugs and medicines
1883, and to present all the extra information this edition of Martindale around the world
maintains the recent return to a two-volume publication. The first volume • to provide accurate, unbiased, reasonably comprehensive, and regularly re-
contains this preface and the drug monographs, and the second holds the evaluated information in a concise format
proprietary preparations and the index, as well as manufacturers’ contact
• to provide a lead-in to the published evidence base from which we derive our
information.
information
As always the contents have been extensively revised, with all the text scanned
In order to achieve the aims specified above, our working practices have to
and revalidated where necessary by a team of experienced pharmacists. Over
optimise internal knowledge management.
260 monographs have been added, and 89 removed from the book (abbreviated
information on the latter remains available in the electronic versions). In our MARTINDALE STAFF. Martindale is currently produced by a team of 21 people,
continuing attempts to improve the clinical relevance of the book, the chapters 18 of whom are pharmacists or pharmacy technicians with relevant expertise.
on Prostaglandins and Hypothalamic and Pituitary Hormones have been split up The team is divided into 5 revising groups each of 2 staff editors, as well as 5
and most of their contents added to new chapters on Obstetric Drugs and Growth assistant editors, 1 editor-in-chief, a co-ordinator for the processing of
Hormone and its Modulators. The chapter on Sex Hormones has been information on proprietary medicines, and 4 clerical and support staff. A number
reorganised and renamed Sex Hormones and their Modulators. of pharmacists work as external evaluators to maintain coverage of non-UK
preparations.
The disease treatment reviews, 668 in all and generally located in the chapter
introductions, have also been revised in order to reflect current trends and Staff editors receive formal training in literature evaluation and searching
provide key references. Cross-references to these reviews appear in the techniques, as well as specific, ‘on-the-job’ training in internal procedures. Each
monographs of the drugs cited; the reviews can also be accessed via the general revision team has responsibility for the re-evaluation and update of a particular
index. It is hoped that these reviews will be of use to readers who want an group of chapters. Senior editorial staff edit and approve the output of the teams.
overview of a particular disease and its drug treatment and will provide a useful Staff are responsible for ongoing data collection as well as the revision process.
starting point for those who want to pursue particular aspects further. DATA COLLECTION. In order to reduce the amount of formal data collection
Martindale contains much nomenclature information intended to assist the required at revision, a prospective data-collection roster is in operation. This
reader in identifying a particular drug or compound, and for this edition we have involves all staff members in hand-searching selected major medical journals, as
again greatly expanded our coverage of synonyms, with the addition of names well as regular searches of the internet sites of regulatory authorities (EMEA,
from Poland and Turkey, and increased coverage of Russian synonyms and FDA, and MHRA), and sources of high-quality systematic reviews and
‘street names’ for substances of abuse. Coverage of ATC codes has been guidelines (such as Bandolier, Clinical Evidence, Cochrane, and NICE), for
expanded to include codes assigned to veterinary medicines drug information. In addition, pharmacopoeial, governmental and WHO
This edition of Martindale also sees the number of graphical representations publications are hand-searched for information relating to drugs and drug
of the chemical structures increased. therapy.
The information on proprietary preparations, an important feature of The list of sources used has been iteratively developed over many years by
Martindale, has been updated and more countries have been covered for this analysis of previous citations, and is reviewed and updated regularly.
edition. PROPRIETARY PREPARATIONS. The Martindale proprietary preparations team
Martindale is based on published information and more than 47 700 selected evaluate licensed product information for 40 countries and regions, in order
references are included. The amount of drug information now published to maintain the widest possible coverage of drugs in use internationally.
electronically has increased significantly since the last printed edition of Preparation names, manufacturers, ingredients, and licensed uses are included in
Martindale and this edition now includes nearly 2700 citations to material the internal Martindale database for review during the revision process, and any
available on the Internet as web pages. Because of the nature of the Internet, significant additional information is forwarded to the relevant revision team.
there is no way to guarantee that the material referred to by a URL will remain REVISION. In order to maintain the quality and currency of our content, it is
at that location, as many sites are subject to periodic reorganisation; additionally, constantly revised and updated. Our revision processes cover both scheduled, in-
the content of Internet documents may change without warning. All URLs in depth revision of the content of every chapter in the book on a chapter-by-
Martindale are rechecked shortly before publication to ensure that a document is chapter basis, and updates in reaction to new information as it arrives. The
present. The accession date given in the citation represents the last date on which revision procedure involves the formalised re-evaluation of all standing
the content of the document referred to was revalidated. information, the assessment of new collected references for quality and
Our objective is to evaluate the literature, covering important studies, relevance, and the selective use of search techniques on bibliographic databases
guidelines, and useful reviews and placing them in context. Multicentre studies, and the Internet to identify further candidate information.
meta-analyses, and systematic reviews play an important role in the study of CHECKING. Once the material for a given chapter has been re-evaluated and
drug treatment, and their findings and conclusions are considered in many of our updated it undergoes a rigorous check, designed to ensure not only that all
chapters. However, there is also a place for the anecdotal report and the small changes are valid and appropriate, but also that important points have not been
study, and information from such sources is included where appropriate. In missed.
v
vi Preface
EDITING. The chapter is then passed to a member of the senior editorial staff, Nomenclature
who performs a second check and preliminary editing of the data. This process
is designed to ensure consistency of approach and style, as well as offering an TITLES AND SYNONYMS. The title of each monograph is in English, with
opportunity to pick up any errors missed at the first check. Changes and preference usually being given to International Nonproprietary Names (INN),
questions are fed back to the revision team in an iterative process that may British Approved Names (BAN), and United States Adopted Names (USAN).
involve more than one cycle. Once past its preliminary edit the chapter is sent to These 3 authorities are shown where appropriate. A European Directive
the Editor for a final check and approval, which again may require changes to be (92/27/EEC) requires the use of Recommended International Nonproprietary
made and checked, before passing it to the next stage. Names (rINNs) in the labelling of medicinal products throughout member states
of the European Community and where the BAN and INN differed in the past
KEYING, PROOF-READING, AND DOSE-CHECKING. Once approved by the Editor, the BAN has been changed to accord with the rINN. The major exception to this
amendments can be incorporated into the database, which remains untouched convention is the retention of the names adrenaline and noradrenaline, these
until this stage as a security measure. These changes are then proofread for being the terms used as the titles of the monographs in the European
errors, corrected if necessary, and any corrections checked. Extensive electronic Pharmacopoeia and therefore the official names in the member states. In some
testing for spelling, style, and format is also carried out at all stages. The approved names it is now general policy to use ‘f’ for ‘ph’ in sulpha, ‘t’ for ‘th’,
amended chapter then undergoes an independent check of the dose information and ‘i’ for ‘y’; for this reason entries in alphabetical lists and indexes should be
against its recorded sources. This check is performed by a member of staff sought in alternative spellings if the expected spellings are not found. Inevitably
outside the original revising and editing team, and is an additional safeguard there may be some inconsistencies of style with older approved names but
against the inadvertent introduction of potentially dangerous dose errors. Once
wherever possible the names used for drugs or radicals in Martindale have been
past these stages the data are cleared for release, and can be published in the next
altered in accordance with the guidelines on the use of INNs for pharmaceutical
update of the Martindale electronic products, and, at appropriate points in the
substances. A table of contracted names for ions and groups used in approved
publishing cycle, in the book.
names and titles is given on page xi. INNs in the four other main official
ADDITIONAL CHECKS FOR PUBLICATION. Some additional checks are made languages (French, Latin, Russian, and Spanish) have also been included in the
before publishing a print edition of Martindale. An second independent dose list of synonyms where these differ from the English INN. BAN names for
check of all chapters is made by an external expert, all cross-references are substance combinations and United States Pharmacy Equivalent Names (PEN)
revalidated, and tests of the typesetting and page structure are made. In addition for dosage forms containing two or more active ingredients are given in the text
our extensive index is generated and carefully checked for accuracy, order, and of the relevant monographs; these names start with the prefix ‘Co-’.
consistency.
This section also includes names given as synonyms such as commonly used
FEEDBACK. We are always grateful to get feedback from our users and, abbreviated names; Latin versions of the titles in the European Pharmacopoeia;
whenever possible, we try to incorporate information or suggestions that English, American, and Latin synonyms; names used in other languages when
help us to improve Martindale. Anyone wishing to comment on the editorial these may not be readily identifiable; manufacturers’ code numbers; and chem-
content of Martindale can contact us at the following e-mail address: ical names. Official titles and synonyms used in the British, European, and US
martindale@rpsgb.org Pharmacopoeias are given in the section on pharmacopoeias where the relevant
Arrangement pharmacopoeial substance is described.
VOLUME 1: • MONOGRAPHS ON DUGS AND ANCILLARY SUBSTANCES (pages 1– STREET NAMES. This edition of Martindale once again includes greatly
2418). This section contains 5827 monographs arranged in 54 chapters. These expanded coverage of 'street names' for substances of abuse. Street terms and
chapters generally bring together monographs on drugs and groups of drugs that other slang names for drugs of abuse are included for guidance only and should
be used with caution. Because of the very nature of their origin they cannot be
have similar uses or actions. The introductions of those chapters that describe
relied upon for definitive identification of a substance. The use of such terms
drugs used in the management of disease may contain disease treatment
changes rapidly, and can vary between different geographical locations, and any
reviews—descriptions of those diseases together with reviews of the choice of
given name may potentially be applied to more than one substance or even to a
treatments.The last chapter in this section consists of a series of monographs
mixture of substances. Furthermore, established or well recognised generic drug
arranged in the alphabetical order of their main titles. It includes monographs on
names or herbal names have sometimes been misused as street terms for
drugs not easily classified, on herbals, and on drugs no longer used clinically but
completely unrelated substances. In order to enable the reader to distinguish
still of interest. There are also monographs on toxic substances, the effects of them from better validated synonyms, in the index, such names are included in
which may require drug therapy. italics and in quotation marks.
VOLUME 2: • PREPARATIONS (pages 2191–2880). This section contains over
CAS REGISTRY NUMBERS. Chemical Abstracts Service (CAS) registry numbers
146 000 proprietary preparations from a range of countries and regions. For this are provided, where available, for each monograph substance to help readers
edition we have covered Argentina, Australia, Austria, Belgium, Brazil, Canada, refer to other information systems. Numbers for various forms of the monograph
Chile, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong substance are listed with the variation in form given in parentheses.
Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Malaysia, Mexico, the
Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Russia, ATC CODES. Codes from the Anatomical Therapeutic Chemical (ATC)
Singapore, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, the classification system (see http://www.whocc.no) have been provided, where
United Arab Emirates, UK, USA, and Venezuela. We have also included some available, for each monograph substance to help readers refer to other
proprietary preparations from Japan. The information provided includes the information systems. The codes assigned in the equivalent classification system
proprietary name, the manufacturer or distributor, the active ingredients with for veterinary medicines (ATC Vet—see http://www.whocc.no/atcvet) have
cross-references to the drug monographs, and a summary of the indications as been included where possible.
given by the manufacturer. Atomic and Molecular Weights
• DIRECTORY OF MANUFACTURERS (pages 3205–3274). In Martindale the Atomic weights are based on the table of Atomic Weights as revised in 2007 by
names of manufacturers and distributors are abbreviated. Their full names are the Commission on Atomic Weights and Isotopic Abundance, International
given in this directory together with the full address and website if it is available. Union of Pure and Applied Chemistry (IUPAC) and based on the 12C scale (see
This directory contains nearly 13 000 entries. page xiii). Molecular weights are given corrected to one place of decimals or to
• GENERAL INDEX (pages 3275–3694). To make fullest use of the contents of four significant figures for relative weights of less than 100.
Martindale the general index should always be consulted. The exhaustive index,
prepared from 153 000 entries, includes entries for drugs (approved names, Pharmacopoeias
synonyms, and chemical names), preparations, pharmacological and therapeutic The selected pharmacopoeias in which each substance appears are listed. A
groups, and clinical uses (disease treatment reviews). As in previous editions, the description of the substance and a summary of the pharmaceutical information
index is arranged alphabetically ‘word-by-word’ rather than ‘letter-by-letter’. (see below) that appears in the British, European, or US Pharmacopoeias is also
The index indicates the column in which the relevant entry appears as well as the included. Current copies of the pharmacopoeias and their addenda should be
page. To improve clarity and the ease of location of index entries long chemical consulted for confirmation and for details of standards.
names have been omitted from the index. The pharmacopoeias covered include: British, British Veterinary, Chinese,
This edition includes both nonproprietary and proprietary names in Russian, European, French, German, International, Italian, Japanese, Polish, Spanish,
and these names may be found in Russian alphabetical order in the Cyrillic Swiss, United States (including the National Formulary), and Vietnamese. The
section of the index immediately following the entries in the Latin alphabet. abbreviations for these pharmacopoeias are included in the list of abbreviations
 Preface vii
used in Martindale, see page viii, which also includes details of the edition and/or Pharmacological and Therapeutic Information
supplement(s) consulted.
Several countries are parties to the Convention on the Elaboration of a Information on adverse effects, treatment of adverse effects, precautions
European Pharmacopoeia. This means that they must adopt the standards of the (including contra-indications), interactions, pharmacokinetics, and uses and
European Pharmacopoeia. These countries are currently Austria, Belgium, administration of each substance is provided by concise statements and these
Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, the Czech Republic, may be elaborated and expanded by referenced reviews and abstracts from
Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, papers and other publications. This edition contains about 15 000 such abstracts
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, the or reviews based on information in an ever widening range of publications.
Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak Republic,
Much information has been found in sources such as World Health
Slovenia, Spain, Sweden, Switzerland, Turkey, the United Kingdom, and the
Former Yugoslav Republic of Macedonia. Hence the European Pharmacopoeia Organization publications, government reports and legislation, and other official
is cited in the drug monograph lists of pharmacopoeias rather than these and standard publications. Licensed product information and manufacturers'
individual national pharmacopoeias. literature has been considered in the light of other available information.

Official preparations, mainly from the current British, European, and US The risks of giving drugs in pregnancy are well known and the general
Pharmacopoeias, are listed at the end of drug monographs. principle is to give a drug only when the benefit to the individual mother
outweighs the risk to the fetus. Where there is a clear risk it is noted under the
Pharmaceutical Information Precautions or Adverse Effects heading but safety should not be inferred from
the absence of a statement for any drug.
Information on the chemical and physical properties of each substance is given
when it is likely to be of use or interest, but only when it is certain that it applies Some drugs given to the mother are distributed into breast milk and therefore
to the form of substance being described in the monograph. may pose a risk to a breast-fed infant. Whenever possible, information has been
PERCENTAGE STRENGTHS. Unless otherwise stated, solutions of solids in liquids included to help determine the safety of continuing to breast feed while the
are expressed as percentage w/v, of liquids in liquids as percentage v/v, and of mother is receiving a particular drug. Safety during breast feeding should not be
gases in liquids as percentage w/w. inferred from the absence of a statement for any drug.
SOLUBILITY. The figures given for solubility in each monograph have generally
been obtained from the major pharmacopoeias in which the substance is Doses
described, but should not be considered absolute. Unless otherwise indicated in
the text, the figures are for solubility at temperatures between 15° and 25°. The Doses are described under the Uses and Administration heading with as much
information usually relates to w/v solubilities but in some cases is v/v if the detail as is necessary and available. Unless otherwise stated the doses represent
monograph substance itself is a liquid. Where solubilities are given in words, the the average range of quantities which are generally regarded as suitable for
following terms describe the indicated solubility ranges: adults when given by mouth. More information on doses and drug
administration may be given in the abstracts or reviews. Unless otherwise
solubility specified, glucose injection is 5% w/v and sodium chloride injection is 0.9% w/v.
very soluble 1 in less than 1 When doses for children are expressed as a range of quantities within specified
freely soluble 1 in 1 to 1 in 10 age limits, the lower dose applies at the lower age and the higher dose at the
soluble 1 in 10 to 1 in 30 higher age.
sparingly soluble 1 in 30 to 1 in 100
slightly soluble 1 in 100 to 1 in 1000
Acknowledgements
very slightly soluble 1 in 1000 to 1 in 10 000 The Editor gratefully acknowledges the advice and assistance of the many
practically insoluble 1 in more than 10 000 experts who have suggested amendments to the text of Martindale. Thanks are
also due to K Baxter, M Jane, CR Lee, DK Mehta, F Post, and AB Prasad, for
STORAGE. Substances and preparations should be stored under conditions which advice and comments on specific issues during revision. The Editor is grateful
prevent contamination and diminish deterioration, and the conditions of storage to the many organisations that have helped in providing information, including
given in the text indicate the precautions recommended in specific cases. The the World Health Organization, the British Pharmacopoeia Commission, and
term ‘a cool place’ is generally used to describe a place in which the temperature our Spanish colleagues at Grupo Ars XXI.
is between 8° and 15°. In general, the storage conditions apply to the monograph
substance and not its solutions or preparations. Martindale staff have been able to call on the expertise of other members
TEMPERATURE. Temperatures are expressed in degrees Celsius (centigrade) of the Royal Pharmaceutical Society's staff. In particular the Editor is
unless otherwise indicated. grateful to J Martin and the staff of the British National Formulary, and the
staff of the library and information department. Thanks are due to I Baxter,
Drugs in Sport M Davis, S Driver, EJ Laughton, R McLarney, and SJ Shankie for their
editorial tasks. Thanks are also due to PJ Weller, C Fry and the staff of the
Wherever possible we have attempted to indicate those drugs and substances Pharmaceutical Press for their support.
that may be subject to restriction in some or all sports, either in their own right,
or because they are a derivative of a restricted substance or a member of a The contents of this 36th edition were planned, written, checked, indexed,
prohibited group. Proprietary preparations containing such compounds are also keyed, proofed, and processed by the Martindale staff. The Editor is pleased to
marked in the preparation section in Volume 2. The definitive guide used for acknowledge the skills and commitment of all the Martindale staff and to record
identifying restricted drugs for this edition is the 2008 Prohibited List issued by his gratitude: to Christine Iskandar for clerical assistance; to Michael Evans for
the World Anti-Doping Agency (WADA—see www.wada-ama.org). However, Knowledge Systems support; to Chloë Hatwal, Elizabeth King, James O’Reilly,
these regulations, which are issued annually, are subject to interpretation and and Elen Shute for editorial assistance; to the Staff Editors Catherine Cadart,
therapeutic exemption, and may vary from sport to sport; particular sporting Kathleen Eager, Sue Handy, Fauziah Hashmi, Sue Ho, Joanna Humm,
authorities may also issue additional restrictions, and competitors should always Jean Macpherson, Melissa Siew, Sandra Sutton, and Gerda Viedge; to the
check with the appropriate body. The rules are constantly evolving and the Assistant Editors Alison Brayfield, Julie McGlashan, Gail Neathercoat, and
absence of any indication of restriction in Martindale should not be taken as Anne Parsons; and to the Senior Assistant Editor Paul Blake.
absolute confirmation that the substance may legitimately be taken by a
competitor. London October 2008
Abbreviations
For abbreviations of the names of manufacturers or their distributors, see DEFRA—Department for Environment, Food, and Rural Affairs (UK).
Directory of Manufacturers, page 3205. Denm.—Denmark.
DHSS—the former Department of Health and Social Security (UK).
ACE—angiotensin-converting enzyme. dL—decilitre(s).
ADHD—attention deficit hyperactivity disorder. DNA—deoxyribonucleic acid.
agg.—aggregate (in botanical names), including 2 or more species which DoH—Department of Health (UK).
resemble each other closely.
DTF—Drug Tariff Formulary.
AIDS—acquired immunodeficiency syndrome.
ECG—electrocardiogram.
a.m.—ante meridiem, ‘before noon’.
ECT—electroconvulsive therapy.
ARC—AIDS-related complex.
Ecuad.—Ecuador.
Arg.—Argentina.
ed.—editor(s) or edited by or edition.
ATC—Anatomical Therapeutic Chemical classification.
EEC—European Economic Community, now the European Union.
AUC—area under the concentration-time curve.
EEG—electro-encephalogram.
Austral.—Australia.
e.g.—exempli gratia ‘for example’.
AV—atrioventricular.
EMEA—European Medicines Agency.
BAN—British Approved Name.
ENL—erythema nodosum leprosum.
BANM—British Approved Name Modified.
ESRD—end-stage renal disease.
Belg.—Belgium.
et al.—et alii, ‘and others’: for three or more co-authors or co-workers.
BMA—British Medical Association.
et seq.—and what follows.
BMI—body mass index.
EU—European Union.
BNF—British National Formulary.
Eur. P.—see Ph. Eur.
BNFC—British National Formulary for Children.
Ext. D & C—designation applied in USA to dyes permitted for use in
b.p.—boiling point.
external drug and cosmetic preparations.
BP—British Pharmacopoeia. Unless otherwise specified, BP references are
°F—degrees Fahrenheit.
to the 2008 edition.
FAC—Food Additives and Contaminants Committee of the former
BP(Vet)—British Pharmacopoeia (Veterinary) 2008.
Ministry of Agriculture, Fisheries and Food (UK).
BPC—British Pharmaceutical Codex.
FAO—Food and Agriculture Organization of the United Nations.
Br.—British.
FAO/WHO—Food and Agriculture Organization of the United Nations
Braz.—Brazil.
and the World Health Organization.
Bulg.—Bulgaria.
FDA—Food and Drug Administration of USA.
BUN—Blood-urea-nitrogen.
FdAC—Food Advisory Committee of the former Ministry of Agriculture,
°C—degrees Celsius (centigrade). Unless otherwise indicated in the text,
Fisheries and Food (UK).
temperatures are expressed in this thermometric scale.
FD & C—designation applied in USA to dyes permitted for use in foods,
Canad.—Canada.
drugs, and cosmetics.
CAPD—continuous ambulatory peritoneal dialysis.
FEV1—forced expiratory volume in 1 second.
CAS—Chemical Abstracts Service.
Fin.—Finland.
CCPD—continuous cycle peritoneal dialysis.
FIP—Fédération Internationale Pharmaceutique.
CDC—Centers for Disease Control and Prevention (USA) (formerly
f.p.—freezing point.
Centers for Disease Control).
FPA—Family Planning Association (UK).
Chin. P.—Chinese Pharmacopoeia 2005.
Fr.—France.
CHM—Commission on Human Medicines (UK).
Fr. P.—French Pharmacopoeia 1982 (Pharmacopée Francaise, Xe Edition)
CI—Colour Index.
and updates up to 2003.
CMV—cytomegalovirus.
g—gram(s).
CNS—central nervous system.
Ger.—Germany.
cP—centipoise(s).
Ger. P.— German Pharmacopoeia (Deutsches Arzneibuch, 2007).
CPMP—Committee on Proprietary Medicinal Products of the European
Union. GFR—glomerular filtration rate.
CSF—cerebrospinal fluid. G6PD—glucose-6-phosphate dehydrogenase.
CSM—Committee on Safety of Medicines (UK) (now subsumed within the Gr.—Greece.
Commission on Human Medicines). HAART—highly active antiretroviral therapy.
cSt—centistokes. Hb— haemoglobin.
Cz.—Czech Republic. Hib—Haemophilus influenzae type b.
D & C—designation applied in USA to dyes permitted for use in drugs and HIV—human immunodeficiency virus.
cosmetics. HLA—human lymphocyte antigens.
d.c.—direct current. HLB—hydrophilic-lipophilic balance.
viii
 Preface ix
HRT—hormone replacement therapy. mosmol—milliosmole.
HSE—Health and Safety Executive (UK). m.p.—melting point.
Hung.—Hungary. MRC—Medical Research Council (UK).
IARC—International Agency for Research on Cancer. MRSA—meticillin-resistant Staphylococcus aureus.
ibid.—ibidem, ‘in the same place (journal or book)’. μg—microgram(s).
idem—‘the same’: used for the same authors and titles. μm—micrometre(s).
i.e.—id est, ‘that is’. Neth.—The Netherlands.
Ig—immunoglobulin. NICE—National Institute for Health and Clinical Excellence (formerly the
Indon.—Indonesia. National Institute for Clinical Excellence) (UK).
INN—International Nonproprietary Name. NIH—National Institutes of Health (USA).
INNM—International Nonproprietary Name Modified. nm—nanometre(s).
Int. P.—International Pharmacopoeia 4th ed., 2006. NMDA—N-methyl-D-aspartate.
IPCS—International Programme on Chemical Safety. NNRTI—non-nucleoside reverse transcriptase inhibitor.
IQ—intelligence quotient. Norw.—Norway.
Irl.—Ireland. NRTI—nucleoside reverse transcriptase inhibitor.
ISH—International Society of Hypertension. NSAID—nonsteroidal anti-inflammatory drug.
It. P.—Italian Pharmacopoeia 11th ed., 2002 (Farmacopea Ufficiale della NYHA—New York Heart Association.
Repubblica Italiana, XI Edizione, 2002). NZ—New Zealand.
Ital.—Italy. OP—over proof.
IUD—intra-uterine device. o/w—oil-in-water.
IUPAC—International Union of Pure and Applied Chemistry. P—probability.
IVF—in-vitro fertilisation. Pa—pascal(s).
J—joule(s). pCO2—plasma partial pressure (concentration) of carbon dioxide.
Jpn—Japan. paCO2—arterial plasma partial pressure (concentration) of carbon dioxide.
Jpn P.—The Pharmacopoeia of Japan, 15th ed., 2006. PEN—Pharmacy Equivalent Name, see page vi.
K—kelvin. pg—picogram(s).
kcal—kilocalorie(s). pH—the negative logarithm of the hydrogen ion concentration.
kg—kilogram(s). Ph. Eur.—European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1
kJ—kilojoule(s). and 6.2.
lb—pound(s) avoirdupois. Pharm. Soc. Lab. Rep.—Royal Pharmaceutical Society’s Laboratory
LD50—a dose lethal to 50% of the specified animals or micro-organisms. Report.
m—metre(s). Philipp.—Philippines.
m2—square metre(s). PHLS—Public Health Laboratory Service (UK).
m3—cubic metre(s). pINN—Proposed International Nonproprietary Name.
M—molar. pINNM—Proposed International Nonproprietary Name Modified.
MAFF—the former Ministry of Agriculture, Fisheries and Food (UK), now pKa—the negative logarithm of the dissociation constant.
Department of Environment, Food, and Rural Affairs (DEFRA). p.m.—post meridiem, ‘afternoon’.
MAOI—monoamine oxidase inhibitor. pO2—plasma partial pressure (concentration) of oxygen.
max.—maximum. paO2—arterial plasma partial pressure (concentration) of oxygen.
MBC—minimum bactericidal concentration. Pol.—Poland.
MCA—Medicines Control Agency, now MHRA (UK). Pol. P.—Polish Pharmacopoeia 6th ed., 2002 (Farmakopea Polska VI, 2002)
mEq—milliequivalent(s). and Supplement 2005.
Mex.—Mexico. Port.—Portugal.
mg—milligram(s). ppm—parts per million.
MHRA—Medicines and Healthcare products Regulatory Agency (UK). PSGB—The Pharmaceutical Society of Great Britain. Now the Royal
MIC—minimum inhibitory concentration. Pharmaceutical Society of Great Britain.
min—minute. PUVA—psoralen with UVA light irradiation.
min.—minimum. PVC—polyvinyl chloride.
MJ—megajoule(s). RCGP—Royal College of General Practitioners (UK).
mL—millilitre(s). RIMA—reversible inhibitor of monoamine oxidase type A.
mm—millimetre(s). rINN—Recommended International Nonproprietary Name.
mm2—square millimetre(s). rINNM—Recommended International Nonproprietary Name Modified.
mm3—cubic millimetre(s). RNA—ribonucleic acid.
mmHg—millimetre(s) of mercury. RPSGB—The Royal Pharmaceutical Society of Great Britain.
mmol—millimole. RSV—respiratory syncytial virus.
mol—mole. S. Afr.—South Africa.
mol. wt—molecular weight. SGOT—serum glutamic oxaloacetic transaminase (serum aspartate amino-
Mon.—Monaco. transferase now preferred).
x Preface
SGPT—serum glutamic pyruvic transaminase (serum alanine amino- UK—United Kingdom.
transferase now preferred). UNICEF—United Nations Children’s Fund.
SI—Statutory Instrument or Système International d’Unités (International UP—under proof.
System of Units). Urug.—Uruguay.
sic—written exactly as it appears in the original. US and USA—United States of America.
SLE—systemic lupus erythematosus. USAN—United States Adopted Name.
sp.—species (plural spp.). USNF—The United States ‘National Formulary 26’, 2008, and
sp. gr.—specific gravity. Supplements 1 and 2.
Span.—Spanish. USP—The United States Pharmacopeia 31, 2008, and Supplements 1 and 2.
Span. P.—Spanish Pharmacopoeia 2nd ed., 2002 (Real Farmacopoea UV—ultraviolet.
Española, Segunda Edición, 2002) and Supplement 2.1. var.—variety.
SSRI—selective serotonin reuptake inhibitor. Venez.—Venezuela.
St—stokes. Viet.—Vietnamese.
subsp.—subspecies. Viet. P.—Vietnamese Pharmacopoeia 2002 (Pharmacopoeia Vietnamica,
suppl—supplement(s). Editio III).
Swed.—Sweden. vol.—volume(s).
Swiss P.—Swiss Pharmacopoeia 2006 (Pharmacopoea Helvetica, 10 v/v—volume in volume.
Ausgabe, Deutsche Ausgabe). v/w—volume in weight.
Switz.—Switzerland. WHO—World Health Organization.
Thai.—Thailand. w/o—water-in-oil.
TNF—tumour necrosis factor. wt—weight.
TPN—total parenteral nutrition. wt per mL—weight per millilitre.
Turk.—Turkey. w/v—weight in volume.
UAE—United Arab Emirates. w/w—weight in weight.
Contracted Names for Ions and Groups
Contracted Name Chemical Name Contracted Name Chemical Name

acefurate acetate (ester) and furan-2-carboxylate (ester) crosfumaril (2E)-but-2-enedioyl

aceglumate rac-hydrogen N-acetylglutmate cyclamate cyclohexylsulfamate
aceponate acetate (ester) and propionate (ester) daloxate L-alaninate(ester) and (5-methyl-2-oxo-1,3-di-
acetonide isopropylidenedioxy or propane-2,2-diylbis(oxy) oxol-4-yl)methyl

aceturate N-acetylglycinate daropate (dapropate) N,N-dimethyl-β-alaninate or 3-(dimethylamino)pro-

panoate
acibutate acetate (ester) and 2-methylpropanoate (ester)
deanil 2-(dimethylamino)ethyl
acistrate acetate (ester) and stearate (salt)
decil decyl
acoxil acetoxymethyl or (acetyloxy)methyl
defalan des-1B-L-phenylalanine-insulin
alfoscerate (2R)-2,3-dihydroxypropyl hydrogen phosphate
detemir tetradecanoyl
alideximer poly([oxy(2-hydroxyethane-1,1-diyl)]{oxy[1-
(hydroxymethyl)ethane-1,2-diyl]}) partly O- dibudinate 2,6-di-tert-butylnaphthalene-1,5-disulfonate
etherified with carboxymethyl groups with
some carboxy groups amide linked to the dibunate 2,6-di-tert-butylnaphthalene-1-sulfonate
tetrapeptide residue (glyglyglycyl-L-phenyla-
lanylglycyl) dicibate dicyclohexylmethyl carbonate
amsonate 4,4′-diaminostilbene-2,2′-disulfonate or 2,2′- diftitox N-L-methionyl-387-L-histidine-388-L-alanine-1-
ethene-1,2-diylbis(5-aminobenzene-1-sul- 388-toxin (Corynebacterium diphtheriae
fonate) strain C7) (388→2′)-protein
anisatil 2-(4-methoxyphenyl)-2-oxoethyl or p-methoxy- digolil 2-(2-hydroxyethoxy)ethyl
phenacyl
diolamine 2,2′-azanediyldiethanol or diethanolamine
arbamel 2-(dimethylamino)-2-oxoethyl or ester with
N,N-dimethylglycolamide docosil docosyl
argine 30Bα−L-argine-30Bβ-L-argine dofosfate octadecyl hydrogen phosphate
aritox ricin A chain-MAB immunotoxine
ecamate N-ethylcarbamate
aspart 28B-L-aspartic acid-
edamine ethane-1,2-diamine or ethylenediamine
axetil (RS)-1-acetoxyethyl or rac-1-(acetyloxy)ethyl
edetate ethylenediamine-NNN′N′-tetra-acetate
beloxil benzyloxy
edisilate (edisylate) ethane-1,2-disulfonate
benetonide N-benzoyl-2-methyl-β-alanine (ester) and ace-
tonide embonate 4,4′-methylenebis(3-hydroxynaphthalene-2-car-
boxylate) or 4,4′-methylenebis(3-hydroxy-2-
besilate (besylate) benzenesulfonate naphthoate) (=pamoate)

betadex β-cyclodextrin enantate (enanthate) heptanoate

bezomil (benzoyloxy)methyl enbutate acetate (ester) and butanoate (ester)

buciclate trans-4-butylcyclohexanecarboxylate epolamine 1-pyrrolidineethanol or 2-(pyrrolidin-1-yl)etha-

nol
bunapsilate 3,7-di-tert-butylnaphthalene-1,5-disulfonate
erbumine tert-butylamine or 2-methylpropan-2-amine
buteprate butyrate (ester) and propionate (ester)
esilate (esylate) ethanesulfonate
camsilate (camsylate) camphor-10-sulfonate or (7,7-dimethyl-2-oxo-
bicyclo[2.2.1]heptan-1-yl)methanesulfonate estolate propanoate (ester) and dodecyl sulfate (salt) or
propionate dodecyl sulfate
caproate hexanoate
etabonate (ethoxycarbonyl)oxy (=ethyl carbonate)
carbesilate 4-sulfobenzoate
etilsulfate ethyl sulfate
ciclotate (cyclotate) 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylate
farnesil (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-
cilexetil (RS)-1-{[(cyclohexyloxy)carbonyl]oxy}ethyl or yl
rac-1-{[(cyclohexyloxy)carbonyl]oxy}ethyl
fendizoate 2-(6-hydroxybiphenyl-3-carbonyl)benzoate
cipionate (cypionate) cyclopentanepropionate or 3-cyclopentylpro-
panoate fostedate tetradecyl hydrogen phosphate
cituxetan rac-N-(4-{2-[bis(carboxymethyl)amino]-3-({2- furetonide 1-benzofurane-2-carboxylate (ester) and pro-
[bis(carb oxymet hyl )am ino ]et hyl }(car- pane-2,2-diylbis(oxy)
boxymethyl)amino)propyl}phenyl)thiocar-
bamoyl
gamolenate (6Z,9Z,12Z)-octadeca-6,9,12-trienoate
clofibrol 2-(4-chlorophenoxy)-2-methylpropyl
glargine 21A-glycine-30Bα-L-arginine-30Bβ-L-arginine
closilate (closylate) 4-chlorobenzene-1-sulfonate
gluceptate D-glycero-D-gulo-heptanoate or D-glycero-D-
crobefate rac-{3-[(3E)-4-methoxybenzylidene]-2-(4-meth- gulo-heptonate
oxyphenyl)chroman-6-yl phosphate(2-)}
glulisine [3B-L-lysine,29B-L-glutamic acid]
cromacate 2-[(6-hydroxy-4-methyl-2-oxo-2H-chromen-7-
yl)oxy]acetate glutamer glutaraldehyde polymer

cromesilate 6,7-dihydroxycoumarin-4-methanesulfonate or guacil 2-methoxyphenyl

(6,7-dihydroxy-2-oxo-2H-chromen-4-
yl)methanesulfonate hemisuccinate hydrogen butanedioate

xi
xii Contracted Names for Ions and Groups
Contracted Name Chemical Name Contracted Name Chemical Name

hexacetonide 3,3-dimethylbutanoate (ester) and propan-2,2- pivoxil (2,2-dimethyl-1-oxopropoxy)methyl or [(2,2-

diylbis(oxy) or 3,3-dimethylbutyrate (ester) dimethylpropanoyl)oxy]methyl or (pivaloyl-
and acetonide oxy)methyl

hibenzate (hybenzate) 2-(4-hydroxybenzoyl)benzoate poliglumex [poly(L-glutamic acid)z—(L-glutamate-γ-ester)

—poly(L-glutamic acid)y]n
hyclate monohydrochloride hemi-ethanolate hemihy-
drate probutate 17-(1-oxobutoxy) (ester) and 21-(1-oxopro-
poxy) (ester) or propionate (ester) and bu-
hydroxynaphtoate 3-hydroxynapthalene-2-carboxylate tyrate (ester)
isetionate (isethionate) 2-hydroxyethane-1-sulfonate proxetil 1-[(isopropoxycarbonyl)oxy]ethyl or rac-1-
{[(propan-2-yloxy)carbonyl]oxy}ethyl
laurate dodecanoate

lauril dodecyl raffimer (2S,4R,6R,8S,11S,13S)-2,4,8,13-tetrakis(hy-

d r o x y m e t h y l ) - 4 , 6 , 11 - t r i s ( y l o m e t h y l ) -
3,5,7,10,12-pentaoxatetradecane-1,14-diyl
laurilsulfate (lauryl sulphate) dodecyl sulfate

lisetil L-lysinate (ester) and diethyl (ester) salicylate 2-hydroxybenzoate

lisicol {N-[(5S)-5-carboxy-5-(3α,7α,12α-trihydroxy- sesquioleate (9Z)-octadec-9-enoate(1.5)

5β-cholan-24-amido)pentyl]carbamothio-
yl}amino soproxil {[(propan-2-yloxy)carbonyl]oxy}methyl

lispro 28B-L-lysine-29B-L-proline steaglate 2-(octadecanoyloxy)acetate (ester)

mafenatox enterotoxin A (227-alanine) (Staphylococcus stearate octadecanoate
aureus)
stinoprate N-acetylcysteinate (salt) and propanoate (ester)
medoxomil (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl

megallate 3,4,5-trimethoxybenzoate succinil 3-carboxypropanoyl

meglumine N-methylglucamine sudotox 248-L-histidine-249-L-methionine-250-L-

alanine-251-L-glutamic acid-248-613-endo-
merpentan 4,5-bis(2-mercaptoacetamido) valeric acid or toxin A (Pseudomonas aeruginosa reduced)
{N,N′-[1-(3-oxopropyl)ethane-1,2-diyl]bis(2-
sulfanylacetamidato)}(4-) suleptanate monosodium 8-[methyl(2-sulfoethyl)amino]-8-
oxooctanoate or monosodium 7-[methyl(2-
mertansine tetrakis{(4RS)-4[(3-{[(1S)-2- sulfonatomethyl)carbamoyl]heptanoyl
{[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-
c h l o r o - 2 1 - h y d ro x y - 1 2 , 2 0 - d i m e t h o x y - sulfoxylate sulfinomethyl, monosodium salt
2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-
9,22-diazatetracyclo[19.3.1.110,14.03,5]hexaco- tafenatox enterotoxin A (Staphylococcus aureus)
sa-10,12,14(26),16,18-pentaen-6-yl]oxy}-1-
methyl-oxoethyl]methylamino}-3-oxopro- tartrate (2R,3R)-2,3-dihydroxybutanedioate
pyl)disulfanyl]pentanoyl}
tebutate tert-butylacetate or 3,3-dimethylbutyrate
mesilate (mesylate) methanesulfonate

metembonate 4,4′-methylenebis(3-methoxynaphthalene-2-car- tenoate thiophene-2-carboxylate

boxylate)
teoclate 8-chloro-1,3-dimethyl-2,6-dioxo-3,6-dihydro-
methonitrate N-methyl, nitrate (salt) 1H-purin-7-(2H)-ide or 8-chlorotheophyllin-
ate
metilsulfate methyl sulfate
teprosilate 3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-
metiodide N-methyl, iodide (salt) 7H-purin-7-yl)propane-1-sulfonate

methylbromide N-methyl, bromide (salt) tidoxil rac-2-(decyloxy)-3-(dodecylsulfanyl)propyl

mofetil 2-(morpholino)ethyl or 2-(morpholin-4-yl)ethyl tiuxetan N-(4-{(2S)-2-[bis(carboxymethyl)amino]-3-

[(2RS)-{2-[bis(carboxymethyl)amino]pro-
napadisilate naphthalene-1,5-disulfonate pyl}(carboxymethyl)amino]propyl}phenyl)
thiocarbamoyl
napsilate (napsylate) naphthalene-2-sulfonate
tocoferil rac-(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-
nicotinate pyridine-3-carboxylate trimethyltridecyl]chroman-6-yl
octil octyl tofesilate 3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-
7H-purin-7-yl)ethane-1-sulfonate
olamine 2-aminoethanol or ethanolamine
tosilate (tosylate) 4-methylbenzene-1-sulfonate or toluene-4-sul-
oleate (9Z)-octadec-9-enoate
fonate
oxoglurate hydrogen 2-oxopentanedioate
triclofenate 2,4,5-trichlorophenolate
palmitate hexadecanoate
triflutate trifluoroacetate
pamoate 4,4′-methylenebis(3-hydroxy-2-naphthoate)
(=embonate) trioleate (9Z)-octadec-9-enoate(3) or tris[(9Z)-octadec-9-
enoate]
pegol α-(2-carboxyethyl)-ω-methoxypoly(oxyethane-
1,2-diyl) tristearate octadecanoate(3) or tris(octadecanoate)
6
pendetide N -{N-[2-({2-[bis(carboxymethyl)amino]- trolamine 2,2′,2″-nitrilotriethanol or triethanolamine
ethyl}(carboxymethyl)amino)ethyl]-N-(car-
boxymethyl)glycyl}-N2-(N-glycyl-L-tyrosyl)- troxundate [2-(2-ethoxyethoxy)ethoxy]acetate or 3,6,9-tri-
L-lysine
oxaundecanoate
pentexil (RS)-1-[(2,2-dimethylpropanoyl)oxy]ethyl
undecylate undecanoate
phenpropionate 3-phenylpropionate
undecylenate undec-10-enoate
pivalate 2,2-dimethylpropanoate (ester) or trimethylace-
tate valerate pentanoate

pivoxetil rac-1-[(2-methoxy-2-methylpropanoyl)oxy]ethyl xinafoate 1-hydroxynaphthalene-2-carboxylate or 1-hy-

or 1-(2-methoxy-2-methylpropionyloxy)ethyl droxy-2-naphthoate
Atomic Weights of the Elements— 12C=12
Atomic Name Symbol Atomic Weight Atomic Name Symbol Atomic Weight
Number Number

89 Actinium Ac * 102 Nobelium No *

13 Aluminium Al 26.9815386 76 Osmium Os 190.23
95 Americium Am * 8 Oxygen O 15.9994
51 Antimony Sb 121.760 46 Palladium Pd 106.42
18 Argon Ar 39.948 15 Phosphorus P 30.973762
33 Arsenic As 74.92160 78 Platinum Pt 195.084
85 Astatine At * 94 Plutonium Pu *
56 Barium Ba 137.327 84 Polonium Po *
97 Berkelium Bk *
19 Potassium K 39.0983
4 Beryllium Be 9.012182
59 Praseodymium Pr 140.90765
83 Bismuth Bi 208.98040
107 Bohrium Bh * 61 Promethium Pm *
†
5 Boron B 10.811 91 Protactinium Pa 231.03588
35 Bromine Br 79.904 88 Radium Ra *
48 Cadmium Cd 112.411 86 Radon Rn *
55 Caesium Cs 132.9054519 75 Rhenium Re 186.207
20 Calcium Ca 40.078 45 Rhodium Rh 102.90550
98 Californium Cf * 111 Roentgenium Rg *
6 Carbon C 12.0107 37 Rubidium Rb 85.4678
58 Cerium Ce 140.116 44 Ruthenium Ru 101.07
17 Chlorine Cl 35.453 104 Rutherfordium Rf *
24 Chromium Cr 51.9961 62 Samarium Sm 150.36
27 Cobalt Co 58.933195 21 Scandium Sc 44.955912
29 Copper Cu 63.546 106 Seaborgium Sg *
96 Curium Cm * 34 Selenium Se 78.96
110 Darmstadtium Ds *
14 Silicon Si 28.0855
105 Dubnium Db *
47 Silver Ag 107.8682
66 Dysprosium Dy 162.500
99 Einsteinium Es * 11 Sodium Na 22.98976928
68 Erbium Er 167.259 38 Strontium Sr 87.62
63 Europium Eu 151.964 16 Sulfur S 32.065
100 Fermium Fm * 73 Tantalum Ta 180.94788
9 Fluorine F 18.9984032 43 Technetium Tc *
87 Francium Fr * 52 Tellurium Te 127.60
64 Gadolinium Gd 157.25 65 Terbium Tb 158.92535
31 Gallium Ga 69.723 81 Thallium Tl 204.3833
32 Germanium Ge 72.64 90 †Thorium Th 232.03806
79 Gold Au 196.966569 69 Thulium Tm 168.93421
72 Hafnium Hf 178.49 50 Tin Sn 118.710
108 Hassium Hs * 22 Titanium Ti 47.867
2 Helium He 4.002602 74 Tungsten W 183.84
67 Holmium Ho 164.93032 112 Ununbium Uub *
1 Hydrogen H 1.00794
116 Ununhexium Uuh *
49 Indium In 114.818
118 Ununoctium Uuo *
53 Iodine I 126.90447
77 Iridium Ir 192.217 115 Ununpentium Uup *
26 Iron Fe 55.845 114 Ununquadium Uuq *
36 Krypton Kr 83.798 113 Ununtrium Uut *
†
57 Lanthanum La 138.90547 92 Uranium U 238.02891
103 Lawrencium Lr * 23 Vanadium V 50.9415
82 Lead Pb 207.2 54 Xenon Xe 131.293
3 ‡Lithium Li 6.941 70 Ytterbium Yb 173.054
71 Lutetium Lu 174.9668 39 Yttrium Y 88.90585
12 Magnesium Mg 24.3050 30 Zinc Zn 65.38
25 Manganese Mn 54.938045 40 Zirconium Zr 91.224
109 Meitnerium Mt *
101 Mendelevium Md * Elements marked (*) have no stable nuclides and IUPAC states “there is no general
80 Mercury Hg 200.59 agreement on which of the isotopes of the radioactive elements is, or is likely to be
42 Molybdenum Mo 95.96 judged ‘important’ and various criteria such as ‘longest half-life’, ‘production in quan-
60 Neodymium Nd 144.242 tity’, ‘used commercially’, etc., have been applied in the Commission’s choice.” How-
10 Neon Ne 20.1797 ever, atomic weights are given for radioactive elements marked (†) as they do have a
characteristic terrestrial isotopic composition. Commercially available lithium (‡) mate-
93 Neptunium Np * rials have atomic weights ranging from 6.939 to 6.996; if a more accurate value is re-
28 Nickel Ni 58.6934 quired, it must be determined for the specific material.
41 Niobium Nb 92.90638 IUPAC Commission on Atomic Weights and Isotopic Abundances. Atomic Weights of
7 Nitrogen N 14.0067 the Elements 2007. Available at http://www.chem.qmul.ac.uk/iupac/AtWt/

xiii
Volume 1
Monographs on Drugs and Ancillary Substances
Analgesics Anti-inflammatory Drugs and Antipyretics
Aspirin and other salicylates, p.1 Specific pain states, p.5 Pancreatic pain, p.9
Disease-modifying antirheumatic drugs, p.1 Biliary and renal colic, p.5 Phantom limb pain, p.9
Gold compounds, p.1 Cancer pain, p.5 Postherpetic neuralgia, p.9
Nonsteroidal anti-inflammatory drugs, p.1 Central post-stroke pain, p.6 Sickle-cell crisis, p.9
Opioid analgesics, p.1 Complex regional pain syndrome, p.6 Trigeminal neuralgia, p.9
Paracetamol and other para-aminophenols, p.2 Diabetic neuropathy, p.6 Increased Body Temperature, p.10
Analgesia and Pain, p.2 Dysmenorrhoea, p.6 Fever and hyperthermia, p.10
Choice of analgesic, p.2 Musculoskeletal and Joint Disorders, p.10
Headache, p.7
Juvenile idiopathic arthritis, p.10
Choice of analgesics in children, p.3 Labour pain, p.7 Osteoarthritis, p.11
Nerve blocks, p.4 Low back pain, p.7 Rheumatoid arthritis, p.11
Patient-controlled analgesia, p.4 Myocardial infarction pain, p.8 Soft-tissue rheumatism, p.13
Postoperative analgesia, p.4 Neuropathic pain syndromes, p.8 Spondyloarthropathies, p.13
Rubefacients and topical analgesia, p.5 Orofacial pain, p.8 Still’s disease, p.13

The drugs described in this chapter are used mainly in ials chloroquine (p.599) and hydroxychloroquine (p.604), Described in this chapter are
the relief of pain, inflammation and, in some cases, fe- rituximab (p.767), and the immunosuppressants azathio- Aceclofenac, p.14 Indometacin, p.66
Acemetacin, p.15 Isonixin, p.72
ver. They can be grouped broadly into one of the cate- prine (p.1818), ciclosporin (p.1822), cyclophosphamide Alminoprofen, p.18 Kebuzone, p.72
gories briefly described below. (p.702), and methotrexate (p.745). Aminophenazone, p.19 Ketoprofen, p.73
Aminopropylone, p.19 Ketorolac, p.74
Described in this chapter are Ampiroxicam, p.19 Lonazolac, p.77
Abatacept, p.14 Etanercept, p.50 Amtolmetin Guacil, p.19 Lornoxicam, p.77
Aspirin and other salicylates Actarit, p.15 Golimumab, p.62 Azapropazone, p.26 Loxoprofen, p.78
Aspirin and other salicylates have analgesic, anti-inflam- Adalimumab, p.15 Infliximab, p.69 Bendazac, p.27 Lumiracoxib, p.78
matory, and antipyretic properties. Like other NSAIDs Anakinra, p.19 Leflunomide, p.75 Benoxaprofen, p.27 Meclofenamic acid, p.79
(see below) they are inhibitors of the enzyme cyclo-oxyge- Benzydamine, p.27 Mefenamic Acid, p.80
Beta-aminopropionitrile, Meloxicam, p.80
nase; however, aspirin (though not the non-acetylated sal- p.28 Mofebutazone, p.86
icylates) irreversibly acetylates the enzyme whereas other Gold compounds Bromfenac, p.28 Mofezolac, p.86
NSAIDs compete with arachidonic acid for the active site. Gold compounds are used mainly for their anti-inflamma- Bufexamac, p.28 Morniflumate, p.86
Salicylates are used for the relief of mild to moderate pain, tory effect in active progressive rheumatoid arthritis and Bumadizone, p.28 Nabumetone, p.91
minor febrile conditions, and for acute and chronic inflam- progressive juvenile idiopathic arthritis; they may also be Butibufen Sodium, p.31 Naproxen, p.92
beneficial in psoriatic arthritis. The mechanism of action Carprofen, p.34 Nepafenac, p.95
matory disorders such as osteoarthritis, rheumatoid arthri- Celecoxib, p.34 Niflumic Acid, p.95
tis, juvenile idiopathic arthritis, and ankylosing spondyli- of gold compounds in rheumatic disorders is as yet
Clofexamide, p.37 Nimesulide, p.95
tis. Some salicylates are applied topically in rubefacient unknown. Clofezone, p.37 Oxaprozin, p.105
preparations for the relief of muscular and rheumatic pain. Clonixin, p.37 Oxyphenbutazone, p.107
For further discussion of the actions and uses of gold com- Dexibuprofen, p.39 Parecoxib, p.111
Aspirin also inhibits platelet aggregation and is used in
pounds, see Sodium Aurothiomalate, p.122. Diclofenac, p.44 Phenazone, p.116
cardiovascular disorders. Non-acetylated salicylates do
Dipyrone, p.49 Phenylbutazone, p.117
not have antiplatelet activity. Described in this chapter are Eltenac, p.50 Piketoprofen, p.117
Auranofin, p.25 Sodium Aurothiomalate, Epirizole, p.50 Piroxicam, p.117
For further discussion of the actions and uses of sali- Aurothioglucose, p.26 p.122 Etodolac, p.52 Pranoprofen, p.119
cylates, see Aspirin, p.20. Aurotioprol, p.26 Sodium Aurotiosulfate, Etofenamate, p.53 Proglumetacin, p.119
Gold Keratinate, p.62 p.124 Etoricoxib, p.53 Propyphenazone, p.119
Described in this chapter are Felbinac, p.54 Proquazone, p.119
Aloxiprin, p.18 Lithium Salicylate, p.77 Fenbufen, p.54 Ramifenazone, p.120
Aluminium Aspirin, p.19 Lysine Aspirin, p.79 Fenoprofen, p.55 Rofecoxib, p.121
Ammonium Salicylate, Magnesium Salicylate,
Nonsteroidal anti-inflammatory drugs Fentiazac, p.60 Sulindac, p.126
p.19 p.79 Nonsteroidal anti-inflammatory drugs (NSAIDs) are a Fepradinol, p.60 Suprofen, p.128
Amyl Salicylate, p.19 Methyl Butetisalicylate, group of structurally unrelated organic acids that have Feprazone, p.60 Suxibuzone, p.128
Aspirin, p.20 p.85 analgesic, anti-inflammatory, and antipyretic properties Firocoxib, p.60 Tenoxicam, p.128
Bornyl Salicylate, p.28 Methyl Salicylate, p.85 (see p.96). NSAIDs are inhibitors of the enzyme cyclo-ox- Floctafenine, p.60 Tepoxalin, p.129
Carbasalate Calcium, Morpholine Salicylate, Flufenamic Acid, p.60 Tetridamine, p.129
ygenase, and so directly inhibit the biosynthesis of pros- Flunixin, p.61 Tiaprofenic Acid, p.129
p.33 p.91
Choline Magnesium Salamidacetic Acid, p.121 taglandins and thromboxanes from arachidonic acid (see Flurbiprofen, p.61 Tiaramide, p.129
Trisalicylate, p.36 Salicylamide, p.121 p.2374). There are 2 forms of cyclo-oxygenase (COX), Furprofen, p.62 Tolfenamic Acid, p.130
Choline Salicylate, p.36 Salix, p.121 COX-1, which is the constitutive form of the enzyme, and Glafenine, p.62 Tolmetin, p.130
Diethylamine Salicylate, Salol, p.122 COX-2, which is the form induced in the presence of in- Glucametacin, p.62 Valdecoxib, p.132
p.47 Salsalate, p.122 flammation. Inhibition of COX-2 is therefore thought to be Ibuprofen, p.64 Vedaprofen, p.133
Diflunisal, p.47 Sodium Salicylate, p.124 Ibuproxam, p.66 Zaltoprofen, p.133
Ethenzamide, p.51 Sodium Thiosalicylate,
responsible for at least some of the analgesic, anti-inflam-
Ethyl Salicylate, p.52 p.124 matory, and antipyretic properties of NSAIDs whereas in-
Fosfosal, p.62 Thurfyl Salicylate, p.129 hibition of COX-1 is thought to produce some of their tox- Opioid analgesics
Glycol Salicylate, p.62 Trolamine Salicylate, ic effects, particularly those on the gastrointestinal tract. Opioid analgesics include the opium alkaloids morphine
Imidazole Salicylate, p.132 Most of the NSAIDs currently available for clinical use
p.66
and codeine and their derivatives as well as synthetic sub-
inhibit both COX-1 and COX-2, although selective COX- stances with agonist, partial agonist, or mixed agonist and
2 inhibitors such as celecoxib are now available. antagonist activity at opioid receptors (see p.101). The
term opiate analgesics refers only to those opioids derived
Disease-modifying antirheumatic drugs NSAIDs are used for the relief of mild to moderate pain,
from opium, or their semisynthetic congeners. The term
Disease-modifying antirheumatic drugs (DMARDs) have minor febrile conditions, and for acute and chronic inflam-
narcotic analgesics has legal connotations and is no longer
anti-inflammatory properties thought to be mediated, in matory disorders such as osteoarthritis, rheumatoid arthri-
used pharmacologically or clinically.
some cases, by the inhibition of the release or activity of tis, juvenile idiopathic arthritis, and ankylosing spondyli-
cytokines. They are used in the treatment of rheumatoid tis. Indometacin and some other NSAIDs are used to close Most opioids are used as analgesics, and morphine is the
arthritis and juvenile idiopathic arthritis; some are also of patent ductus arteriosus in premature neonates. Some standard against which all other opioid analgesics are com-
benefit in ankylosing spondylitis and psoriatic arthritis. NSAIDs are applied topically for the relief of muscular pared. Opioids such as codeine or dextropropoxyphene are
Many DMARDs also possess other therapeutic properties and rheumatic pain, and some are used in ophthalmic prep- used in the treatment of less severe pain, and are often
and are used in non-rheumatic conditions. The DMARD arations for ocular inflammatory disorders. Aspirin (see combined with non-opioid analgesics such as aspirin, oth-
gold is referred to below; other DMARDs include sul- above) is considered to be an NSAID, although it also has er NSAIDs, or paracetamol. More potent opioids such as
fasalazine (p.1773), penicillamine (p.1456), the antimalar- other properties. morphine are used in severe acute and chronic pain, in-
1
2 Analgesics Anti-inflammatory Drugs and Antipyretics
cluding cancer pain. Some opioids such as codeine, mor- Inflammatory mediators such as bradykinin, histamine, serot- and transcutaneous electrical nerve stimulation
phine, and diamorphine are also used as antitussives, al- onin, and prostaglandins produced in response to tissue dam- (TENS) are also used.
though the latter two are usually reserved for use in age can produce peripheral sensitisation so that receptors re-
spond to low intensity or innocuous stimuli; central ◊ General references to pain and its management.
terminal lung disease. Some opioid analgesics such as fen-
sensitisation also occurs. Pain associated with tissue damage 1. Melzack R, Wall PD. Pain mechanisms: a new theory. Science
tanyl and its congeners are used mainly as adjuncts to 1965; 150: 971–9.
anaesthesia; some of these may also be used in higher dos- hence results in increased sensitivity of the sensory system so 2. International Association for the Study of Pain. Classification of
es as the sole anaesthetic drug. that the pain can occur in the absence of a clear stimulus. There chronic pain: descriptions of chronic pain syndromes and defi-
may be a reduction in the pain threshold (allodynia) resulting nitions of pain terms. Pain 1986; (suppl 3): S1–S225.
Some opioids are rarely if ever used as analgesics and are 3. Lewis KS, et al. Effect of analgesic treatment on the physiolog-
in an exaggerated response (hyperalgesia) or a prolonged ef- ical consequences of acute pain. Am J Hosp Pharm 1994; 51:
described elsewhere; they include the antitussives dex-
fect (hyperpathia). 1539–54.
tromethorphan (p.1555) and pholcodine (p.1570), and the 4. Loeser JD, Melzack R. Pain: an overview. Lancet 1999; 353:
antidiarrhoeals diphenoxylate (p.1724) and loperamide Pain is often classified as being acute or chronic in 1607–9.
(p.1741). 5. Ashburn MA, Staats PS. Management of chronic pain. Lancet
nature. 1999; 353: 1865–9.
Opioids can produce physical dependence and withdrawal 6. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms,
symptoms if suddenly stopped. They are also subject to • Acute pain is associated with trauma or disease and mechanisms, and management. Lancet 1999; 353: 1959–64.
7. Carr DB, Goudas LC. Acute pain. Lancet 1999; 353: 2051–8.
abuse. usually has a well-defined location, character, and 8. Cervero F, Laird JM. Visceral pain. Lancet 1999; 353: 2145–8.
Described in this chapter are timing. It is accompanied by symptoms of autonom- 9. American Society of Anesthesiologists Task Force on Acute
Pain Management. Practice guidelines for acute pain manage-
Alfentanil, p.16 Levacetylmethadol, p.77 ic hyperactivity such as tachycardia, hypertension, ment in the perioperative setting: an updated report by the
Anileridine, p.20 Levomethadone, p.77 sweating, and mydriasis. American Society of Anesthesiologists Task Force on Acute
Buprenorphine, p.29 Levorphanol, p.77 Pain Management. Anesthesiology 2004; 100: 1573–81. Also
Butorphanol, p.32 Meptazinol, p.81 available at: http://www.asahq.org/publicationsAndServices/
Carfentanil, p.34 Methadone, p.82 • Chronic pain is usually regarded as pain lasting pain.pdf (accessed 23/06/08)
Codeine, p.37 Morphine, p.86 more than a few months. It may not be clearly asso- 10. Gordon DB, et al. American Pain Society recommendations for
Dextromoramide, p.39 Nalbuphine, p.91 improving the quality of acute and cancer pain management:
ciated with trauma or disease or may persist after the American Pain Society Quality of Care Task Force. Arch Intern
Dextropropoxyphene, p.40 Nicomorphine, p.95
Diamorphine, p.42 Opium, p.105 initial injury has healed; its localisation, character, Med 2005; 165: 1574–80. Also available at:
http://archinte.ama-assn.org/cgi/reprint/165/14/1574 (accessed
Dihydrocodeine, p.48 Oxycodone, p.106 and timing are more vague than with acute pain. Fur- 23/06/08)
Dipipanone, p.49 Oxymorphone, p.107 thermore, as the autonomic nervous system adapts, 11. Spacek A. Modern concepts of acute and chronic pain manage-
Embutramide, p.50 Papaveretum, p.105 ment. Biomed Pharmacother 2006; 60: 329–35.
Ethoheptazine, p.52 Pentazocine, p.112
the signs of autonomic hyperactivity associated with 12. Markman JD, Philip A. Interventional approaches to pain man-
Ethylmorphine, p.52 Pethidine, p.113 acute pain disappear. Some forms of pain regarded agement. Anesthesiol Clin 2007; 25: 883–898.
13. European Association of Urology. Guidelines on pain manage-
Etorphine, p.54 Piritramide, p.117 as being chronic may consist of intermittent attacks ment (issued March 2007). Available at:
Fentanyl, p.55 Remifentanil, p.120 of pain followed by relatively long pain-free periods. http://www.uroweb.org/fileadmin/user_upload/Guidelines/
Hydrochlorides of Mixed Sufentanil, p.124 21_Pain_Management_2007.pdf (accessed 23/06/08)
Opium Alkaloids, p.105 Tilidine, p.129 Patients with chronic pain experience physical, psy- 14. Brennan F, et al. Pain management: a fundamental human right.
Hydrocodone, p.63 Tramadol, p.130 chological, social, and functional deterioration Anesth Analg 2007; 105: 205–21.
Hydromorphone, p.63 Trimeperidine, p.132 which contributes towards exacerbation of the pain. 15. Knape JT, et al. Board of Anaesthesiology of the European Un-
Ketobemidone, p.73 ion of Medical Specialists. Guidelines for sedation and/or anal-
gesia by non-anaesthesiology doctors. Eur J Anaesthesiol 2007;
Physiologically, pain may be divided into nociceptive 24: 563–7.
pain and neuropathic pain. 16. Manchikanti L, et al. Evidence-based interventional pain man-
Paracetamol and other para-aminophenols agement: principles, problems, potential and applications. Pain
Paracetamol is the principal para-aminophenol derivative Physician 2007; 10: 329–56.
in use. Acetanilide and phenacetin have generally been re- • Nociceptive pain follows activation of nociceptors
placed by safer analgesics. Propacetamol is hydrolysed to by noxious stimuli as described above but is not as-
Choice of analgesic
paracetamol in the plasma. sociated with injury to peripheral nerves or the CNS. Paracetamol and NSAIDs are the first choice analgesics
Paracetamol has analgesic and antipyretic properties and It may be somatic or visceral, depending on which for treating mild to moderate pain and are also used in
weak anti-inflammatory activity. The mechanism of receptors or nerves are involved. Somatic pain is moderate to severe pain to potentiate the effects of opioids.
analgesic action remains to be fully elucidated, but may be usually well localised and may be described as deep- They are suitable for use in acute or chronic pain. Effective
due to inhibition of prostaglandin synthesis both centrally ly located, sharp or dull, nagging, stabbing, throb- relief of acute pain can be achieved with oral NSAIDs and
and peripherally. Paracetamol is used for the relief of mild bing, or pressure-like. Visceral pain is generally less with paracetamol (particularly in combination with an opi-
to moderate pain and minor febrile conditions. localised and more diffuse than somatic pain and oid—see below). Dependence and tolerance are not a
Described in this chapter are may be referred to remote areas of the body. De- problem with non-opioid analgesics but they have a rather
Acetanilide, p.15 Phenacetin, p.115 pending on the structure involved it is variously de- flat dose-response curve: as the dose is increased, the in-
Paracetamol, p.108 Propacetamol, p.119 crease in pain relief may be quite small. Aspirin and other
scribed as deeply located, aching, nagging, cramp-
non-selective NSAIDs inhibit blood platelet function, ad-
ing, or pressing and may be accompanied by nausea versely affect the gastrointestinal tract, and can precipitate
Analgesia and Pain and vomiting. Nociceptive pain usually responds to
Pain is defined by the International Association for the hypersensitivity reactions including asthma. The risk of
treatment with conventional analgesics. severe upper gastrointestinal adverse effects may be less
Study of Pain as ‘an unpleasant sensory and emotional
with selective inhibitors of cyclo-oxygenase-2 (COX-2)
experience associated with actual or potential tissue • Pain resulting from damage or dysfunction of pe- such as the coxibs, but their use has been greatly restricted
damage, or described in terms of such damage.’ ripheral nerves/receptors or of the CNS is known as by concerns about serious cardiovascular effects. Para-
Under normal circumstances pain is the result of stimulation of neuropathic pain (or neurogenic pain). The term cetamol does not have the haematological or gastrointesti-
peripheral receptors that transmit impulses through pain path- covers sympathetically maintained pain including nal adverse effects of aspirin but large doses can produce
ways to the brain. Pain receptors or nociceptors are of two ba- causalgia and reflex sympathetic dystrophy, and severe or sometimes fatal hepatotoxicity. Giving paraceta-
sic types: painful conditions such as postherpetic and trigemi- mol with an NSAID improves analgesia.
• mechanoheat receptors have a high stimulation threshold nal neuralgia, and diabetic neuropathy. Neuropathic For the treatment of moderate or moderate to severe opio-
and respond to intense or potentially damaging noxious pain associated with central nervous tissue, such as id-sensitive pain codeine is the traditional choice; alterna-
stimuli. These receptors are associated with rapidly con- in central post-stroke pain (the thalamic syndrome) tives include dihydrocodeine and tramadol. They are of-
ducting, thinly myelinated Aδ fibres, and their stimulation ten given with non-opioid analgesics. Combinations of
produces rapid sharp localised pain that serves to activate
is referred to as central pain. The clinical signs of
codeine with paracetamol at full doses produce a small but
withdrawal reflexes neuropathic pain can vary greatly. Some of the more significant increase in analgesia compared with paraceta-
common features include heightened pain sensitivity mol alone and are one of the most effective options for
• polymodal nociceptors respond to mechanical, thermal, or
chemical insults. These receptors are also activated by cell- and sensations of superficial burning or stabbing acute pain, but the incidence of adverse effects increases
ular components that are released after tissue damage. Their (lancinating) pain. The pain may be associated with with repeated use. Combinations of dextropropoxyphene
impulses are transmitted slowly along unmyelinated C type areas of sensory deficit or some form of autonomic with paracetamol or aspirin are no more effective in acute
fibres and produce dull, aching, and poorly localised pain instability. Neuropathic pain responds poorly to con- pain than the non-opioid alone; efficacy in chronic pain is
with a slower onset ventional analgesics and can be difficult to treat. unclear and adverse effects may become troublesome. The
Nerve fibres from nociceptors terminate in the dorsal root of combination preparation co-proxamol (dextropropoxy-
the spinal cord before transmission by ascending pathways to Early treatment of pain is important as unrelieved phene with paracetamol) has been gradually withdrawn
the brain. There have been many theories on the processing of pain can have profound psychological effects on the from the UK market because of poorly established effica-
pain signals at the spinal level but the ‘gate theory’ proposed patient, and acute pain that is poorly managed initially cy and the risk of toxicity in overdose.
by Melzack and Wall is one of the best known. This theory can degenerate into chronic pain, which may prove to More potent opioids such as morphine are mainly used in
postulates that the transmission of impulses to the brain is be much more difficult to treat. It is important to assess the treatment of severe acute non-malignant pain and
modulated by a gate mechanism in the substantia gelatinosa. cancer pain (see below). Their use in chronic non-malig-
and treat the mental and emotional aspects of the pain
Stimulation of small fibres opens the gate and facilitates trans- nant pain is somewhat controversial because of fears of
as well as its physical aspects. Although drug therapy psychological dependence and respiratory depression.
mission whereas stimulation of large fibres, which normally
carry non-painful sensory input, can close the gate and inhibit is a mainstay of pain treatment (see below), physical However, in practice such problems rarely occur and those
transmission. Transmission also appears to be modulated by methods such as physiotherapy (including massage fears should not prevent patients being given effective an-
several other mechanisms which can influence the sensitivity and the application of heat and cold), surgery, and nerv- algesic therapy. Opioids may also be of value in neuro-
of the gate. ous system stimulation techniques such as acupuncture pathic pain in some patients.
 Analgesics Anti-inflammatory Drugs and Antipyretics 3
Morphine is the opioid of choice in severe pain. It is ab- Miscellaneous drugs. Following the discovery that epi- The opioids are still the mainstay of analgesia for moder-
sorbed when given orally and has a short half-life so that dural or intrathecal injection of opioids can produce effec- ate to severe pain in paediatric patients, and morphine is
the use of immediate-release oral preparations offers a tive analgesia many other drugs have been tried by these the standard against which the others are compared. It is
flexible means of dosage titration in, for example, pallia- routes, either alone or with opioids or local anaesthetics, given intravenously for rapid relief of severe pain (for ex-
tive care. Once initial pain relief has been achieved, ad- but their role, if any, in the management of pain remains to ample after burns, fractures or other injuries), and is titrat-
ministration of a modified-release preparation every 12 or be determined. Some of these drugs, such as clonidine and ed to achieve a suitable analgesic dose.4,5,7,8 Where intra-
24 hours is more convenient for maintenance of analgesia ketamine, also appear to have analgesic properties when venous access is not readily achievable, oral morphine
in severe chronic pain. It may also be given parenterally given by other routes, and ketamine may be useful in re- may be given but its onset is slower and less predictable;
(e.g. for control of acute severe pain in emergency depart- ducing opioid requirements. Some antiarrhythmics (in- some favour intranasal diamorphine as an alternative to in-
ments or in patient-controlled analgesia—see also below), cluding systemic lidocaine) may be effective in chronic travenous morphine.4 Continuous intravenous morphine
or rectally or transdermally, where there would be prob- neuropathic pain, but must be used with extreme caution. infusion with or without initial loading doses has become
lems with the oral route. The use of antipsychotics, such as the phenothiazines, as popular for postoperative pain relief,6,8 but titration of the
Occasionally other opioids may be useful. Switching to adjuvant analgesics is controversial; levomepromazine is infusion rate is necessary to achieve a balance between
an alternative opioid may be effective in patients who have sometimes used as an adjunct in palliative care. analgesia and respiratory depression (particular care is
inadequate pain control or intolerable adverse effects with See below for discussions of the use of patient-controlled needed in neonates, see below). Subcutaneous infusions of
morphine. Methadone (which also acts as an NMDA analgesia, and rubefacients and topical analgesics. Nerve morphine have also been used,5 mostly for the relief of ter-
antagonist) or oxycodone have a longer duration of action blocks are discussed under Pain, on p.1852. minal cancer pain in children. Intramuscular injections are
than morphine, but it should be noted that methadone, References. painful7-10 and therefore probably only suitable for short-
which has a long half-life, should not be given more than 1. Sawynok J. Pharmacological rationale for the clinical use of term use. Fentanyl has also been widely used for short-
twice daily when used long term because of the risk of pro- caffeine. Drugs 1995; 49: 37–50. term analgesia in surgical procedures,6-8,10,11 and other
2. Watson CP. The treatment of neuropathic pain: antidepressants opioids such as buprenorphine, hydromorphone, oxyco-
gressive CNS depression and overdosage. A rapid onset of and opioids. Clin J Pain 2000; 16 (suppl): S49–S55.
action is provided by alfentanil and fentanyl but use of 3. Curatolo M, Sveticic G. Drug combinations in pain treatment: a done, and tramadol have been given.5 Patient-controlled
pethidine is no longer recommended. Diamorphine or hy- review of the published evidence and a method for finding the analgesia using morphine has been tried in children (see
optimal combination. Best Pract Res Clin Anaesthesiol 2002; below).
dromorphone may be preferred to morphine when the 16: 507–19.
parenteral route has to be used because they are more sol- 4. Backonja M. Anticonvulsants for the treatment of neuropathic Morphine has also been given to children by the epidural
pain syndromes. Curr Pain Headache Rep 2003; 7: 39–42.
uble and can be given in a smaller volume. Tramadol, 5. McQuay H. Pain and its control. Available at: route;8 experience with the intrathecal route is more limit-
which may impair respiratory and gastrointestinal function http://www.jr2.ox.ac.uk/bandolier/booth/painpag/wisdom/ ed. Other methods of opioid drug delivery of possible val-
less than other opioids at equianalgesic doses, is also of C13.html (accessed 23/06/08) ue in paediatric analgesia include transmucosal,6,11 na-
6. McQuay HJ. Neuropathic pain: evidence matters. Eur J Pain
benefit in neuropathic pain. 2002; 6 (suppl A): 11–18. sal,4,7 and transdermal6,9 dosage.
Adverse effects of opioids include sedation, nausea, vom- 7. Anonymous. Acute pain (Bandolier Extra, issued February Cancer pain in children may be treated using the analgesic
iting, constipation, and, most seriously, respiratory depres- 2003). Available at: http://www.jr2.ox.ac.uk/bandolier/
Extraforbando/APain.pdf (accessed 23/06/08) ladder scheme described under Cancer Pain (see below).
sion. Tolerance generally develops to all of these effects 8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl
except constipation, which may be prevented by regular J Med 2003; 349: 1943–53. Inhaled nitrous oxide and oxygen mixtures may be useful
use of laxatives. 9. British Association for Emergency Medicine. Clinical Effec- for preliminary pain relief and short, painful proce-
tiveness Committee guideline for the management of pain in dures.4,7,8,10
A number of other groups of drugs have significant roles adults (2004). Available at: http://www.emergencymed.org.uk/
BAEM/CEC/assets/cec_pain_i n_adults.pdf (acces sed Local anaesthetics are especially suitable for the manage-
in pain management either alone or as analgesic adju- 23/06/08)
vants. 10. Attal N, et al. Systemic lidocaine in pain due to peripheral nerve ment of acute pain in day-care situations. Single injections
injury and predictors of response. Neurology 2004; 62: 218–25. given by the epidural route are often used to provide
Subantidepressant doses of tricyclic antidepressants 11. British Pain Society. Recommendations for the appropriate use analgesia during and after surgery. Continuous epidural in-
(usually amitriptyline) are considered to be useful in re- of opioids for persistent non-cancer pain (issued March 2004).
fusions of local anaesthetics have also been used. Howev-
fractory chronic pain, including neuropathic pain of the Available at: http://www.britishpainsociety.org/book_opioid_
main.pdf (accessed 23/06/08) er, simpler techniques such as wound infiltration or periph-
burning, dysaesthetic type such as postherpetic neuralgia 12. Quigley C. Opioid switching to improve pain relief and drug eral nerve blocks can also provide effective analgesia for
and diabetic neuropathy; shooting pain has also been re- tolerability. Available in The Cochrane Database of Systematic
some procedures and are free of the problems of lower
ported to respond. They may be used in addition to con- Reviews; Issue 3. Chichester: John Wiley; 2004 (accessed
23/06/08). limb weakness or urinary retention associated with caudal
ventional analgesics, notably in the treatment of cancer 13. Rathmell JP, et al. The role of intrathecal drugs in the treatment blocks.5,7,8,10 Application of eutectic creams (see Surface
pain of mixed aetiology. There is little evidence for benefit of acute pain. Anesth Analg 2005; 101 (suppl): S30–S43.
Anaesthesia, p.1866) containing lidocaine with prilocaine
in acute pain although musculoskeletal pain has some- 14. Australian and New Zealand College of Anaesthetists and Fac-
ulty of Pain Medicine. Acute pain management: scientific evi- to intact skin, to produce surface anaesthesia, may be suf-
times responded. Amitriptyline has also been found to be dence. 2nd ed, 2005. Available at: http://www.anzca.edu.au/ ficient for some minor painful procedures in children.6-9,11
useful for tension-type headache and for the prophylaxis of resources/books-and-publications/acutepain.pdf (accessed
migraine. The role of other antidepressants in the treat- 23/06/08) Ketamine is used in outpatients for brief, painful proce-
15. Eisenberg E, et al. Efficacy and safety of opioid agonists in the
ment of neuropathic pain is less clear although venlafaxine treatment of neuropathic pain of nonmalignant origin: systemat- dures such as fracture reduction and to provide immobility
may be useful. ic review and meta-analysis of randomized controlled trials. for repair of facial lacerations in young children.11,12 The
JAMA 2005; 293: 3043–52. emergence reactions that limit its use in adults are less
Antiepileptics (often carbamazepine and, more recently, 16. Davis MP, et al. Controversies in pharmacotherapy of pain man-
gabapentin and pregabalin) have been found useful in the agement. Lancet Oncol 2005; 6: 696–704. common in children,11 and can be ameliorated by benzodi-
relief of neuropathic pain, especially when there is a stab- 17. Nicholas MK, et al. Using opioids with persisting noncancer azepines.7,10
pain: a biopsychosocial perspective. Clin J Pain 2006; 22:
bing (lancinating) element, as in trigeminal neuralgia; 137–46. Most neonates requiring analgesia and receiving respira-
there have also been reports of efficacy in the treatment of 18. McQuay HJ, Moore RA. Dose-response in direct comparisons tory support can be managed with an infusion of morphine
of different doses of aspirin, ibuprofen and paracetamol (aceta-
diabetic neuropathy and for migraine prophylaxis. minophen) in analgesic studies. Br J Clin Pharmacol 2007; 63: but in neonates who are breathing spontaneously there is a
Benzodiazepines and other muscle relaxants such as ba- 271–8. substantial risk of respiratory depression. Morphine has
clofen or dantrolene are useful for relieving painful muscle
19. Knotkova H, Pappagallo M. Adjuvant analgesics. Anesthesiol been used in such neonates8 but should be limited to those
Clin 2007; 25: 775–86.
spasm in acute or chronic conditions. 20. Tamchès E, et al. Acute pain in adults admitted to the emergen- under intensive care, as for example after major surgery
cy room: development and implementation of abbreviated (see also Intensive Care, p.957). Fentanyl citrate1 and co-
Bone modulating drugs such as calcitonin and bisphos- guidelines. Swiss Med Wkly 2007; 137: 223–7. deine phosphate have also been used in neonates. Sucrose
phonates may be useful in cancer pain arising from bone 21. Australian and New Zealand College of Anaesthetists and Fac-
and other sweet tasting solutions have been shown to re-
metastases (see below) but have a slow onset of action and ulty of Pain Medicine. Acute pain management: scientific evi-
dence. Update to 2nd ed., December 2007. Available at: http:// duce physiologic and behavioural indicators of stress and
are second choice to NSAIDs. Bisphosphonates may www.anzca.edu.au/resources/books-and-publications/ pain in neonates undergoing painful procedures9 although
cause an initial transient increase in bone pain. acutepain_update.pdf (accessed 23/06/08)
there had been some doubt expressed over whether this in-
22. Guindon J, et al. Recent advances in the pharmacological man-
Caffeine has been used with the aim of enhancing the ef- agement of pain. Drugs 2007; 67: 2121–33. dicates effective analgesia.13 The American Academy of
fects of non-opioid and opioid analgesics but is of debata- Pediatrics has suggested that oral sucrose together with
ble benefit. There are similar doubts about whether caf- other non-pharmacological methods such as swaddling
Choice of analgesics in children
feine enhances the effect of ergotamine in the treatment of should be used for minor routine procedures; topical local
Pain has often been undertreated in infants and children
migraine (see Pharmacokinetics, p.621); it may also add to anaesthetics may be used for more painful procedures such
because of fears of respiratory depression, cardiovascular
gastrointestinal adverse effects and in large doses can itself as venepuncture if time permits. Opioids should be the ba-
collapse, depressed levels of consciousness, and addiction
cause headache. sis of postoperative analgesia after major surgery in the ab-
with potent opioid analgesics. Assessment of pain is also a
Corticosteroids have produced improvement, often sub- problem in children of all ages1-3 and it is not that long sence of regional anaesthesia; a rapidly acting opioid such
stantial, in neuropathic pain. They can also relieve head- since it was widely believed that neonates were incapable as fentanyl is advocated, together with infiltration of the
ache caused by raised intracranial pressure and refractory of feeling pain. site with a local anaesthetic where time permits, for inser-
pain caused by bone metastases, and have the added bene- tion of a chest drain.14 Similar recommendations for pain-
Non-opioid analgesics are used in infants and children, ful procedures in neonates have been made by an interna-
fits of increasing well-being and appetite. either alone for minor pain or as an adjunct to opioid tional consensus group.15
Some inhalational anaesthetics are used in subanaesthet- analgesics in severe pain,4,5 (they can reduce opioid re-
ic doses as inhalation analgesics for acute pain. In particu- quirements,1,6 perhaps by up to 40%5). Paracetamol is fre- The use of analgesic adjuncts (see Choice of Analgesic,
lar, nitrous oxide is given with oxygen for pain relief in quently used but it lacks any anti-inflammatory effect. above) has also been advocated in some children.16
obstetrics and during dental and other procedures, and in NSAIDs such as ibuprofen are useful for minor pain,4,5,7 1. American Academy of Pediatrics and Canadian Paediatric Soci-
emergency management. Isoflurane, enflurane, and in especially when associated with inflammation or trauma. ety. Prevention and management of pain and stress in the ne-
onate. Pediatrics 2000; 105: 454–61. Also available at:
some countries methoxyflurane or trichloroethylene have The use of aspirin is greatly restricted by its association h t t p : / / a a p p o l i c y. a a p p u b l i c a t i o n s . o r g / c g i / r e p r i n t /
been used similarly. with Reye’s syndrome. pediatrics;105/2/454.pdf (accessed 23/06/08)

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
4 Analgesics Anti-inflammatory Drugs and Antipyretics
2. American Academy of Pediatrics Committee on Psychosocial dine.2 Drugs with very short (remifentanil) or very long regimen, may be an alternative.3 Careful monitoring for
Aspects of Child and Family Health, American Pain Society
Task Force on Pain in Infants, Children, and Adolescents. The (methadone) half-lives may be less suitable for use. potential adverse effects, in particular respiratory de-
assessment and management of acute pain in infants, children, Although generally perceived as safer than conventional pression, is needed.3
and adolescents. Pediatrics 2001; 108: 793–7. Also available at: opioid analgesia, occasional serious adverse effects and Opioids injected centrally via the epidural and intrathe-
http://pediatrics.aappublications.org/cgi/reprint/108/3/793.pdf
(accessed 23/06/08) fatalities have resulted from errors in programming, or cal routes provide effective regional analgesia2,4,9 (and
3. Maurice SC, et al. Emergency analgesia in the paediatric popu- incorrect or inappropriate use (including operation by per- may be more effective than intravenous opioids,10 al-
lation (part I): current practice and perspectives. Emerg Med J sons other than the patient). These risks can be minimised though whether this improves the ultimate outcome is
2002; 19: 4–7.
4. British Association for Emergency Medicine. Clinical Effec- by safety features built into the PCA device itself, and by unclear3). Morphine is the opioid most commonly given
tiveness Committee guideline for the management of pain in the development of standard protocols for the use of the centrally, but others such as fentanyl, which is more lip-
children (2004). Available at: technique.2,3 id soluble, may be preferable in the case of epidural in-
http://www.emergencymed.org.uk/BAEM/CEC/assets/
cec_pain_in_children.pdf (accessed 23/06/08) Most experience relates to the use of the intravenous route. jection. The epidural and intrathecal routes have also
5. Morton NS. Management of postoperative pain in children. However, epidural PCA is also used. It appears to be as been used for patient-controlled analgesia.
Arch Dis Child Educ Pract Ed 2007; 92: ep14–ep19. effective, or more effective, than intravenous PCA,2,3 al-
6. Berde CB, Sethna NF. Analgesics for the treatment of pain in
Oral opioids may not be suitable in the immediate post-
children. N Engl J Med 2002; 347: 1094–1103. though it may not be suitable in all cases, and carries addi- operative period, but oral regimens are generally pre-
7. Maurice SC, et al. Emergency analgesia in the paediatric popu- tional risks to do with the placement of the epidural cathe- ferred if the patient can swallow and gastrointestinal
lation (part II): pharmacological methods of pain relief. Emerg ter.3 Epidural PCA generally produces analgesia with a function has recovered.1,3 Tramadol is useful in patients
Med J 2002; 19: 101–5.
8. Alder Hey Royal Liverpool Children’s NHS Trust. Guidelines
combination of a lipid-soluble opioid such as fentanyl or undergoing minor or intermediate surgery.3
on the management of pain in children. 1st edn, 1998. Available sufentanil plus a long-acting local anaesthetic such as Management of postoperative pain in patients who have
at: http://painsourcebook.ca/pdfs/pps55.pdf (accessed bupivacaine or ropivacaine; the optimum combination has been receiving long-term opioids before surgery may be
23/06/08) yet to be defined.2,3 In addition, unlike intravenous PCA,
9. Zempsky WT, et al. Relief of pain and anxiety in pediatric pa- particularly difficult.3,11 Baseline requirements should
tients in emergency medical systems. Pediatrics 2004; 114: the use of a background infusion is recommended. be calculated for each patient, but may go up or down
1348–56. Other routes have been investigated, including intranasal7 after surgery; typically, at least 50% of the baseline dose
10. Harvey AJ, Morton NS. Management of procedural pain in chil- and, in particular, transdermal2,8 PCA. An iontophoretic
dren. Arch Dis Child Educ Pract Ed 2007; 92: ep20–ep26. will be needed postoperatively, with additional opioids
11. Krauss B, Green SM. Sedation and analgesia for procedures in patient-controlled delivery system for transdermal fenta- titrated according to pain requirements. Such patients
children. N Engl J Med 2000; 342: 938–45. nyl has been developed,8,9 and allows PCA to be given in may thus require larger than normal doses of opioids to
12. Howes MC. Ketamine for paediatric sedation/analgesia in the a non-invasive manner. be given, and a balanced multimodal approach to anal-
emergency department. Emerg Med J 2004; 21: 275–80.
13. Stevens B, et al. Sucrose for analgesia in newborn infants un- Although it is not always considered in terms of PCA, in- gesia is particularly important.11
dergoing painful procedures. Available in The Cochrane Data- haled nitrous oxide in oxygen also has a long history of • NSAIDs and paracetamol are useful analgesic ad-
base of Systematic Reviews; Issue 3. Chichester: John Wiley; effective use as a patient-controlled analgesic during child-
2004 (accessed 23/06/08). juncts that can improve pain relief,3 but are not suitable
14. American Academy of Pediatrics Committee on Fetus and New- birth; opioid PCA may not be suitable for such pain al- alone after major surgery.2 After minor or intermediate
born and Section on Surgery, Canadian Paediatric Society Fetus though local anaesthetics have been used with satisfactory surgery an oral regimen of paracetamol plus an NSAID
and Newborn Committee. Prevention and management of pain results.10 such as naproxen may be adequate, with oxycodone or
in the neonate: an update. Pediatrics 2006; 118: 2231–41. Cor-
rection. ibid. 2007; 119: 425. Also available at: 1. Walder B, et al. Efficacy and safety of patient-controlled opioid tramadol being given for breakthrough pain.3 NSAIDs
http://pediatrics.aappublications.org/cgi/reprint/118/5/ analgesia for acute postoperative pain: a quantitative systematic
review. Acta Anaesthesiol Scand 2001; 45: 795–804. can be used effectively with other drugs, and use of an
2231.pdf (accessed 23/06/08)
15. Anand KJ; International Evidence-Based Group for Neonatal
2. Grass JA. Patient-controlled analgesia. Anesth Analg 2005; 101 NSAID with an opioid after major surgery enables the
(suppl): S44–S61. dose of the opioid to be reduced without loss of analge-
Pain. Consensus statement for the prevention and management 3. Momeni M, et al. Patient-controlled analgesia in the manage-
of pain in the newborn. Arch Pediatr Adolesc Med 2001; 155: ment of postoperative pain. Drugs 2006; 66: 2321–37. sic effect.1-5,9 However, the risk of gastric ulceration,
173–80. Also available at: http://archpedi.ama-assn.org/cgi/
reprint/155/2/173.pdf (accessed 23/06/08) 4. Hudcova J, et al. Patient controlled opioid analgesia versus con- impaired coagulation, and reduced renal function may
16. Chambliss CR, et al. The assessment and management of chron-
ventional opioid analgesia for postoperative pain. Available in
The Cochrane Database of Systematic Reviews; Issue 4. Chich-
limit the use of NSAIDs in some patients,3,9 and the po-
ic pain in children. Paediatr Drugs 2002; 4: 737–46. ester: John Wiley; 2006 (accessed 23/06/08). tential cardiovascular effects of the selective inhibitors
5. Bainbridge D, et al. Patient-controlled versus nurse-controlled of cyclo-oxygenase-2 (COX-2) have also been a cause
analgesia after cardiac surgery—a meta-analysis. Can J Anaesth of great concern.3
Nerve blocks 2006; 53: 492–9.
For a discussion of the use of nerve blocks in the manage- 6. Macintyre PE. Safety and efficacy of patient-controlled analge- Diclofenac, flurbiprofen, ketoprofen, ketorolac, lornox-
sia. Br J Anaesth 2001; 87: 36–46. icam, and naproxen are among the NSAIDs used for
ment of pain, see under Pain, p.1852. 7. Lehmann KA. Recent developments in patient-controlled anal-
gesia J Pain Symptom Manage 2005; 29 (suppl): S72–S89. postoperative pain; the COX-2 inhibitors including
8. Sinatra R. The fentanyl HCl patient-controlled transdermal sys- parecoxib have also been used. Diclofenac, ketoprofen,
Patient-controlled analgesia tem (PCTS): an alternative to intravenous patient-controlled an- ketorolac, and parecoxib may be given by injection, and
Patient-controlled analgesia (PCA) involves the use of au- algesia in the postoperative setting. Clin Pharmacokinet 2005;
44 (suppl 1): 1–6. a parenteral formulation of paracetamol is available in
tomated delivery systems that enable patients to receive 9. Eberhart L. The safety and tolerability of the fentanyl HCl ion- some countries.
doses of an analgesic on demand. The technique is now tophoretic transdermal system: an alternative to currently avail-
• Infiltration of local anaesthetics at the site of operation
able analgesic modalities. J Opioid Manag 2007; 3: 249–56.
widely favoured in the management of acute pain,1-3 and 10. van der Vyver M, et al. Patient-controlled epidural analgesia is a simple method of preventing postoperative wound
appears to produce slightly better analgesia, and greater versus continuous infusion for labour analgesia: a meta-analy- pain.1,4 Central nerve blocks obtained with epidural or
patient acceptance, than conventional analgesic meth- sis. Br J Anaesth 2002; 89: 459–65.
intrathecal local anaesthetics produce excellent analge-
ods.4,5 It has been used successfully in children as young sia,1,2,4 although again, whether this improves outcome
as 4 years, and in elderly patients.6 Most experience relates Postoperative analgesia is unclear.2,3 Insertion of a catheter during the operation
to systems using intravenous opioids. Pain relief after surgery has often been inadequate and it is allows subsequent infusion or bolus injection.9 Howev-
Initial analgesia must be established by giving the patient now recognised that pain control should be adjusted for er, there may be complications related to both the proce-
bolus doses of the analgesic, to achieve effective blood each patient and each situation.1-3 Multimodal regimens, dure and the drugs used (see also Adverse Effects of
concentrations.2,3 In the simplest type of PCA the patient using several classes of analgesic, and ideally more than Central Block, p.1850). Local anaesthetics are rarely
is then able to self-administer a small fixed dose on de- one route, are now generally favoured.3-5 Pre-operative used alone, as a mixture of an opioid and a local anaes-
mand; further doses are not permitted until a pre-pro- evaluation of the patient,2,4 and frequent assessment of thetic produces effective analgesia using relatively
grammed lockout interval has expired. The demand dose pain intensity after surgery (both to allow appropriate smaller doses of each drug.9 Such combinations are also
should be large enough to produce an appreciable analge- analgesia, and to detect possible complications)3 are fun- used in patient-controlled epidural analgesia (see
sic effect, but not large enough to lead readily to toxic con- damental. Evidence-based procedure-specific guidelines above).
centrations; the lockout period should also be long enough are under development.6 Giving pain control on a prevent- • There is growing interest in the use of analgesic adju-
for the maximum analgesic effect to be felt before another ative basis (pre-emptive analgesia) has been recommend- vants, including antiepileptics such as gabapentin or
dose is permitted, and should therefore relate to the speed ed, and may be more effective than conventional manage- pregabalin,12 or the NMDA antagonist ketamine,13,14 to
of onset of action of the drug.2 Some devices allow the ment, at least for some regimens, although results have modulate opioid dosage and efficacy for postoperative
dose to be given as a short infusion2 to reduce adverse ef- varied.7,8 pain. (For further discussion of analgesic adjuvants see
fects associated with high peak concentrations of opioids. Patients undergoing minor surgery can be adequately man- Choice of Analgesic, above.)
In another commonly used method, sometimes described aged with oral analgesics, such as paracetamol, NSAIDs, 1. Shang AB, Gan TJ. Optimising postoperative pain management
as patient-augmented analgesia, the patient is given a con- tramadol, and oxycodone. Those undergoing more exten- in the ambulatory patient. Drugs 2003; 63: 855–67.
tinuous background infusion which is supplemented by sive surgery usually require parenteral opioids or local 2. Rosenquist RW, Rosenberg J. United States Veterans Adminis-
tration. Postoperative pain guidelines. Reg Anesth Pain Med
self-administered bolus doses.2,3,6 However, with this analgesic techniques such as regional block, sometimes in 2003; 28: 279–88. Also available at:
method patients may receive more opioids without any combination.3 http://www.oqp.med.va.gov/cpg/PAIN/PAIN_base.htm (ac-
improvement in analgesia;6,7 There is also a greater risk of • Opioid analgesics, in particular morphine, are the cessed 23/06/08)
3. Myles PS, Power I. Clinical update: postoperative analgesia.
adverse effects, including respiratory depression.2,3,7 It re- mainstay of treatment for moderate to severe postoper- Lancet 2007; 369: 810–12.
mains to be seen if there is any advantage with the more ative pain.3 Opioid dose should be individually titrated; 4. American Society of Anesthesiologists Task Force on Acute
sophisticated devices that can be programmed to adjust the they may be given by numerous routes, but intravenous Pain Management. Practice guidelines for acute pain manage-
ment in the perioperative setting: an updated report by the
background infusion according to the frequency of the bo- doses give more predictable results than intramuscular American Society of Anesthesiologists Task Force on Acute
lus demands.6,7 or subcutaneous doses and are widely favoured.2,3,9 In- Pain Management. Anesthesiology 2004; 100: 1573–81. Also
available at: http://www.asahq.org/publicationsAndServices/
Most of the common opioids have been used successfully travenous patient-controlled analgesia (see above) is pain.pdf (accessed 23/06/08)
for PCA.2 Morphine remains the gold standard, and fenta- now a standard method of management for postopera- 5. Elia N, et al. Does multimodal analgesia with acetaminophen,
nyl, hydromorphone, or tramadol are widely used alterna- tive pain.3,4 Where it is unavailable, intramuscular or nonsteroidal antiinflammatory drugs, or selective cyclooxygen-
ase-2 inhibitors and patient-controlled analgesia morphine offer
tives.2,3 Use of pethidine is no longer advised because of subcutaneous dosage every 2 hours as needed for 24 to advantages over morphine alone? Meta-analyses of randomized
the risk of accumulation of its toxic metabolite, norpethi- 72 hours, followed by conversion to an oral analgesic trials. Anesthesiology 2005; 103: 1296–1304.
 Analgesics Anti-inflammatory Drugs and Antipyretics 5
6. The PROSPECT Working Group. PROSPECT: procedure spe- should either be avoided in patients with biliary disorders rather than treatment as required aims to prevent pain re-
cific postoperative pain management. Available at:
http://www.postoppain.org (accessed 23/06/08) or that they should be given with an antispasmodic. Histor- emerging and to minimise the expectation of pain. The
7. Ong CK-S, et al. The efficacy of preemptive analgesia for acute ically, pethidine has been regarded as a more suitable analgesic ladder consists of 3 stages, treatment beginning
postoperative pain management: a meta-analysis. Anesth Analg choice because it was thought to have less smooth muscle at step 1 and progressing to step 3 if pain is uncontrolled or
2005; 100: 757–73.
8. Grape S, Tramèr MR. Do we need preemptive analgesia for the activity than morphine; however, this has been questioned. increases. The stages are as follows:
treatment of postoperative pain? Best Pract Res Clin Anaesthe- Prostaglandins have also been implicated in the aetiology 1. a non-opioid analgesic such as aspirin, other
siol 2007; 21: 51–63. of biliary colic and NSAIDs such as diclofenac or ketoro-
9. Brown AK, et al. Strategies for postoperative pain management. NSAIDs, or paracetamol; an adjuvant (see below) may
Best Pract Res Clin Anaesthesiol 2004; 18: 703–17. lac have been successfully used to relieve the pain.1-3 also be given if necessary to tackle specific pain or asso-
10. Block BM, et al. Efficacy of postoperative epidural analgesia: a Antimuscarinic antispasmodics have been tried for their ciated symptoms
meta-analysis. JAMA 2003; 290: 2455–63. action on biliary smooth muscle and the sphincter of Oddi.
11. James C, Williams JE. How should postoperative pain in pa- 2. an opioid analgesic such as codeine, dihydrocodeine,
tients on long-term opioids be managed? Br J Hosp Med 2006; Ureteral obstruction, such as in the formation and passage
67: 500. of renal calculi (see p.2181), produces painful renal or or tramadol plus a non-opioid analgesic; an adjuvant
12. Dahl JB, et al. ‘Protective premedication’: an option with
ureteral colic.4-6 The acute pain of renal or ureteral colic may also be given
gabapentin and related drugs? A review of gabapentin and pre-
gabalin in the treatment of post-operative pain. Acta Anaesthe- has been traditionally relieved using opioid analgesics 3. a potent opioid analgesic such as oral morphine; a
siol Scand 2004; 48: 1130–6. such as pethidine that have a minimal effect on smooth non-opioid analgesic may also be given, as may an ad-
13. Subramaniam K, et al. Ketamine as adjuvant analgesic to opio-
ids: a quantitative and qualitative systematic review. Anesth An- muscle, although morphine has also been used.4,6 Howev- juvant.
alg 2004; 99: 482–95. er, opioids, and especially pethidine, are particularly asso-
Combining analgesics with different pharmacological
14. Bell RF, et al. Perioperative ketamine for acute postoperative ciated with nausea and vomiting,5,7 and NSAIDs are in-
pain. Available in The Cochrane Database of Systematic Re- actions can produce additive or synergistic increases in
views; Issue 1. Chichester: John Wiley; 2006 (accessed creasingly used in their place; they appear to be at least
analgesia but only one analgesic from each of the 3 groups
23/06/08). comparable with the opioids in terms of efficacy.4-7 They
(non-opioid, less potent opioid, potent opioid) should be
can be given intramuscularly, intravenously, orally, and
used at the same time.
Rubefacients and topical analgesia rectally, although the best route is unclear.5,8 Diclofenac
Substances applied topically can relieve local pain through sodium given intramuscularly is recommended as first- Evidence to support the choice of analgesic is often
a number of different mechanisms.1 Rubefacients or coun- line treatment by some authors.6 Parenteral ketorolac also scanty. A systematic review12 found some evidence of
ter-irritants can relieve superficial or deep-seated local seems to be effective.5 The use of intranasal desmopressin benefit from the use of NSAIDs to treat cancer pain, and
pain probably by producing counter stimulation, which ac- is also being studied.4,5 supported their use in mild pain (WHO step 1), but there
cording to the ‘gate theory’ of pain (see Analgesia and 1. Akriviadis EA, et al. Treatment of biliary colic with diclofenac: was little to support the choice of one NSAID over anoth-
a randomized, double-blind, placebo-controlled study. Gastroen- er, and little evidence for the addition of an opioid to an
Pain, above) helps to inhibit the transmission of pain sig- terology 1997; 113: 225–31.
nals. Their topical application produces hyperaemia or 2. Dula DJ, et al. A prospective study comparing im ketorolac with
NSAID in moderate pain (WHO step 2).
irritation of the skin and they are used alone or as an ad- im meperidine in the treatment of acute biliary colic. J Emerg In moderate to severe pain (WHO step 3), morphine is
Med 2001; 20: 121–4.
junct to massage in the management of a variety of painful 3. Henderson SO, et al. Comparison of intravenous ketorolac and generally held to be the opioid of choice;5 alternatives in-
musculoskeletal conditions.2 Some are also traditionally meperidine in the treatment of biliary colic. J Emerg Med 2002; clude fentanyl, hydrocodone, and oxycodone.5,9 Partial
used in preparations for the symptomatic relief of minor 23: 237–41. agonists or opioids with long half-lives (such as methadone
4. Shokeir AA. Renal colic: new concepts related to pathophysiol-
peripheral vascular disorders such as chilblains. Substanc- ogy, diagnosis and treatment. Curr Opin Urol 2002; 12: 263–9. or levorphanol) are less suitable for treatment than pure
es commonly used in rubefacient preparations include 5. Heid F, Jage J. The treatment of pain in urology. BJU Int 2002; opioid agonists with less prolonged actions.9 In patients
nicotinate and salicylate compounds, essential oils, 90: 481–8. who do not achieve effective analgesia at an acceptable
capsicum, solutions of ammonia, camphor, and noni- 6. Wright PJ, et al. Managing acute renal colic across the primary- level of adverse effects with one opioid, opioid rotation,
secondary care interface: a pathway of care based on evidence
vamide. They may be of benefit in acute pain, but seem to and consensus. BMJ 2002; 325: 1408–12. switching to an alternative opioid at an equivalent dose,
be less effective in chronic arthritic and rheumatic pain.3 7. Holdgate A, Pollock T. Non-steroidal anti-inflammatory drugs may enable pain control.9,13
Capsaicin, which is one of the active ingredients of capsi- (NSAIDS) versus opioids in the treatment of acute renal colic.
Available in The Cochrane Database of Systematic Reviews; Is- The optimal route for use is by mouth. For best effect,
cum, is used alone as a topical analgesic in a range of pain- sue 1. Chichester: John Wiley; 2004 (accessed 23/06/08). both conventional (for dose titration) and modified-release
ful conditions, including neuropathic pain and rheumatic 8. Lee C, et al. Rectal or intravenous non-steroidal anti-inflamma- (for maintenance) dosage forms are required. The Europe-
disorders; its benefits are modest though it may be useful tory drugs in acute renal colic. Emerg Med J 2005; 22: 653–4.
an Association for Palliative Care (EAPC) suggests5 that
in some patients.4 It does not rely on vasodilatation in the Cancer pain. The pain cancer patients experience may the simplest method of dose titration is with conventional
skin and it is therefore not considered to be a traditional be acute, chronic, or intermittent. It may result from tu- morphine dosage every 4 hours, and the same dose for
counter-irritant. mour involvement of the viscera and extension into soft breakthrough pain. This ‘rescue’ dose may be given as of-
Some NSAIDs have been used topically in the treatment tissues, tumour-induced nerve compression and injury, ten as required, up to hourly. The total daily dose of mor-
of soft-tissue injuries and inflammatory musculoskeletal raised intracranial pressure, or bone metastases. Pain may phine should be reviewed each day and the regular dose
conditions, although this route does not necessarily avoid also arise as a result of adverse effects of treatment, or from adjusted to take account of the amount needed for break-
the adverse effects of systemic treatment. There is some a concurrent disease, and may be exacerbated by emotion- through pain. If pain returns consistently before the next
evidence5 to suggest that topical NSAIDs might be more al or mental changes. Many patients will have more than dose is due the regular dose should be increased. Conven-
effective than placebo. one type of pain. There may also be exacerbations due to tional formulations do not generally need to be given more
Other agents used as topical analgesics include com- movement (incident pain) or worsening of cancer: pain oc- often than every 4 hours, and modified-release products
pounds such as ethyl chloride and the halogenated hydro- curs in about a quarter of patients with newly diagnosed should be given according to the intended duration of the
carbon propellants; their evaporation produces an intense malignancies, but in up to three-quarters of those with ad- preparation (usually every 12 or 24 hours). Patients stabi-
cold that numbs the tissues. Transdermal clonidine has been vanced disease. lised on regular oral morphine require continued access to
used in the treatment of chronic pain. Ketamine also appears Pain relief involves the treatment of the cause of the pain a rescue dose for breakthrough pain. For patients taking
to have some local analgesic effect when applied topically.1 as well as treatment of the pain itself, together with expla- conventional morphine preparations every 4 hours, a dou-
Local anaesthetics are sometimes included in topical nation, reassurance, and supportive care to improve any ble dose at bedtime is effective to prevent pain disturbing
preparations used for the relief of painful skin and muscu- mental and social complicating factors. The mainstay of sleep.
loskeletal disorders. cancer pain management is drug treatment with non-opio- Similar recommendations are given by the NCCN.9 They
Application of heat to the skin can also help to relieve pain id or opioid analgesics, or both together, plus adjuvant advise that the oral rescue dose for breakthrough pain
and melted hard paraffin has been used in wax baths as an analgesics if necessary. A small proportion of patients should be calculated as 10 to 20% of the total 24-hour re-
adjunct to physiotherapy for painful joints and sprains. (about 10 to 20%) may experience pain that responds quirement; this may then be increased by 50 to 100% in
Warm kaolin poultices have also been used as a means of poorly or not at all to opioid analgesics given at tolerable patients who still have increased pain, with hourly reas-
applying heat for pain relief. doses, e.g. neuropathic pain resulting from nerve destruc- sessment of efficacy and adverse effects. If inadequate re-
1. Argoff CE. Topical agents for the treatment of chronic pain. Curr tion or compression, incident bone pain, pancreatic pain, sponse is still seen after 2 or 3 cycles, a change of route
Pain Headache Rep 2006; 10: 11–19. and muscle spasm.
2. Sawynok J. Topical and peripherally acting analgesics. Pharma- (e.g. intravenous titration) may be considered.
col Rev 2003; 55: 1–20. In the management of cancer pain the aim is to achieve
3. Mason L, et al. Systematic review of topical rubefacients con- adequate continuous pain relief with the minimum of ad- If patients are unable to take morphine orally the EAPC
taining salicylates for the treatment of acute and chronic pain. verse effects and this calls for appropriate assessment of considers the preferred alternative route to be subcutane-
BMJ 2004; 328: 995–7.
the intensity and quality of pain, and regular monitoring of ous,5 and the NCCN suggests either continuous parenteral
4. Mason L, et al. Systematic review of topical capsaicin for the
treatment of chronic pain. BMJ 2004; 328: 991–4. the treatment. Guidelines for the relief of cancer pain, pub- infusion, intravenous, or subcutaneous dosage.9 There is
5. Mason L, et al. Topical NSAIDs for chronic musculoskeletal lished by WHO in 19861 and revised in 1996,2 are widely no indication for intramuscular morphine for cancer pain
pain: systematic review and meta-analysis. BMC Musculoskelet endorsed by specialists in pain relief and the care of the since subcutaneous dosage is simpler and less painful.5 In
Disord 2004; 5: 28. Available at: http://www.biomedcentral.com/ the UK diamorphine hydrochloride is often preferred to
1471-2474/5/28 (accessed 23/06/08) terminally ill3-7 despite some questions about the robust-
ness of supporting studies.7 Subsequent guidelines8 issued morphine sulfate for parenteral use because it is more sol-
by the Scottish Intercollegiate Guidelines Network in 2000 uble and allows a smaller dose volume; hydromorphone
Specific pain states and the annually updated guidelines of the US National hydrochloride is an alternative to diamorphine.
Biliary and renal colic. Gallstones (see Ursodeoxy- Comprehensive Cancer Network (NCCN)9 are also wide- Epidural or intrathecal opioids, either by injection or infu-
cholic Acid, p.2409) or other biliary disorders that result in ly referred to. Specific guidelines for the relief of cancer sion, have been used when conventional routes have
obstruction of the bile ducts may produce biliary colic. pain in children have also been published.10,11 failed.9,14 Some advocate the use of these routes because
Morphine may relieve the accompanying pain, but as it Treatment should be given regularly, by mouth if possible, smaller doses may produce analgesia equivalent to that of
can also produce spasm of the sphincter of Oddi it can raise and should follow the accepted three-step ‘analgesic lad- larger doses given orally or parenterally, although there
intrabiliary pressure and exacerbate the pain. It is therefore der’.1,2 This approach is often described as treatment ‘by has been little conclusive evidence for a lower incidence of
usually recommended that morphine and its derivatives mouth, by the clock, and by the ladder’. Regular dosage adverse effects or a better quality of analgesia.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
6 Analgesics Anti-inflammatory Drugs and Antipyretics
The buccal, sublingual, and nebulised routes have been in- 12. McNicol E, et al. NSAIDS or paracetamol, alone or combined respond to a sympathetic nerve block may be given an epi-
with opioids, for cancer pain. Available in The Cochrane Data-
vestigated, but these are not recommended for morphine base of Systematic Reviews; Issue 2. Chichester: John Wiley; dural block. Other methods that have been tried in refrac-
because there is no current evidence of clinical advantage 2005 (accessed 23/06/08). tory pain include spinal cord stimulation and intrathecal
over conventional routes.5 However, buprenorphine is giv- 13. Vielhaber A, et al. Advances in cancer pain management. He- baclofen or opioids. There are small studies or anecdotal
matol Oncol Clin North Am 2002; 16: 527–41.
en sublingually and may be a useful alternative in patients 14. Ballantyne JC, Carwood CM. Comparative efficacy of epidural, reports of the use of a variety of other drugs and interven-
with dysphagia, although experience of long-term use in subarachnoid, and intracerebroventricular opioids in patients tions.
cancer pain is limited. Buprenorphine or fentanyl can be with pain due to cancer. Available in The Cochrane Database of References.
Systematic Reviews; Issue 2. Chichester: John Wiley; 2005 (ac-
given via a transdermal system that provides continuous cessed 23/06/08). 1. Kingery WS. A critical review of controlled clinical trials for
and controlled delivery for up to 72 hours. Calculating an 15. Skaer TL. Practice guidelines for transdermal opioids in malig- peripheral neuropathic pain and complex regional pain syn-
nant pain. Drugs 2004; 64: 2629–38. dromes. Pain 1997; 73: 123–39.
appropriate conversion regimen for transfer of patients 16. Lussier D, et al. Adjuvant analgesics in cancer pain manage- 2. Baron R, Wasner G. Complex regional pain syndromes. Curr
from oral or parenteral therapy to transdermal can be diffi- ment. Oncologist 2004; 9: 571–91. Pain Headache Rep 2001; 5: 114–23.
cult,15 but the NCCN suggests that the total daily require- 3. Schott GD. Reflex sympathetic dystrophy. J Neurol Neurosurg
ment of oral morphine is equivalent to about 2000 times Central post-stroke pain. Central pain is a neuropath- Psychiatry 2001; 71: 291–5.
ic pain arising from lesions of the CNS.1-4 Pain following 4. Rho RH, et al. Complex regional pain syndrome. Mayo Clin
the hourly dose of transdermal fentanyl.9 An oral transmu- Proc 2002; 77: 174–80.
cosal dosage form of fentanyl is also available for the man- a cerebrovascular accident has been referred to as thalamic 5. Wasner G, et al. Complex regional pain syndrome—diagnostic,
agement of breakthrough cancer pain.9 syndrome but is now commonly known as central post- mechanisms, CNS involvement and therapy. Spinal Cord 2003;
41: 61–75.
stroke pain and may arise not only from classical stroke 6. Hord ED, Oaklander AL. Complex regional pain syndrome: a
Automated delivery systems for self-administration of but also from surgery or trauma to the head. The pain, review of evidence-supported treatment options. Curr Pain
parenteral analgesics (patient-controlled analgesia) have which has been described as burning, stabbing, and ach- Headache Rep 2003; 7: 188–96.
been used to administer opioid analgesics (see above). ing, may be mild to intolerable and occurs spontaneously 7. Ghai B, Dureja GP. Complex regional pain syndrome: a review.
J Postgrad Med 2004; 50: 300–7.
Adjuvant drugs that may be necessary at any stage in- or in response to a mild stimulus. 8. Harden RN. Pharmacotherapy of complex regional pain syn-
clude antidepressants, antiepileptics, and class I As in other types of neuropathic pain, whether opioid drome. Am J Phys Med Rehabil 2005; 84 (suppl): S17–S28.
antiarrhythmics for neuropathic pain, corticosteroids for 9. Quisel A, et al. Complex regional pain syndrome: which treat-
analgesics can be of benefit is controversial: it has been ments show promise? J Fam Pract 2005; 54: 599–603.
nerve compression and headache resulting from raised in- suggested that the value of conventional opioids such as 10. Cepeda MS, et al. Local anesthetic sympathetic blockade for
tracranial pressure, and muscle relaxants for muscle high-dose morphine is modest, but that NMDA receptor complex regional pain syndrome. Available in The Cochrane
Database of Systematic Reviews; Issue 4. Chichester: John Wi-
spasm. Radiotherapy and radioisotopes such as strontium- antagonists such as methadone may be of more benefit.2 ley; 2005 (accessed 23/06/08).
89 may be of use when the bone pain of metastases is Ketamine, another NMDA antagonist, may also be of val- 11. Sharma A, et al. Advances in treatment of complex regional
unresponsive to NSAIDs alone. Bone modulating drugs ue. Conventional management of central post-stroke pain pain syndrome: recent insights on a perplexing disease. Curr
Opin Anaesthesiol 2006; 19: 566–72.
such as calcitonin and bisphosphonates may be of addi- involves the use of antidepressants such as amitriptyline 12. Rowbotham MC. Pharmacologic management of complex re-
tional benefit but have a slow onset of action and bisphos- and antiepileptics including lamotrigine or gabapentin. gional pain syndrome. Clin J Pain 2006; 22: 425–9.
phonates may cause an initial transient increase in pain. 13. Nelson DV, Stacey BR. Interventional therapies in the manage-
Early peripheral sympathetic blockade may produce tem- ment of complex regional pain syndrome. Clin J Pain 2006; 22:
Corticosteroids have been used as an alternative to porary relief in some cases. Mexiletine may be of use in 438–42.
NSAIDs in refractory bone pain but long-term use should patients with refractory pain; it has often been given with
be avoided. Nerve blocks with local anaesthetics or neuro- amitriptyline. Oral or intrathecal baclofen may be tried. Diabetic neuropathy. Sensory polyneuropathy, a com-
lytic solutions may benefit a few patients, in particular Transcutaneous electrical nerve stimulation (TENS) may plication of diabetes mellitus, is the commonest of the neu-
those with sympathetically maintained pain or specific lo- occasionally be of help but some advocate brain or spinal ropathies producing neuropathic pain. The pain is mainly
calised pain (see under Pain, p.1852). Topical local anaes- cord stimulation. Surgical treatment generally gives disap- experienced as a burning sensation, sometimes accompa-
thetics or capsaicin may also be of use in some patients.9 pointing results. nied by shooting, or aching pain. Painful neuropathy may
Physiotherapy and relaxation techniques may be useful for 1. Bowsher D. The management of central post-stroke pain. Post-
benefit from optimal diabetic control (see under Diabetic
painful muscle spasm. The addition of an NMDA antago- grad Med J 1995; 71: 598–604. Complications, p.433). Non-opioid analgesics such as as-
nist such as dextromethorphan or ketamine to convention- 2. Bowsher D. Central post-stroke (‘thalamic syndrome’) and other pirin or other NSAIDs, or paracetamol may be tried, al-
central pains. Am J Hosp Palliat Care 1999; 16: 593–7. though neuropathic pain is often resistant to conventional
al analgesic regimens has been tried with some success in 3. Frese A, et al. Pharmacologic treatment of central post-stroke
patients with refractory pain.13 Adjuvant therapy should be pain. Clin J Pain 2006; 22: 252–60. analgesics, and the treatment of painful diabetic neuropa-
fully explored before moving on to the next ‘rung’ of the 4. Canavero S, Bonicalzi V. Central pain syndrome: elucidation of thy is generally as for postherpetic neuralgia (see below).
genesis and treatment. Expert Rev Neurother 2007; 7: 1485–97. Relief may be obtained using tricyclic antidepressants and
treatment ladder or increasing the dosage of an opioid
analgesic.16 For further details of analgesic adjuvants, see Complex regional pain syndrome. Complex re- the BNF considers them to be the drugs of choice. SSRIs
Choice of Analgesic, above. gional pain syndrome (CRPS) is a regional, post-traumatic have been tried but studies suggest that they are ineffective
neuropathic pain that generally affects the limbs. CRPS or less effective than tricyclic antidepressants. Duloxetine,
Management of cancer pain also requires monitoring to a serotonin and noradrenaline reuptake inhibitor, is li-
prevent and reduce adverse effects of therapy, particularly has also been referred to as reflex sympathetic dystrophy,
post-traumatic dystrophy, causalgia, Sudeck’s atrophy, censed for use in diabetic neuropathy. Antiepileptics such
of opioids. Appropriate bowel regimes to manage consti- as carbamazepine, gabapentin, phenytoin, and pregabalin
pation should be started at the same time as opioid therapy, and shoulder-hand syndrome. Causalgia has also been
used to describe the burning pain that follows a penetrating can be used to control any shooting or stabbing compo-
as should antiemetic therapy; sedation and nausea usually nents of the pain; lamotrigine and topiramate are also un-
become less marked as treatment progresses,5 and warrant injury. Historically, it was considered that the pain was
maintained by the sympathetic nervous system and the der investigation. Antiarrhythmics such as lidocaine given
reassessment if they persist for longer than a week.9 Con- intravenously or mexiletine given orally have been shown
cerns about respiratory depression and dependence should term ‘reflex sympathetic dystrophy’ was commonly used
to describe the syndrome (although recent studies have to be effective against some components of the pain. Top-
not be allowed to interfere with appropriate treatment: pa- ical application of capsaicin or lidocaine may have some
tients whose pain ameliorates can generally reduce and shown that the sympathetic nervous system is not always
involved). However, the terms given above are now con- effect. Neuropathic pain may respond partially to some
stop opioid treatment without difficulty.5 opioid analgesics and they may be of use when other treat-
1. WHO. Cancer pain relief. Geneva: WHO, 1986.
sidered to be inappropriate and CRPS is now broadly clas-
sified as: ments are ineffective.
2. WHO. Cancer pain relief. 2nd ed. Geneva: WHO, 1996.
3. American Society of Anesthesiologists Task Force on Pain • Type I: (previously reflex sympathetic dystrophy) References.
Management, Cancer Pain Section. Practice guidelines for can- which develops after tissue trauma, such as that accom- 1. Jensen PG, Larson JR. Management of painful diabetic neuropa-
cer pain management. Anesthesiology 1996; 84: 1243–57. Also thy. Drugs Aging 2001; 18: 737–49.
available at: http://www.asahq.org/publicationsAndServices/ panying myocardial infarction, stroke, burns, frostbite, 2. Boulton AJ. Treatments for diabetic neuropathy. Curr Diab Rep
cancer.html (accessed 23/06/08) fractures, and shoulder or limb injury, but where there is 2001; 1: 127–32.
4. Portenoy RK, Lesage P. Management of cancer pain. Lancet no identifiable nerve lesion 3. Barbano R, et al. Pharmacotherapy of painful diabetic neuropa-
1999; 353: 1695–1700. thy. Curr Pain Headache Rep 2003; 7: 169–77.
5. Hanks GW, et al. Expert Working Group of the Research Net-
• Type II: (previously causalgia) which develops after 4. Llewelyn JG. The diabetic neuropathies: types, diagnosis and
work of the European Association for Palliative Care. Morphine trauma to a major peripheral nerve management. J Neurol Neurosurg Psychiatry 2003; 74 (suppl II):
and alternative opioids in cancer pain: the EAPC recommenda- ii15–ii19.
Clinically the two subsets are identical and typical symp- 5. Vinik A. Use of antiepileptic drugs in the treatment of chronic
tions. Br J Cancer 2001; 84: 587–93. Also available at: http://
www.eapcnet.org/download/forPublications/BJC_English.pdf toms include pain, allodynia, and hyperalgesia; as the syn- painful diabetic neuropathy. J Clin Endocrinol Metab 2005; 90:
(accessed 23/06/08) drome becomes chronic, trophic changes to the bone, mus- 4936–45.
6. European Society for Medical Oncology Guidelines Task Force. cles, and skin may occur. Sympathetic dysfunction may 6. Argoff CE, et al. Consensus guidelines: treatment planning and
ESMO Minimum Clinical Recommendations for the manage- options. Diabetic peripheral neuropathic pain. Mayo Clin Proc
ment of cancer pain. Ann Oncol 2005; 16 (suppl 1): i83–i85.
also be present. If the pain is relieved by a sympathetic 2006; 81 (suppl 4): S12–S25.
Also available at: http://annonc.oxfordjournals.org/cgi/reprint/ block (see below), this pain is regarded as ‘sympathetical- 7. Wong M-C, et al. Effects of treatments for symptoms of painful
16/suppl_1/i83.pdf (accessed 23/06/08) ly-maintained’, if not it is known as ‘sympathetically-inde- diabetic neuropathy: systematic review. Abridged version: BMJ
7. Mercadante S, Fulfaro F. World Health Organization guidelines 2007; 335: 87–90. Full version: http://www.bmj.com/cgi/
pendent’ pain. reprint/335/7610/87 (accessed 23/06/08)
for cancer pain: a reappraisal. Ann Oncol 2005; 16 (suppl 4):
iv132–iv135. The treatment of CRPS is difficult especially in chronic 8. Chong MS, Hester J. Diabetic painful neuropathy: current and
8. Scottish Intercollegiate Guidelines Network. Control of pain in disorders and is usually aimed at pain control and restoring future treatment options. Drugs 2007; 67: 569–85. Correction.
patients with cancer: a national clinical guideline (issued June ibid.; 1702.
limb function. The cornerstone of treatment is physiother-
2000). Available at: http://www.sign.ac.uk/pdf/sign44.pdf (ac-
cessed 23/06/08) apy, with pain relief provided in order to allow physical Dysmenorrhoea. Dysmenorrhoea is painful menstrua-
9. National Comprehensive Cancer Network. Clinical practice exercise. Patients with mild disease may not require pain tion. The primary form arises from uterine contractions
guidelines in oncology: adult cancer pain (version 1.2008). management; those with moderate pain should be tried produced by release of prostaglandins from the endometri-
Available at: http://www.nccn.org/professionals/physician_gls/
PDF/pain.pdf (accessed 23/06/08) with a tricyclic antidepressant, an antiepileptic such as um in the luteal phase of the menstrual cycle. For this rea-
10. WHO. Cancer pain relief and palliative care in children. Gene- gabapentin, or a less potent opioid. Oral or intravenous bis- son, drugs that inhibit ovulation or prostaglandin produc-
va: WHO, 1998. phosphonates have also produced some promising results. tion are often effective treatments.1 NSAIDs inhibit cyclo-
11. National Comprehensive Cancer Network. Clinical practice A sympathetic nerve block with bretylium or perhaps a lo- oxygenase (prostaglandin synthetase) and are usually the
guidelines in oncology: pediatric cancer pain (version 1.2007).
Available at: http://www.nccn.org/professionals/physician_gls/ cal anaesthetic may be useful in carefully selected patients drugs of first choice.1-3 They are taken at the onset of dis-
PDF/pediatric_pain.pdf (accessed 23/06/08) with sympathetically-maintained pain; those who do not comfort and continued for a few days while symptoms
 Analgesics Anti-inflammatory Drugs and Antipyretics 7
persist. Those most commonly used have included aspirin, dine.7,10 However, its effectiveness has been queried,7,10 Pudendal nerve blocks with lidocaine followed by a local
diflunisal, flurbiprofen, ibuprofen, indometacin, ketopro- and its use has declined in many countries.7 Fentanyl and anaesthetic given into the perineum provide pain relief
fen, mefenamic acid, naproxen, and piroxicam. Theoreti- its derivatives sufentanil and alfentanil have been used, during labour.12 However, the technique of paracervical
cally, mefenamic acid has the advantage of inhibiting both particularly when given as intravenous patient-controlled local anaesthetic block is now largely of historic interest in
the synthesis and the peripheral action of prostaglandins, analgesia,7 but it is not clear that they have any great ad- labour analgesia21 because of reports of fetal arrhythmias,
but clinical studies have not consistently shown fenamates vantages, and as with other opioids they may cross the pla- acidosis, and asphyxia and isolated reports of fetal death.
to be more effective than other cyclo-oxygenase inhibitors. centa and produce respiratory depression and other ad- Local anaesthetics have been applied topically for
Paracetamol has also been given for pain relief. A syste- verse effects in the newborn. The use of the very short- perineal pain caused by tearing or episiotomy in women
matic review2 comparing several of these drugs concluded acting opioid remifentanil for patient-controlled analgesia who have given birth. However, a systematic review22
that ibuprofen appeared to have the best risk-benefit ratio during labour has been investigated, with some benefit,11 considered that the evidence of effectiveness was not com-
in dysmenorrhoea and was the preferred analgesic; but although it is less likely to produce effects on neonatal pelling.
naproxen, mefenamic acid, and aspirin were also effective, respiration it is not clear that the degree of supervision re- 1. Carroll D, et al. Transcutaneous electrical nerve stimulation in
but the limited data on paracetamol did not show such quired to guard against unacceptable respiratory depres- labour pain: a systematic review. Br J Obstet Gynaecol 1997;
104: 169–75.
clear benefits. Another such review considered that there sion in the mother can be widely achieved on busy labour 2. Smith CA, et al. Complementary and alternative therapies for
was insufficient evidence to determine which NSAID wards.7 Nalbuphine has been used in some countries be- pain management in labour. Available in The Cochrane Data-
should be preferred.3 cause of its mixed agonist/antagonist action,7 although base of Systematic Reviews; Issue 4. Chichester: John Wiley;
2006 (accessed 23/06/08).
Patients who fail to respond to analgesics may benefit there does not seem to be clear evidence that it conveys 3. Cluett ER, et al. Immersion in water in pregnancy, labour and
from the use of progestogens either alone for part of the any substantial benefit. birth. Available in The Cochrane Database of Systematic Re-
views; Issue 2. Chichester: John Wiley; 2002 (accessed
cycle or more usually together with oestrogens in the form Epidural analgesia with a local anaesthetic is now con- 23/06/08).
of oral contraceptive preparations. sidered the gold standard for treatment and provides the 4. Mårtensson L, Wallin G. Labour pain treated with cutaneous in-
jections of sterile water: a randomised controlled trial. Br J Ob-
Antispasmodic drugs such as hyoscine butylbromide are most effective pain relief during labour.9,12-14 Medical in- stet Gynaecol 1999; 106: 633–7.
included in some preparations promoted for the relief of dications may include a history of malignant hyperther- 5. Bahasadri S, et al. Subcutaneous sterile water injection for la-
spasm associated with dysmenorrhoea but the BNF con- mia, certain cardiovascular or respiratory disorders, or pre- bour pain: a randomised controlled trial. Aust N Z J Obstet Gy-
naecol 2006; 46: 102–6.
siders that they do not generally provide significant relief. eclampsia, but the primary indication is the patient’s desire 6. Rosen MA. Nitrous oxide for relief of labor pain: a systematic
There is limited evidence4 that vitamin B1 may be effective for pain relief.9,13 Bupivacaine is one of the local anaes- review. Am J Obstet Gynecol 2002; 186 (suppl 1): S110–S126.
and some consider1 that it may be worth trying; evidence thetics most often used in epidural analgesia; others in- 7. Bruyère M, Mercier FJ. Alternatives à l’analgésie péridurale au
cours du travail. Ann Fr Anesth Reanim 2005; 24: 1375–82.
of benefit from other therapies such as magnesium or vita- clude ropivacaine and lidocaine.14 8. Halpern SH, et al. Effect of epidural vs parenteral opioid anal-
min E is considered to be weaker.1,4,5 Epidural block has few contra-indications and serious ad- gesia in the progress of labor. JAMA 1998; 280: 2105–10.
Secondary dysmenorrhoea is associated with various other 9. Goetzl LM, et al. American College of Obstetricians and Gyne-
verse events are rare. Nonetheless, it has been associated cologists. ACOG Practice Bulletin. Clinical management guide-
disorders such as endometriosis, and treatment is primarily with an increased risk of prolonged second-stage labour, lines for obstetrician-gynecologists number 36, July 2002: ob-
aimed at the underlying cause. forceps delivery, and caesarean section9,13,14 (although stetric analgesia and anesthesia. Obstet Gynecol 2002; 100:
177–91.
1. Lefebvre G, et al. Society of Obstetricians and Gynaecologists of meta-analysis8 and a systematic review14 refute the latter), 10. Bricker L, Lavender T. Parenteral opioids for labor pain relief:
Canada. SOGC clinical practice guidelines no. 169, December a systematic review. Am J Obstet Gynecol 2002; 186 (suppl 1):
2005: Primary dysmenorrhea consensus guideline. J Obstet Gy- and it may not improve maternal experience of childbirth.
S94–S109.
naecol Can 2005; 27: 1117–30. Also available at: http:// Many centres stop epidural analgesia for the second stage 11. Evron S, et al. Remifentanil: a novel systemic analgesic for la-
www.sogc.org/guidelines/public/169E-CPG-December2005.pdf of labour to reduce the incidence of forceps delivery but bor pain. Anesth Analg 2005; 100: 233–8.
(accessed 23/06/08)
2. Zhang WY, Li Wan Po A. Efficacy of minor analgesics in prima-
substantive evidence for this is lacking.15 Central blocks 12. Findley I, Chamberlain G. ABC of labour care. Relief of pain.
BMJ 1999; 318: 927–30.
ry dysmenorrhoea: a systematic review. Br J Obstet Gynaecol may also produce adverse effects including shivering, 13. Eltzschig HK, et al. Regional anesthesia and analgesia for labor
1998; 105: 780–9. post-puncture headache, and hypotension (for further de- and delivery. N Engl J Med 2003; 348: 319–32.
3. Marjoribanks J, et al. Nonsteroidal anti-inflammatory drugs for tails of the adverse effects of and precautions for epidural 14. Anim-Somuah M, et al. Epidural versus non-epidural or no an-
primary dysmenorrhoea. Available in The Cochrane Database of algesia in labour. Available in The Cochrane Database of Sys-
Systematic Reviews; Issue 4. Chichester: John Wiley; 2003 (ac- block see p.1850 and p.1851, respectively). Occasionally tematic Reviews; Issue 4. Chichester: John Wiley; 2005 (ac-
cessed 23/06/08). epidural local anaesthetic does not produce adequate cessed 23/06/08).
4. Proctor ML, Murphy PA. Herbal and dietary therapies for prima- analgesia due to patchy or incomplete block. 15. Torvaldsen S, et al. Discontinuation of epidural analgesia late in
ry and secondary dysmenorrhoea. Available in The Cochrane labour for reducing the adverse delivery outcomes associated
Database of Systematic Reviews; Issue 2. Chichester: John Wi- Some of the adverse effects associated with epidural with epidural analgesia. Available in The Cochrane Database of
ley; 2001 (accessed 23/06/08). Systematic Reviews; Issue 4. Chichester: John Wiley; 2004 (ac-
analgesia are associated with the motor block and pro- cessed 23/06/08).
5. Proctor M, Farquhar C. Diagnosis and management of dysmen-
orrhoea. BMJ 2006; 332: 1134–8. found analgesia resulting from traditional techniques us- 16. Comparative Obstetric Mobile Epidural Trial (COMET) Study
ing relatively high concentrations of local anaesthetic. Group UK. Effect of low-dose mobile versus traditional epidur-
Headache. Aspirin and other NSAIDs, or paracetamol al techniques on mode of delivery: a randomised controlled tri-
There has therefore been an increasing trend to the use of al. Lancet 2001; 358: 19–23.
are often tried first for the symptomatic treatment of vari- lower-dose techniques. Although opioid analgesics are not 17. Comparative Obstetric Mobile Epidural Trial (COMET) Study
ous types of headache including migraine (p.616) and particularly effective for labour analgesia when given sys- Group UK. Randomized controlled trial comparing traditional
with two "mobile" epidural techniques: anesthetic and analgesic
tension-type headache (p.617). NSAIDs may also be temically (see above), addition of a small amount of an efficacy. Anesthesiology 2002; 97: 1567–75.
effective for the prophylaxis of migraine, although they are opioid to epidural solutions enables effective analgesia to 18. Simmons SW, et al. Combined spinal-epidural versus epidural
not considered first-line options. be achieved with lower concentrations of local anaesthetic, analgesia in labour. Available in The Cochrane Database of Sys-
tematic Reviews; Issue 3. Chichester: John Wiley; 2007 (ac-
Opioid analgesics such as codeine are sometimes included and with less motor block;9,12,16,17 however, the incidence cessed 23/06/08).
in oral compound analgesic preparations used in the initial of pruritus (a known effect of opioids) is greater than with 19. Roelants F, et al. Epidural administration of neostigmine and
clonidine to induce labor analgesia: evaluation of efficacy and
treatment of migraine or tension-type headache, but are a local anaesthetic alone.18 There is no standard combina- local anesthetic-sparing effect. Anesthesiology 2005; 102:
best avoided, especially in patients who have frequent at- tion of local anaesthetic and opioid, although one large 1205–10.
tacks. s t u d y u s e d b u p i v a c ai n e 0 . 1 % w i t h f e n t a n y l 20. Roberts CL, et al. Impact of first-stage ambulation on mode of
delivery among women with epidural analgesia. Aust N Z J Ob-
2 micrograms/mL.16 Sufentanil is also widely used with stet Gynaecol 2004; 44: 489–94.
Labour pain. It is important to assess the adverse effects, either bupivacaine18 or ropivacaine. The epidural use of 21. Rosen MA. Paracervical block for labor analgesia: a brief his-
on both the mother and the fetus, when selecting any meth- other adjuvants such as clonidine and neostigmine is also toric review. Am J Obstet Gynecol 2002; 186 (suppl 1):
od for the management of labour pain. Non-pharmacolog- being studied.19 Low-dose techniques are the basis of so-
S127–S130.
ical methods of pain relief may include relaxation tech- 22. Hedayati H, et al. Topically applied anaesthetics for treating
called ‘ambulatory’ or ‘walking’ epidural management, perineal pain after childbirth. Available in The Cochrane Data-
niques, transcutaneous electrical nerve stimulation (which although it is unclear to what extent this mobility improves base of Systematic Reviews; Issue 2. Chichester: John Wiley;
is popular with patients, although there is no robust evi- outcomes or patient satisfaction.20
2005 (accessed 23/06/08).
dence of benefit1), and various other complementary ther- Low back pain. Low back pain (sometimes referred to
apies: of the latter, there is some evidence of benefit with Once an initial block is established, additional analgesia
can be provided through a catheter by intermittent ‘top-up’ as lumbago), is a common complaint but only a small per-
the use of acupuncture and hypnosis.2 Water immersion centage of patients suffer from a recognised organic dis-
(use of a birthing pool) during the first stage of labour has doses or by a continuous epidural infusion; a combination
of the two methods forms the basis of some types of pa- ease, most frequently disc disease. In patients with a lum-
been shown to reduce reported maternal pain.3 Subcutane- bar disc prolapse or herniation, the rupture of one of the
ous or intradermal injection of sterile water into the back tient-controlled epidural analgesia.
fibrocartilagenous intervertebral discs can exert pressure
has also been used for the relief of low back pain during Another method of reducing the adverse effects of tradi- on spinal nerve roots and produce a condition character-
labour.4,5 tional epidural techniques is to combine a spinal block, ised by severe and often acute pain radiating from the back
However, at some point during labour many women will which is quick acting but not long lasting enough to be along the distribution of the nerves affected (radiculopa-
request some sort of pharmacological analgesia. used alone for analgesia in labour, with epidural delivery. thy). The sciatic nerve may be involved and patients expe-
The inhalational anaesthetic nitrous oxide, given with oxy- Although studies have reported superior pain relief17 with rience pain (sciatica), usually in one leg along the typical
gen, is suitable for self-administration and is commonly such combined spinal-epidural analgesia, a systematic distribution of the nerve. Non-specific back pain (back
used to relieve labour pain. It is relatively safe and can pro- review18 considered that there was no overall benefit with pain of unknown origin) is usually self-limiting with a
duce substantial analgesia in most patients.6 Other inhala- the technique when compared with low-dose epidural good prognosis, although recurrence is common.1-3 Back
tional analgesics such as isoflurane or sevoflurane are also techniques, although onset of analgesia was faster. pain is considered to be acute if it lasts for less than 6
sometimes used7 (see Choice of Analgesic, above). The use of spinal blocks in obstetrics has been more com- weeks, sub-acute if it lasts for 6 to 12 weeks, or chronic if
Opioid analgesics have been given systemically in the monly associated with anaesthesia and management of it persists for more than 12 weeks.4
management of labour pain for many years, although they postoperative pain in caesarean section.12 Spinal blocks Treatment for acute back pain should be given early to
do not appear to provide adequate analgesia in most pa- with local anaesthetics have a greater tendency to produce prevent the condition becoming chronic. For simple back
tients at a tolerable dosage.8,9 There is no clear evidence to hypotension and headache than epidural blocks (for fur- pain (in the absence of nerve root symptoms or signs of
favour one opioid over another.10 Morphine is considered ther details of the adverse effects of and precautions for serious spinal pathology) paracetamol should be tried first.
unsuitable,7 and the widest experience has been with pethi- spinal block see p.1850 and p.1851, respectively). NSAIDs are probably more effective,1,5 but are associated
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
8 Analgesics Anti-inflammatory Drugs and Antipyretics
with a higher frequency of adverse effects and should be 9. van Tulder MW, et al. Muscle relaxants for non-specific low- 110: 588–636. Correction. ibid. 2005; 111: 2013. Full guidelines
back pain. Available in The Cochrane Database of Systematic available at: http://circ.ahajournals.org/cgi/reprint/110/9/
reserved for those in whom paracetamol is ineffective.1,4-7 Reviews; Issue 4. Chichester: John Wiley; 2003 (accessed e82.pdf (accessed 23/06/08)
If these treatments fail, muscle relaxants, including ba- 23/06/08). 4. Anderson JL, et al. ACC/AHA 2007 guidelines for the manage-
clofen or tizanidine, may be added to therapy, although ad- 10. Ehrlich GE. Low back pain. Bull WHO 2003; 81: 671–6. ment of patients with unstable angina/non–ST-elevation myocar-
verse effects may limit their usefulness;1-6,8,9 benzodi- 11. Hagen KB, et al. Bed rest for acute low-back pain and sciatica. dial infarction: a report of the American College of Cardiolo-
Available in The Cochrane Database of Systematic Reviews; Is- gy/American Heart Association Task Force on Practice
azepines such as diazepam (which should only be given sue 4. Chichester: John Wiley; 2004 (accessed 23/06/08). Guidelines (Writing Committee to Revise the 2002 Guidelines for
for a short period because of the risk of dependence)1 are 12. Chou R, Huffman LH. Nonpharmacologic therapies for acute the Management of Patients With Unstable Angina/Non–ST-Ele-
among the most effective muscle relaxants, but there is lit- and chronic low back pain: a review of the evidence for an vation Myocardial Infarction). Circulation 2007; 116: e148–e304.
tle comparative evidence, and some suggest that they act American Pain Society/American College of Physicians clinical Full guidelines available at: http://circ.ahajournals.org/
practice guideline. Ann Intern Med 2007; 147: 492–504. Also cgi/reprint/116/7/e148.pdf (accessed 23/06/08)
primarily as sedatives.6 Opioids have moderate benefits in available at: http://www.annals.org/cgi/reprint/147/7/492.pdf 5. Antman EM, et al. 2007 focused update of the ACC/AHA 2004
severe or disabling pain not relieved by paracetamol or (accessed 24/06/08) guidelines for the management of patients with ST-elevation my-
NSAIDs,1,5,6 but again should only be used in the short 13. French SD, et al. Superficial heat or cold for low back pain. ocardial infarction: a report of the American College of Cardiol-
Available in The Cochrane Database of Systematic Reviews; Is- ogy/American Heart Association Task Force on Practice Guide-
term.3 There is strong evidence that remaining active sue 1. Chichester: John Wiley; 2006 (accessed 23/06/08). lines. Circulation 2008; 117: 296–329.
speeds recovery and reduces the risk of chronicity, even if 14. Koes BW, et al. Diagnosis and treatment of sciatica. BMJ 2007; Also available at: http://circ.ahajournals.org/cgi/reprint/
pain or discomfort is caused; bed rest delays recovery and 334: 1313–17. CIRCULATIONAHA.107.188209.pdf (accessed 23/06/08)
is not recommended.2-4,8,10,11 Other non-pharmacological 15. Gibson JN, Waddell G. Surgical interventions for lumbar disc
prolapse. Available in The Cochrane Database of Systematic Neuropathic pain syndromes. The definition and
approaches that have evidence of a benefit include topical Reviews; Issue 2. Chichester: John Wiley; 2007 (accessed characteristics of neuropathic pain are described under
heat wraps and spinal manipulation.1,2,4,12,13 There is little 23/06/08).
Analgesia and Pain, above. Treatment can be difficult and
or no clinical evidence that acupuncture, transcutaneous 16. Armon C, et al. Assessment: use of epidural steroid injections
to treat radicular lumbosacral pain: report of the Therapeutics is best undertaken in specialist pain clinics, since neuro-
electrical nerve stimulation (TENS), massage, traction, and Technology Assessment Subcommittee of the American pathic pain often responds poorly to conventional analge-
specific back exercises, or lumbar support are benefi- Academy of Neurology. Neurology 2007; 68: 723–9. Also
sics.1-5 The painful disorders characterised by neuropathic
cial.1,2,4,10,12 However, patient expectations of benefit from available at: http://www.neurology.org/cgi/reprint/68/10/
723.pdf (accessed 24/06/08) pain (either as the predominant form of pain or as one
different therapies may influence outcomes, and this 17. Airaksinen O, et al. COST B13 Working Group on Guidelines component of the overall pain) discussed in this section
should be taken into consideration.1 for Chronic Low Back Pain. Chapter 4. European guidelines for
the management of chronic nonspecific low back pain. Eur
are:
Sciatica usually resolves with conservative management Spine J 2006; 15 (suppl 2): S192–S300. Also available at: http:// • Central Post-stroke Pain
including analgesics and continued activity; however, if www.backpaineurope.org/web/files/WG2_Guidelines.pdf (ac-
• Complex Regional Pain Syndromes
cessed 23/06/08)
sciatic pain persists for longer than 6 to 8 weeks, surgery
may be indicated.14 Dissolution of the disc by injection of
18. Priest TD, Hoggart B. Chronic pain: mechanisms and treatment. • Diabetic Neuropathy
Curr Opin Pharmacol 2002; 2: 310–15.
enzymes (chemonucleolysis) such as chymopapain or col- 19. Urquhart D, et al. Antidepressants for non-specific low back • Phantom Limb Pain
lagenase has been used as an effective alternative to sur- pain. Available in The Cochrane Database of Systematic Re- • Postherpetic Neuralgia
views; Issue 1. Chichester: John Wiley; 2008 (accessed
gery, but concerns about its safety have led to a decline in 23/06/08). • Trigeminal Neuralgia
use, and discectomy is often preferred.15 20. Gibson JN, Waddell G. Surgery for degenerative lumbar spond- 1. Vadalouca A, et al. Therapeutic management of chronic neuro-
ylosis. Available in The Cochrane Database of Systematic Re- pathic pain: an examination of pharmacologic treatment. Ann N
Epidural injections of corticosteroids, using either the cau- views; Issue 4. Chichester: John Wiley; 2005 (accessed Y Acad Sci 2006; 1088: 164–86.
dal or lumbar route, have been given to patients with sciat- 23/06/08).
2. Jackson KC. Pharmacotherapy for neuropathic pain. Pain Pract
ica; any relief is temporary only, the evidence of a benefit 21. Khadilkar A, et al. Transcutaneous electrical nerve stimulation 2006; 6: 27–33.
(TENS) for chronic low-back pain. Available in The Cochrane
is conflicting, and their use is no longer recommended.14,16 Database of Systematic Reviews; Issue 3. Chichester: John Wi- 3. Cruccu G. Treatment of painful neuropathy. Curr Opin Neurol
There is no evidence of benefit in patients with non-specif- ley; 2005 (accessed 23/06/08). 2007; 20: 531–5.
ic acute or chronic back pain.2,4,17 4. Dworkin RH, et al. Pharmacologic management of neuropathic
Myocardial infarction pain. The severe pain of acute pain: evidence-based recommendations. Pain 2007; 132:
About 2 to 7% of patients with acute lower back pain go 237–51.
myocardial infarction is located in the retrosternal area 5. Moulin DE, et al. Pharmacological management of chronic neu-
on to develop chronic pain,4 and in the majority of cases, with radiation to the arms, neck, jaw, and epigastrium. Pain ropathic pain–consensus statement and guidelines from the Ca-
the source of the pain cannot be identified. Chronic pain is relief is of benefit not only in its own right but also because nadian Pain Society. Pain Res Manag 2007; 12: 13–21.
not necessarily the same as prolonged acute back pain and pain may cause adverse haemodynamic effects such as in-
treatment is difficult. Conservative treatment is as for creases in blood pressure, heart rate, and stroke volume. Orofacial pain. Orofacial pain may arise from a wide
acute pain (see above);1,2,5,17,18 tricyclic antidepressants Although early treatment of the myocardial infarction range of disorders so its effective management depends
may also be tried1-3,5,17,18 although a systematic review (p.1175) may relieve pain dramatically, opioid analgesics very much on the correct identification and treatment of
found the evidence of benefit to be lacking.19 Topical ap- are the first-line treatment for pain and should be given in- any underlying cause, which may include:
plication of capsaicin may be considered for short-term re- travenously as soon as possible, that is before hospital ad- • dental disease
lief.17 Surgery may be indicated for disc disease (see mission, to patients with suspected infarction.1-4 Opioids • cluster headache (p.616)
above) or spondylosis,20 although it is not recommended can also help to reduce anxiety. An inhaled mixture of ni- • migraine (p.616)
for non-specific chronic back pain until conservative treat- trous oxide and oxygen has sometimes been used to pro-
ments have been tried for at least 2 years.17 Epidural corti- • trigeminal neuralgia (see below)
vide pain relief before arrival in hospital; sublingual glyc-
costeroids, intra-articular corticosteroid injections, local eryl trinitrate or an alternative fast-acting nitrate may also • sinusitis (p.193)
facet nerve blocks, trigger point injections, and spinal cord be given. • ear disease such as otitis media (p.182)
stimulation also lack evidence of efficacy.17 Other meth- Diamorphine or morphine given by slow intravenous in- • giant cell arteritis (p.1503)
ods that may be tried for intractable chronic back pain in- jection have generally been the opioids of choice, partly • aneurysms
clude multidisciplinary physical and psychological ap- because of a better haemodynamic profile, but pethidine
proaches; 1 -3 , 1 2 ,1 7 evidence for TENS, massage, • neoplasms
has also been used. An intravenous antiemetic such as
acupuncture, laser therapy, and traction is scant, howev- metoclopramide or, if left ventricular function is not com- In the treatment of dental pain, analgesics are used judi-
er.2,17,18,21 promised, cyclizine, should also be given. The intramus- ciously as a temporary measure until the underlying cause
1. Chou R, et al. Diagnosis and treatment of low back pain: a joint cular route should only be used if venous access is unob- has been effectively managed. Paracetamol or aspirin or
clinical practice guideline from the American College of Physi- tainable since it is relatively ineffective in shocked other NSAIDs are adequate for most purposes. Opioid
cians and the American Pain Society. Ann Intern Med 2007;
patients, complicates the enzymatic assessment of the inf- analgesics are relatively ineffective and are rarely needed.
147: 478–91. Correction. ibid. 2008; 148: 247–8. Available at:
http://www.annals.org/cgi/reprint/147/7/478.pdf (accessed arction, and may result in large haematomas when patients Burning mouth syndrome (stomatodynia; glossodynia) is
23/06/08) are given thrombolytics. Alternative analgesics include characterised by a burning sensation or other dysaesthesias
2. Koes BW, et al. Diagnosis and treatment of low back pain. BMJ nalbuphine or buprenorphine, although the latter may not of the oral mucosa in the absence of specific oral lesions.
2006; 332: 1430–4. produce pain relief as quickly as diamorphine. The cardio- It is often accompanied by xerostomia and altered taste.
3. Wilson JF. American College of Physicians. In the clinic: low vascular effects of pentazocine make it unsuitable for use Those treatments for which there is the best evidence of
back pain. Ann Intern Med 2008; 148: ITC5–1–ITC5–16. Also efficacy include topical therapy with clonazepam, system-
available at: http://www.annals.org/cgi/reprint/148/9/ITC5-1.pdf during or after myocardial infarction. Selective cyclo-oxy-
(accessed 15/08/08) genase-2 (COX-2) inhibitors and non-selective NSAIDs ic treatment with thioctic acid, SSRIs, or amisulpride, and
4. van Tulder M, et al. COST B13 Working Group on Guidelines (other than aspirin) should not be used in patients with cognitive therapy. Other treatments that may produce
for the Management of Acute Low Back Pain in Primary Care. acute myocardial infarction because of their known cardi- some benefit include capsaicin used topically or systemi-
Chapter 3. European guidelines for the management of acute ovascular risks5 (see Thrombotic Events under Adverse cally, topical lidocaine, or systemic therapy with other
nonspecific low back pain in primary care. Eur Spine J 2006; 15
(suppl 2): S169–S191. Also available at: http:// Effects of NSAIDs, p.97). antidepressants.
www.backpaineurope.org/web/files/WG1_Guidelines.pdf (ac- 1. Gershlick AH. The acute management of myocardial infarction. In addition, a large number of patients have a type of facial
cessed 23/06/08) Br Med Bull 2001; 59: 89–112. pain of unknown cause which is typically exacerbated by
5. Chou R, Huffman LH. Medications for acute and chronic low 2. Van de Werf F, et al. The Task Force on the Management of stress and can develop into a chronic debilitating disorder.
back pain: a review of the evidence for an American Pain Soci- Acute Myocardial Infarction of the European Society of Cardi-
ety/American College of Physicians clinical practice guideline. ology. Management of acute myocardial infarction in patients Many patients with such idiopathic facial pain respond to
Ann Intern Med 2007; 147: 505–14. presenting with ST-segment elevation. Eur Heart J 2003; 24: non-opioid analgesics, explanation, and reassurance. Anti-
6. Mens JMA. The use of medication in low back pain. Best Pract 2 8 – 6 6 . A l s o a v a i l a b l e a t : h t t p : / / w w w. e s c a r d i o . o rg / depressants such as the tricyclics are often of value. Anti-
Res Clin Rheumatol 2005; 19: 609–21. guidelines-surveys/esc-guidelines/GuidelinesDocuments/
guidelines-AMI-FT.pdf (accessed 29/08/08) epileptics, including carbamazepine and sodium val-
7. Roelofs PDDM, et al. Non-steroidal anti-inflammatory drugs 3. Antman EM, et al. ACC/AHA guidelines for the management of proate, and the oral lidocaine analogue mexiletine have
for low back pain. Available in The Cochrane Database of Sys- patients with ST-elevation myocardial infarction: a report of the been used as adjuncts to the tricyclics. Topical treatment
tematic Reviews; Issue 1. Chichester: John Wiley; 2008 (ac- American College of Cardiology/American Heart Association
cessed 21/07/08). with capsaicin has also been tried. Treatment needs to be
Task Force on Practice Guidelines (Writing Committee to Revise
8. Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001; the 1999 Guidelines for the Management of Patients With Acute continued for several months to avoid pain recurrence on
344: 363–70. Myocardial Infarction). Executive summary: Circulation 2004; withdrawal. Psychological treatments can also be helpful.
 Analgesics Anti-inflammatory Drugs and Antipyretics 9
Botulinum A toxin has been tried for the relief of facial fore and continuing for the duration of surgery or for sev- 7. Collins SL, et al. Antidepressants and anticonvulsants for dia-
betic neuropathy and postherpetic neuralgia: a quantitative sys-
pain associated with some disorders of the orofacial mus- eral days after amputation conferred more protection from tematic review. J Pain Symptom Manage 2000; 20: 449–58.
cles. long-term pain than blockade begun late intra-operatively 8. Johnson R, Patrick D, eds. Recommendations from the Interna-
References. or postoperatively. However, a randomised, double-blind, tional Herpes Management Forum management strategies
workshop: improving the management of varicella, herpes
1. Vickers ER, Cousins MJ. Neuropathic orofacial pain part 2–di- controlled study9 failed to show any benefit of pre-emptive zoster and zoster-associated pain (issued November 2002).
agnostic procedures, treatment guidelines and case reports. Aust analgesia using epidural blockade in such patients. A sub- Available at: http://www.ihmf.org/Library/monograph/
Endod J 2000; 26: 53–63. sequent review4 that included this study concluded that the m_11.pdf (accessed 23/06/08)
2. List T, et al. Pharmacologic interventions in the treatment of 9. Johnson RW, Dworkin RH. Treatment of herpes zoster and post-
temporomandibular disorders, atypical facial pain, and burning pre-emptive use of epidural block was of limited success. herpetic neuralgia. BMJ 2003; 326: 748–50.
mouth syndrome: a qualitative systematic review. J Orofac Pain 1. Wartan SW, et al. Phantom pain and sensation among British vet- 10. Dworkin RH, Schmader KE. Treatment and prevention of post-
2003; 17: 301–10. eran amputees. Br J Anaesth 1997; 78: 652–9. herpetic neuralgia. Clin Infect Dis 2003; 36: 877–82.
3. Lewis MA, et al. Management of neuropathic orofacial pain. 2. Nikolajsen L, Jensen TS. Phantom limb pain. Br J Anaesth 2001; 11. Dubinsky RM, et al. Practice parameter: treatment of posther-
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103 87: 107–16. petic neuralgia—an evidence-based report of the Quality Stand-
(suppl 1): S32.e1–S32.e24. 3. Flor H. Phantom-limb pain: characteristics, causes, and treat- ards Subcommittee of the American Academy of Neurology.
4. Patton LL, et al. Management of burning mouth syndrome: sys- ment. Lancet Neurol 2002; 1: 182–9. Neurology 2004; 63: 959–65. Also available at: http://
tematic review and management recommendations. Oral Surg 4. Halbert J, et al. Evidence for the optimal management of acute www.neurology.org/cgi/reprint/63/6/959 (accessed 29/08/08)
Oral Med Oral Pathol Oral Radiol Endod 2007; 103 (suppl 1): and chronic phantom pain: a systematic review. Clin J Pain 12. Douglas MW, et al. Tolerability of treatments for postherpetic
S39.e1–S39.e13. 2002; 18: 84–92. neuralgia. Drug Safety 2004; 27: 1217–33.
5. Flor H. Phantom-limb pain: characteristics, causes, and treat- 13. Chandra K, et al. Gabapentin versus nortriptyline in post-her-
5. Mínguez Serra MP, et al. Pharmacological treatment of burning petic neuralgia patients: a randomized, double-blind clinical tri-
mouth syndrome: a review and update. Med Oral Patol Oral Cir ment. Lancet Neurol 2002; 1: 182–9.
6. Manchikanti L, Singh V. Managing phantom pain. Pain Physi- al—the GONIP Trial. Int J Clin Pharmacol Ther 2006; 44:
Bucal 2007; 12: E299–E304. 358–63.
6. Sardella A. An up-to-date view on burning mouth syndrome. cian 2004; 7: 365–75.
7. Wiffen P, et al. Diagnostic and treatment issues in postamputa- 14. Khaliq W, et al. Topical lidocaine for the treatment of posther-
Minerva Stomatol 2007; 56: 327–35. petic neuralgia. Available in The Cochrane Database of System-
tion pain after landmine injury. Pain Med 2006; 7 (suppl 2):
atic Reviews; Issue 2. Chichester: John Wiley; 2007 (accessed
Pancreatic pain. Pain in pancreatitis (p.2361) can be se- S209–S212. 23/06/08).
vere and may require opioid analgesics. Concerns over the 8. Katz J. Prevention of phantom limb pain by regional anaesthesia.
Lancet 1997; 349: 519–20. Sickle-cell crisis. The management of pain of sickle-cell
long-term use of opioids in non-malignant pain should not 9. Nikolajsen L, et al. Randomised trial of epidural bupivacaine
prevent the patient being given effective analgesia which and morphine in prevention of stump and phantom pain in lower- crisis (p.1044) is similar to that of other forms of acute
may be achieved by following the general principles rec- limb amputation. Lancet 1997; 350: 1353–7. pain. The pain of mild crises may be controlled using oral
ommended by the WHO for treatment of cancer pain (see analgesics such as paracetamol, an NSAID, codeine, or di-
Postherpetic neuralgia. About 10% of patients who hydrocodeine. Partial agonist and antagonist opioids such
above); this involves giving non-opioid analgesics such as have had acute herpes zoster still experience neuropathic
NSAIDs for mild attacks, with or without antispasmodics as buprenorphine are not recommended to treat acute pain
pain resulting from peripheral nerve injury one month or before transfer to hospital.1 Crises severe enough to need
such as antimuscarinics, and progressing to ‘weak’ opioids more after the rash has healed. The elderly are the most
such as codeine, and ‘strong’ opioids including morphine hospital admission usually require the use of more potent
susceptible. The affected area (commonly head, neck, and parenteral opioid analgesics but NSAIDs may be useful as
according to the severity of pain. limbs) is extremely sensitive to any stimuli; even the pres- an adjunct for bone pain. In most centres, morphine is the
There has been some controversy about the appropriate sure of clothing can produce unbearable pain. Spontane- opioid of choice for moderate to severe pain. Some pa-
choice of opioid: traditionally, morphine and its deriva- ous remission occurs in many patients within a few tients appear to prefer pethidine but many clinicians2-7
tives have been avoided in favour of pethidine, in the belief months. However, in a small percentage of patients the avoid its use if possible as control of pain may be inade-
that they are more likely to cause spasm of the sphincter of pain can last for several years. quate and doses of pethidine needed to manage crises can
Oddi. However, the evidence supporting this has been Attempts have been made to prevent the development of lead to accumulation of its neuroexcitatory metabolite nor-
questioned. Some suggest that κ-receptor agonists such as postherpetic neuralgia. A meta-analysis1 concluded that, if pethidine and precipitate seizures (see also Effects on the
oxycodone may be of value. In addition, there is some ev- started within 72 hours of the onset of rash, aciclovir might Nervous System, p.114). UK guidelines8 recommend that
idence that pancreatic pain may have a neuropathic ele- reduce the incidence of residual pain at 6 months in some pethidine should only be used in exceptional circumstanc-
ment, and the use of an antiepileptic such as gabapentin, or patients. A subsequent analysis2 considered that there was es such as in patients hypersensitive to other opioids.
an SSRI such as paroxetine, may be considered for pain only marginal evidence of a decreased incidence of post- Diamorphine, fentanyl, hydromorphone, and methadone
syndromes associated with chronic pancreatitis. herpetic neuralgia with aciclovir treatment and that there have been used as alternatives to morphine. Nalbuphine
Analgesics are given before meals to help to alleviate the was no reduction in incidence with either famciclovir or may also be suitable.9 As the dose of opioid required to
postprandial exacerbation of pain. They should be given valaciclovir treatments. It is, however, generally agreed control the pain can vary considerably, not only during
on a regular basis and doses titrated for each patient. Pan- that antiviral treatment does reduce the duration of post- each episode but also from one episode to another and be-
creatic extracts may ease the pain but are otherwise re- herpetic neuralgia.2-4 Epidural injection of methylpred- tween individual patients, patient-controlled analgesia (see
served for those with symptomatic malabsorption. Coeliac nisolone with bupivacaine has been shown to reduce short- above) may be of help to manage the pain once initial pain
plexus block has been used for the relief of severe intrac- term pain from herpes zoster, but was ineffective in pre- relief has been obtained with loading doses of parenteral
table pain in some patients with chronic pancreatitis; it has venting postherpetic neuralgia in the longer term,5 and opioids;4,10,11 opioids used have included morphine and
also been used similarly in patients with cancer of the pan- evidence of the preventive value of corticosteroids is gen- fentanyl. The use of continuous epidural analgesia with
creas. However, the benefits of such a block are unclear. erally lacking.6 local anaesthetics alone or with opioids has been tried.
References. Various treatments have been tried once neuralgia devel- However, a randomised study12 of morphine for the man-
1. Thompson DR. Narcotic analgesic effects on the sphincter of ops.2-4,7-12 The value of conventional analgesics is limited agement of severe painful sickle-cell crises in children
Oddi: a review of the data and therapeutic implications in treat- because of the neuropathic character of the pain although showed that oral modified-release morphine was a safe
ing pancreatitis. Am J Gastroenterol 2001; 96: 1266–72.
2. Khalid A, Whitcomb DC. Conservative treatment of chronic
opioid analgesics have been used in refractory cases (see and effective alternative to continuous intravenous mor-
pancreatitis. Eur J Gastroenterol Hepatol 2002; 14: 943–9. below). Low-dose tricyclics such as amitriptyline, or in phine. Inhalation of a mixture of nitrous oxide and oxygen
3. El Kamar FG, et al. Metastatic pancreatic cancer: emerging strat- particular nortriptyline, have been widely used for treat- may be a useful analgesic during transfer to hospital.1,8
egies in chemotherapy and palliative care. Oncologist 2003; 8: ment, and appear to be of benefit in about half of all cases;4 1. Report of a working party of the Standing Medical Advisory
18–34.
4. Mitchell RMS, et al. Pancreatitis. Lancet 2003; 361: 1447–55. however, the antiepileptics gabapentin and pregabalin may Committee on sickle cell, thalassaemia and other haemoglobin-
now be preferred, and gabapentin is licensed for this indi- opathies. London: HMSO, 1993.
5. Ståhl C, et al. Managing pain in chronic pancreatitis: therapeutic 2. Pryle BJ, et al. Toxicity of norpethidine in sickle cell crisis. BMJ
value of opioid treatment. J Pain Palliat Care Pharmacother cation in a number of countries. A comparative study has 1992; 304: 1478–9.
2007; 21: 63–5. suggested that gabapentin is as effective as nortriptyline 3. Davies SC, Oni L. Management of patients with sickle cell dis-
6. Ceyhan GO, et al. Pancreatic pain. Best Pract Res Clin Gastro- ease. BMJ 1997; 315: 656–60.
enterol 2008; 22: 31–44. and better tolerated.13 Topical lidocaine has also been li- 4. Vijay V, et al. The anaesthetist’s role in acute sickle cell crisis.
censed for treatment of postherpetic neuralgia, but the ev- Br J Anaesth 1998; 80: 820–8.
Phantom limb pain. Phantom limb pain is associated idence for such use has been questioned.14 However, it is 5. Marlowe KF, Chicella MF. Treatment of sickle cell pain. Phar-
with an amputated limb and is more common when there likely to be better tolerated than the other main topical al- macotherapy 2002; 22: 484–91.
6. Stinson J, Naser B. Pain management in children with sickle cell
has been severe pre-amputation pain. It is frequently a ternative, capsaicin.4 Opioids, including methadone, mor- disease. Paediatr Drugs 2003; 5: 229–41.
mixture of neuropathic and other types of pain. Manage- phine, and oxycodone, are usually reserved for patients 7. Yaster M, et al. The management of pain in sickle cell disease.
ment may be difficult1-7 but in a survey of war veteran who fail to respond to tricyclics or gabapentin.9 Nerve Pediatr Clin North Am 2000; 47: 699–710.
amputees, for those who took any form of treatment for 8. Rees DC, et al. British Committee for Standards in Haematolo-
blocks and surgical techniques may provide temporary gy. Guidelines for the management of the acute painful crisis in
phantom limb pain, conventional analgesics such as pain relief, but results have generally been disappointing. sickle cell disease. Br J Haematol 2003; 120: 744–52. Also
NSAIDs or paracetamol with or without opioid analgesics Transcutaneous electrical nerve stimulation (TENS) has a v a i l a b l e a t : h t t p : / / w w w. b c s h g u i d e l i n e s . c o m / p d f /
sicklecelldisease_0503.pdf (accessed 23/06/08)
were reported as being satisfactory.1 The use of the WHO also been tried. Topical preparations of aspirin or indomet- 9. Buchanan ID, et al. Opioid selection during sickle cell pain cri-
analgesic ladder, as in cancer pain (see p.5) may guide the acin, have shown some promise. sis and its impact on the development of acute chest syndrome.
choice of analgesic;7 although the use of opioids has been 1. Jackson JL, et al. The effect of treating herpes zoster with oral Pediatr Blood Cancer 2005; 45: 716–24.
10. Grundy R, et al. Practical management of pain in sickling disor-
questioned in what is essentially a neuropathic pain syn- acyclovir in preventing postherpetic neuralgia: a meta-analysis.
ders. Arch Dis Child 1993; 69: 256–9.
drome, many consider them of potential value in phantom Arch Intern Med 1997; 157: 909–12.
2. Alper BS, Lewis PR. Does treatment of acute herpes zoster pre- 11. van Beers EJ, et al. Patient-controlled analgesia versus continu-
limb pain.6,7 Transcutaneous electrical nerve stimulation vent or shorten postherpetic neuralgia? J Fam Pract 2000; 49: ous infusion of morphine during vaso-occlusive crisis in sickle
cell disease, a randomized controlled trial. Am J Hematol 2007;
(TENS) was another method used by some and considered 255–64.
82: 955–60.
to be at least as effective as other therapies.1 Tricyclic anti- 3. Panlilio LM, et al. Current management of postherpetic neural-
gia. Neurolog 2002; 8: 339–50. 12. Jacobson SJ, et al. Randomised trial of oral morphine for pain-
depressants and antiepileptics may be of help for the neu- 4. Tyring SK. Management of herpes zoster and postherpetic neu- ful episodes of sickle-cell disease in children. Lancet 1997; 350:
1358–61.
ropathic components of the pain2,3,5 and some relief may ralgia. J Am Acad Dermatol 2007; 57 (6 suppl): S136–S42.
5. van Wijck AJM, et al. The PINE study of epidural steroids and
be obtained with sympathetic blocks. Intravenous keta- local anaesthetics to prevent postherpetic neuralgia: a ran- Trigeminal neuralgia. Trigeminal neuralgia (tic dou-
mine may also be of use.2,4,5 From a review8 of studies in- domised controlled trial. Lancet 2006; 367: 219–S24. loureux) is a neuropathic pain characterised by sudden,
vestigating the effect of regional anaesthesia in preventing 6. He L, et al. Corticosteroids for preventing postherpetic neural- brief, sharp, agonising, episodic pain in the distribution of
gia. Available in The Cochrane Database of Systematic Re-
phantom limb pain in patients undergoing lower-limb views; Issue 1. Chichester: John Wiley; 2008 (accessed one or more branches of the fifth cranial nerve. There may
amputation it appeared that epidural blockade started be- 23/06/08). be several episodes (lasting several seconds or minutes) a
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
10 Analgesics Anti-inflammatory Drugs and Antipyretics
day over a number of weeks, followed by a pain-free inter- Both physical means and antipyretics may be used to re- thonium is best avoided as it can itself precipitate malig-
val which may last for weeks or years. Trigeminal neural- duce body temperature in fever. Maintaining an adequate nant hyperthermia.
gia generally has a ‘trigger zone’ in which even a very light fluid intake is important. Fanning, removal of clothing, 1. National Collaborating Centre for Women’s and Children’s
stimulus such as a draught of air produces pain. In some and tepid sponging are often used,1-3 but they do not re- Health/NICE. Feverish illness in children: assessment and ini-
tial management in children younger than 5 years (issued May
cases firm pressure applied around but not to the zone it- duce the set-point of the hypothalamus, and lead to shiver- 2007). Available at: http://www.nice.org.uk/nicemedia/pdf/
self may help to relieve pain. Trigeminal neuralgia may be ing (rigor) or other adverse effects as the body tries to meet CG47Guidance.pdf (accessed 23/06/08)
idiopathic or may be secondary to nerve compression the raised set-point, and their value is therefore questiona- 2. Plaisance KI, Mackowiak PA. Antipyretic therapy: physiologic
rationale, diagnostic implications, and clinical consequences.
(such as that caused by a tumour), facial injury, or multiple ble;1 similarly, cold baths should not be used as they may Arch Intern Med 2000; 160: 449–56.
sclerosis. actually increase body temperature by inducing vasocon- 3. Meremikwu M, Oyo-Ita A. Physical methods for treating fever
striction, and the risks of a cold-induced pressor response in children. Available in The Cochrane Database of Systematic
Carbamazepine is the drug of choice for the management Reviews; Issue 2. Chichester: John Wiley; 2003 (accessed
of trigeminal neuralgia and initially may produce satisfac- should be borne in mind. Antipyretics appear mostly to 23/06/08).
tory pain relief in 70% or more of patients, although in- help return the set-point temperature to normal by inhibit- 4. Aronoff DM, Nielson EG. Antipyretics: mechanism of action
and clinical use in fever suppression. Am J Med 2001; 111:
creasingly large doses may be required.1-7 If pain relief is ing central synthesis and release of prostaglandin E2, 304–15.
inadequate phenytoin or baclofen may be added to car- which mediates the effect of endogenous pyrogens in the 5. Meremikwu M, Oyo-Ita A. Paracetamol for treating fever in
bamazepine therapy; these drugs may also be used alone in hypothalamus.4 This mechanism cannot lower the body children. Available in The Cochrane Database of Systematic
Reviews; Issue 2. Chichester: John Wiley; 2002 (accessed
patients intolerant of carbamazepine.4 Other antiepileptics temperature below normal, and antipyretics are ineffective 23/06/08).
such as gabapentin, lamotrigine, oxcarbazepine, valproate, against raised body temperature not associated with fever. 6. Sarrell EM, et al. Antipyretic treatment in young children with
and clonazepam have also been used in patients intolerant fever: acetaminophen, ibuprofen, or both alternating in a rand-
Choice of antipyretic in children has been widely debated. omized, double-blind study. Arch Pediatr Adolesc Med 2006;
of, or resistant to, carbamazepine.1-6 Evidence for the val- 160: 197–202.
ue of non-antiepileptic drugs in trigeminal neuralgia is The drugs most commonly used are paracetamol and ibu- 7. Hay AD, et al. Antipyretic drugs for children. BMJ 2006; 333:
mostly poor.8 profen; salicylates (including aspirin) are generally contra- 4–5.
indicated because of the possible link between their use 8. Wright AD, Liebelt EL. Alternating antipyretics for fever reduc-
In some patients drug therapy eventually fails to control tion in children: an unfounded practice passed down to parents
and the development of Reye’s syndrome. A systematic from pediatricians. Clin Pediatr (Phila) 2007; 46: 146–50.
the pain or produces unacceptable adverse effects and in-
review5 found inconsistent evidence to support the use of 9. Russell FM, et al. Evidence on the use of paracetamol in febrile
vasive procedures become necessary. These may include children. Bull WHO 2003; 81: 367–72.
paracetamol to reduce fever in children, since the number
the selective destruction of pain bearing nerve fibres with 10. Shann F. Antipyretics in severe sepsis. Lancet 1995; 345: 338.
of reliable studies was too low to be sure that it was effec- 11. Joint Working Group of the Research Unit of the Royal College
radiofrequency thermocoagulation, instillation of glycerol
tive. Although studies have found that ibuprofen was supe- of Physicians and the British Paediatric Association. Guidelines
(although the efficacy and safety of the procedure is debat- for the management of convulsions with fever. BMJ 1991; 303:
rior to paracetamol in terms of both efficacy and duration
able), gamma knife radiation, and microvascular decom- 634–6. Also available at: http://www.pubmedcentral.nih.gov/
of action, some of the doses of paracetamol were below picrender.fcgi?artid=1671115&blobtype=pdf (accessed
pression of the trigeminal nerve root.2,3,6,7 24/06/08)
those recommended in the UK and NICE did not consider
1. Zakrzewska JM. Trigeminal neuralgia. Prim Dent Care 1997; 4: 12. Uhari M, et al. Effect of acetaminophen and of low intermittent
17–19. that either drug had a significant advantage over the other.1 doses of diazepam on prevention of recurrences of febrile sei-
2. Joffroy A, et al. Trigeminal neuralgia: pathophysiology and Alternation of the two may be more effective than either zures. J Pediatr 1995; 126: 991–5.
treatment. Acta Neurol Belg 2001; 101: 20–5. alone6 but again this is controversial.1,7,8 13. Anonymous. Prophylactic paracetamol with childhood immuni-
3. Nurmikko TJ, Eldridge PR. Trigeminal neuralgia—pathophysi- sation? Drug Ther Bull 1990; 28: 73–4.
ology, diagnosis and current treatments. Br J Anaesth 2001; 87: 14. Simon HB. Hyperthermia. N Engl J Med 1993; 329: 483–7.
117–32.
Antipyretics should not be given to all children with fever, 15. Slovis CM. Hyperthermia. N Engl J Med 1994; 330: 218–19.
4. Rozen TD. Antiepileptic drugs in the management of cluster but only to those in obvious discomfort or distress.1,9 It has 16. Duthie DJR. Heat-related illness. Lancet 1998; 352: 1329–30.
headache and trigeminal neuralgia. Headache 2001; 41 (suppl been suggested that the use of antipyretics might prolong 17. Bouchama A, Knochel JP. Heat stroke. N Engl J Med 2002; 346:
1978–88.
1): S25–S32. infection,2 and that in severe infection the use of antipyret-
5. Sindrup SH, Jensen TS. Pharmacotherapy of trigeminal neural-
gia. Clin J Pain 2002; 18: 22–7.
ics might increase mortality:10 WHO has10 recommended Musculoskeletal and Joint Disorders
6. Scrivani SJ, et al. Trigeminal neuralgia. Oral Surg Oral Med that in developing countries antipyretics should not be giv-
Oral Pathol Oral Radiol Endod 2005; 100: 527–38. en routinely to children with fever but should be reserved
The rheumatic disorders are painful disorders affect-
7. Bennetto L, et al. Trigeminal neuralgia and its management. for those with severe discomfort or high fever. In the UK, ing primarily the joints and related structures of the
Abridged version: BMJ 2007; 334: 201–5. Full version: http://
the Joint Committee on Vaccination and Immunisation musculoskeletal system, but there may also be wide-
www.bmj.com/cgi/reprint/334/7586/201.pdf (accessed
23/06/08) recommends antipyretic therapy to treat post-immunisa- spread involvement of other systems. The term arthritis
8. He L, et al. Non-antiepileptic drugs for trigeminal neuralgia. tion fever developing after some vaccines. However, if the is used when the disease is largely confined to the
Available in The Cochrane Database of Systematic Reviews; Is- fever persists after the second dose of antipyretic medical joints. Some of the most common forms of arthritis are
sue 3. Chichester: John Wiley; 2006 (accessed 23/06/08).
advice should be sought. discussed in this section and these include rheumatoid
Increased Body Temperature arthritis, osteoarthritis, juvenile idiopathic arthritis, and
Antipyretics have also been given as prophylaxis against
The hypothalamus is the centre of the thermoregulato- the spondyloarthropathies such as ankylosing spond-
febrile convulsions, especially in those with a history of
ry system and is responsible for maintaining the body such seizures or in those with epilepsy. However, antipy- ylitis. Other conditions that are associated with arthritis
temperature at a set point (known as the set-point retic therapy does not appear to prevent recurrence of and which are discussed elsewhere include gout
temperature) which is normally 37°. Mechanisms that febrile convulsions (p.470).1,11,12 There is also little to sup- (p.552) and SLE (p.1513).
produce or conserve body heat include passive heat port the use of antipyretics for prophylaxis of post-immu- The names soft-tissue rheumatism (see below) and
absorption from the environment, peripheral vasocon- nisation fever although some suggest offering it to infants non-articular rheumatism have been used to de-
striction, and thermogenic processes such as metabolic at higher risk of seizures receiving diphtheria-tetanus-per- scribe a number of painful conditions associated with
reactions and shivering. Heat loss is achieved mainly tussis or polio immunisation.13 disease of the structures that surround a joint. For a dis-
through sweating and peripheral vasodilatation. Vari- Recommendations for management of fever in adults are cussion of the management of low back pain, see
ous states may lead to an abnormal increase in body similar to those for children,2,4 although aspirin may also above.
temperature. be used.
Juvenile idiopathic arthritis
Hyperthermia may produce body temperatures greater Juvenile idiopathic arthritis (juvenile chronic arthritis) is a
Fever and hyperthermia than 41°. These high temperatures are life-threatening and
As mentioned above, body temperature is normally regu- term used to describe a clinically heterogeneous group of
need to be lowered immediately. Antipyretics are ineffec- idiopathic arthritides occurring in children under 16 years
lated by the hypothalamus. Fever (pyrexia) is a controlled tive since the high temperatures are a result of thermoreg-
increase in body temperature due to an elevated hypotha- of age; subtypes include systemic arthritis, oligoarthritis
ulatory failure. One of the most rapid and effective means (particularly of leg joints), and polyarthritis, either positive
lamic set-point temperature. Common reasons for this of cooling is to immerse the patient in very cold water but
include infections, inflammatory disorders, neoplastic or negative for rheumatoid factor.1,2
core temperature should be monitored to avoid inducing
disease, and some drug treatment. Hyperthermia (hyper- hypothermia.14 Evaporative cooling methods may be Treatment involves many of the same drugs used for rheu-
pyrexia) implies a disturbance of thermoregulatory con- more efficient.15 Intravenous or intraperitoneal adminis- matoid arthritis in adults (see below), although there may
trol. It is caused by external factors such as injury to the tration of cool fluids, gastric lavage or enemas with ice wa- be limited evidence for their use in children.1-8 Appropri-
hypothalamus, heat stroke following defective heat loss ter have also been used.14,16 ate management will depend on the subtype of disease, but
(as occurs in dehydration or excessive heat production fol- there is no definitive consensus on the drugs of choice.
lowing strenuous activities), excessive dosage of some When hyperthermia is associated with muscle rigidity and • The NSAIDs have been a mainstay of treatment for
drugs, or a reaction to certain drugs such as anaesthetics fulminant hypermetabolism of skeletal muscle, as in the many years, and continue to be important.1,2 Most chil-
(malignant hyperthermia, p.1896) or antipsychotics (neu- neuroleptic malignant syndrome and malignant hyperther- dren begin therapy with an NSAID,1 and they may be
roleptic malignant syndrome, p.972). Underlying ther- mia, temperature reductions may be obtained using the particularly useful in oligoarthritis.2 Naproxen, ibupro-
moregulatory defects may be a particular problem in sed- muscle relaxant dantrolene. There is also anecdotal evi- fen, or indometacin are among the most often used.1 As-
entary elderly subjects. dence that dantrolene may produce beneficial effects for pirin is now rarely prescribed,8 although in many coun-
Whenever possible the underlying cause of fever should the treatment of similar symptoms resulting from poison- tries juvenile idiopathic arthritis remains one of its few
be identified and treated.1 Body temperatures up to 41° are ing with various agents. However, dantrolene is not an ef- licensed indications in children.
relatively harmless2 and it is not clear if there is any value fective treatment for all types of hyperthermia and rigidity • Intra-articular injections of a corticosteroid (often tri-
in treating fever at lower temperatures,1 but some groups accompanying poisoning. Although dantrolene has been amcinolone hexacetonide) are rapidly effective, and
may be more vulnerable, such as young children, pregnant tried in patients with heat stroke, there is no evidence that well tolerated, and are often used in oligoarthritis with,
women, or patients who are already dehydrated or mal- it affects outcome.17 In severe cases of hyperthermia when or instead of, NSAIDs;1,2,5 they may reduce the devel-
nourished or those with cardiac, respiratory, or neurologi- neuromuscular hyperactivity may also impair ventilation, opment of deformity secondary to contracture.1 They
cal diseases. a neuromuscular blocker has been used, although suxame- also have a role in the management of disease flare in
 Analgesics Anti-inflammatory Drugs and Antipyretics 11
patients already taking second-line drugs, although it is and cartilage at the joint margins (osteophytes).1-4 These Surgery, including joint replacement, is of great benefit to
unclear whether multiple intra-articular injections changes result in pain, stiffness (especially after inactivity) patients with severe osteoarthritis that cannot be effective-
would be preferable to systemic corticosteroids in pa- and reduced mobility,1-6 although patients with changes ly managed by physical or medical therapy.2-6,8
tients with polyarthritis.5 characteristic of osteoarthritis are often asymptomatic.4,6 1. Felson DT. Osteoarthritis of the knee. N Engl J Med 2006; 354:
Increased loading of the joint, and mechanical factors such 841–8. Correction. ibid.; 2520.
Moderate or high-dose systemic corticosteroids are 2. Hunter DJ, Felson DT. Osteoarthritis. BMJ 2006; 332: 639–42.
more generally reserved for patients with systemic ar- as misalignment and muscle weakness, contribute to joint 3. Lane NE. Clinical practice. Osteoarthritis of the hip. N Engl J
thritis whose disease is not controlled by NSAIDs. In damage and loss of function.1,2,4 The joints most often af- Med 2007; 357: 1413–21.
fected are hands, hips, and knees.4,6 4. Hunter DJ. American College of Physicians. In the clinic: oste-
other subtypes, the adverse effects of systemic therapy oarthritis. Ann Intern Med 2007; 147: ITC8–1–ITC8–16. Also
are likely to outweigh the benefits. A course of low-dose Current treatment for osteoarthritis is not curative, and available at: http://www.annals.org/cgi/reprint/147/3/
prednisone might be considered for reduction of pain ITC8-1.pdf (accessed 24/06/08)
management is largely concerned with relief of pain and 5. American College of Rheumatology Subcommittee on Osteoar-
and stiffness in patients with severe polyarthritis who maintenance of joint function.1-6 thritis Guidelines. Recommendations for the medical manage-
are unresponsive to other drugs, or awaiting response to ment of osteoarthritis of the hip and knee: 2000 update. Arthritis
slow-acting second-line treatments.1 Physical methods of treatment may be preferred initially, Rheum 2000; 43: 1905–15. Also available at:
and include physiotherapy, heat and cold therapy, exercis- http://www.rheumatology.org/publications/guidelines/
• The second-line treatment of choice in children with es, splinting, correction of misalignment, and weight re- oa-mg-mt/oa-mgmt.asp (accessed 23/06/08)
persistent active arthritis is methotrexate.1,2,6,8 Like duction in the obese.1-8 Acupuncture may also be tried, and
6. Raj N, Jones A. Osteoarthritis. In: Snaith ML, ed. ABC of rheu-
matology. 3rd ed. London: BMJ Publishing Group, 2004: 34–8.
several other second-line drugs it is of less benefit in appears to be of benefit in improving pain and functional- 7. Brosseau L, et al. Thermotherapy for treatment of osteoarthritis.
systemic arthritis than in polyarthritis or refractory oli- ity in knee osteoarthritis.9 Transcutaneous electrical nerve
Available in The Cochrane Database of Systematic Reviews; Is-
goarthritis.8 Improvement may take up to 12 weeks to sue 4. Chichester: John Wiley; 2003 (accessed 23/06/08).
stimulation (TENS) may also be of benefit.8,10 8. National Collaborating Centre for Chronic Conditions/NICE.
be seen.1 Osteoarthritis: national clinical guideline for care and manage-
• The so-called biological therapies have become in- For the management of pain, paracetamol is recommended ment in adults (issued February 2008). Available at: http://
creasingly important in managing more severe or refrac- as the drug of first choice.1-6,8 Despite its benefits it has www.nice.org.uk/nicemedia/pdf/CG059FullGuideline.pdf (ac-
cessed 22/07/08)
tory forms of juvenile idiopathic arthritis.1,2,4,8 The tu- been shown to be less effective than an NSAID in patients 9. Scharf H-P, et al. Acupuncture and knee osteoarthritis: a three-
mour necrosis factor inhibitor etanercept, which is with osteoarthritis,11 and the latter may therefore be con- armed randomized trial. Ann Intern Med 2006; 145: 12–20.
licensed for paediatric use in many countries, produces sidered as an alternative first-line treatment.2,4 However, 10. Osiri M, et al. Transcutaneous electrical nerve stimulation for
knee osteoarthritis. Available in The Cochrane Database of Sys-
excellent responses in many patients with polyarthritis, because of the risk of potentially serious toxicity in a pre- tematic Reviews; Issue 4. Chichester: John Wiley; 2000 (ac-
particularly those who are rheumatoid-factor positive.8 dominantly elderly group of patients, it is generally con- cessed 23/06/08).
sidered that a low-dose NSAID should only be added or 11. Towheed TE, et al. Acetaminophen for osteoarthritis. Available
Like methotrexate, it may be less effective in those with in The Cochrane Database of Systematic Reviews; Issue 1.
systemic juvenile idiopathic arthritis.2 Infliximab, al- substituted in patients with an inadequate response to pa- Chichester: John Wiley; 2006 (accessed 23/06/08).
though unlicensed, also seems to be of benefit,1,2,8 and racetamol alone,2,4,5 and the long-term use needed for os- 12. Bjordal JM, et al. Non-steroidal anti-inflammatory drugs, in-
teoarthritis management may be problematic.12 Like other cluding cyclo-oxygenase-2 inhibitors, in osteoarthritic knee
may be more effective than etanercept in the treatment pain: meta-analysis of randomised placebo controlled trials.
of associated uveitis.2 Other drugs that have been tried treatments NSAIDs do not slow the disease process, and BMJ 2004; 329: 1317–20 .
with some evidence of benefit include abatacept, adali- there has even been a concern that some NSAIDs such as 13. Lin J, et al. Efficacy of topical non-steroidal anti-inflammatory
indometacin might accelerate it.6 drugs in the treatment of osteoarthritis: meta-analysis of ran-
mumab, tocilizumab, and anakinra;1,2,8 there is some evi- domised controlled trials. BMJ 2004; 329: 324–6.
dence that the latter, an interleukin-1 receptor antago- In order to reduce the risk of gastrointestinal toxicity with 14. NICE. Guidance on the use of cyclo-oxygenase (Cox) II selec-
tive inhibitors, celecoxib, rofecoxib, meloxicam and etodolac
nist, may be more effective than the tumour necrosis NSAIDs, use of a gastroprotective drug such as a proton for osteoarthritis and rheumatoid arthritis (issued July 2001).
factor inhibitors in treating patients with systemic arthri- pump inhibitor or misoprostol has been recommended.1-5,8 Available at: ht tp:/ /www.nice.org.uk/nicemedia/pdf/
tis.2 The use of topical NSAIDs has also been advocated,4,6,8 coxiifullguidance.pdf (accessed 23/06/08)
15. Goodwin JL, et al. The use of opioids in the treatment of oste-
• Many other drugs have been tried in juvenile idiopath- although a meta-analysis13 in 2004 found little evidence of oarthritis: when, why, and how? Curr Pain Headache Rep 2005;
ic arthritis, often on the basis of effectiveness in adults. long-term benefit. In the light of concerns about cardiovas- 9: 390–8.
cular safety, treatment with NSAIDs such as celecoxib that 16. Fidelix TSA, et al. Diacerein for osteoarthritis. Available in The
Sulfasalazine may be of benefit in late-onset Cochrane Database of Systematic Reviews; Issue 1. Chichester:
oligoarthritis1 but adverse effects are often trouble- are selective inhibitors of cyclo-oxygenase-2 (COX-2) is John Wiley; 2006 (accessed 23/06/08).
some.8 Concern about adverse effects may also have limited14 to those patients considered to be at high risk of 17. Brandt KD, et al. Effects of doxycycline on progression of oste-
oarthritis: results of a randomized, placebo-controlled, double-
limited the use of cytotoxic and immunosuppressant developing serious gastrointestinal problems if given a blind trial. Arthritis Rheum 2005; 52: 2015–25.
drugs other than methotrexate, and there are few con- non-selective NSAID and who do not have pre-existing 18. Iqbal I, Fleischmann R. Treatment of osteoarthritis with anakin-
trolled studies,8 although benefit has been reported with cardiovascular risk factors (see p.97). ra. Curr Rheumatol Rep 2007; 9: 31–5.
19. Cicero AF, Laghi L. Activity and potential role of licofelone in
leflunomide in polyarticular disease.1,8 Thalidomide has In patients in whom paracetamol and/or NSAIDs are inef- the management of osteoarthritis. Clin Interv Aging 2007; 2:
been suggested for treatment-resistant systemic arthri- fective or not tolerated, addition of an opioid analgesic 73–9.
tis.1 In very severe unremitting disease, autologous bone 20. Arroll B, Goodyear-Smith F. Corticosteroid injections for oste-
may be appropriate;2,3,5,8,15 codeine or dihydrocodeine are oarthritis of the knee: meta-analysis. BMJ 2004; 328: 869–70.
marrow transplantation has been tried.1,7,8 often used as combinations with paracetamol, and there is 21. Bellamy N, et al. Intraarticular corticosteroid for treatment of
Drug treatment aimed at the complications of disease, osteoarthritis of the knee. Available in The Cochrane Database
evidence of benefit with tramadol, but more potent opioids of Systematic Reviews; Issue 2. Chichester: John Wiley; 2006
rather than the disease process itself, may be needed. There such as hydrocodone, oxycodone, transdermal fentanyl, or (accessed 23/06/08).
is some evidence that bisphosphonates may be useful in morphine, may have a role in a selected subgroup of pa- 22. Lo GH, et al. Intra-articular hyaluronic acid in treatment of knee
controlling low bone mineral density and fragility frac- osteoarthritis: a meta-analysis. JAMA 2003; 290: 3115–21.
tients.15 23. Bellamy N, et al. Viscosupplementation for the treatment of os-
tures associated with juvenile idiopathic arthritis.1,9 teoarthritis of the knee. Available in The Cochrane Database of
The anthraquinone derivative diacerein has been widely
Growth hormone has also been widely used to moderate Systematic Reviews; Issue 2. Chichester: John Wiley; 2006 (ac-
used in some countries, and appears to produce a small but cessed 23/06/08).
the severe growth retardation that is often seen.1 Topical
consistent benefit in the treatment of osteoarthritis.16 Top- 24. Rossnagel K, et al. Klinische Wirksamkeit von Hagebuttenpul-
treatment with glucocorticoids and mydriatics may be ver bei Patienten mit Arthrose: eine systematische Ubersicht.
needed for eye disease.1 ical capsaicin also produces some relief of pain.1,4,5,8 There MMW Fortschr Med 2007; 149: 51–6.
are some interesting data17 to suggest that doxycycline 25. Christensen R, et al. Symptomatic efficacy of avocado-soybean
Physiotherapy and occupational therapy are also important may have a favourable effect on the progression of oste- unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-
components of disease management, and surgery may be oarthritis, which might open the way for the development analysis of randomized controlled trials. Osteoarthritis Carti-
needed in selected cases.1 lage 2008; 16: 399–408.
of disease-modifying drugs. Experimental therapies in- 26. Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two
1. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007; clude anakinra 18 and the combined cyclo-oxygen- in combination for painful knee osteoarthritis. N Engl J Med
369: 767–78. 2006; 354: 795–808.
2. Haines KA. Juvenile idiopathic arthritis: therapies in the 21st ase/lipoxygenase inhibitor licofelone.19 27. Towheed TE, et al. Glucosamine therapy for treating osteoar-
century. Bull NYU Hosp Jt Dis 2007; 65: 205–11. thritis. Available in The Cochrane Database of Systematic Re-
3. Cron RQ. Current treatment for chronic arthritis in childhood.
Systemic corticosteroids have no place in the management views; Issue 2. Chichester: John Wiley; 2005 (accessed
Curr Opin Pediatr 2002; 14: 684–7. of osteoarthritis. Intra-articular injection of a corticosteroid 23/06/08).
4. Wilkinson N, et al. Biologic therapies for juvenile arthritis. Arch produces short-term relief of pain and inflamma- 28. Towheed TE, Anastassiades T. Glucosamine therapy for oste-
oarthritis: an update. J Rheumatol 2007; 34: 1787–90.
Dis Child 2003; 88: 186–91. tion,2-4,8,20,21 and may be useful for acute exacerbations. 29. Reichenbach S, et al. Meta-analysis: chondroitin for osteoar-
5. Cleary AG, et al. Intra-articular corticosteroid injections in juve-
nile idiopathic arthritis. Arch Dis Child 2003; 88: 192–6. Triamcinolone hexacetonide appears to be more effective thritis of the knee or hip. Ann Intern Med 2007; 146: 580–90.
6. Ramanan AV, et al. Use of methotrexate in juvenile idiopathic than betamethasone.21 There may also be some benefit
arthritis. Arch Dis Child 2003; 88: 197–200. from intra-articular injection of hyaluronic acid, to im- Rheumatoid arthritis
7. Wedderburn LR, et al. Autologous haematopoietic stem cell prove the viscosity and elasticity of the synovial fluid;22,23 Rheumatoid arthritis is a common chronic systemic in-
transplantation in juvenile idiopathic arthritis. Arch Dis Child
2003; 88: 201–5. improvement may be longer lasting than with intra-articu- flammatory disease that results in progressive disability
8. Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic lar corticosteroids.21 and increased mortality. Early disease is characterised pri-
arthritis. JAMA 2005; 294: 1671–84.
9. Thornton J, et al. Systematic review of effectiveness of bisphos- Alternative and complementary therapies have been wide- marily by inflammation of the synovium (the inner mem-
phonates in treatment of low bone mineral density and fragility ly used in osteoarthritis.2 Powdered rose hip has been re- brane of the capsule of synovial joints); as the disease
fractures in juvenile idiopathic arthritis. Arch Dis Child 2006; ported to be of benefit,24 as has a mixture of unsaponifiable progresses the patient suffers destruction of cartilage and
91: 753–61.
fractions from avocado and soya oils (avocado-soybean bone. Extra-articular features commonly include general
unsaponifiables; ASU).25 Particular attention has focused malaise, fatigue, weight loss, fever, and anaemia. More se-
Osteoarthritis on the use of oral glucosamine and chondroitin. Results, vere disease may be associated with vasculitis, pericardi-
Osteoarthritis is the clinical and pathological outcome of a however, have been ambiguous:26-29 overall it is not clear tis, pleurisy, pleural effusion, pulmonary interstitial fibro-
range of disorders that cause structural and functional fail- to what extent these therapies have a benefit over placebo, sis, peripheral neuropathies, subcutaneous and pulmonary
ure of synovial joints. It is characterised by involvement of but there is some evidence that combined treatment may nodules, scleritis, and Sjögren’s syndrome. Palindromic
the entire joint, with loss and erosion of articular cartilage, be useful in the subset of patients with moderate to severe rheumatism is characterised by repeated episodes of arthri-
subchondral bone changes, meniscal degeneration, mild to knee pain.26 Evidence for chondroitin seems particularly tis and periarthritis without fever; the joints appear normal
moderate synovial inflammation, and outgrowth of bone weak.29 between attacks.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
12 Analgesics Anti-inflammatory Drugs and Antipyretics
The severity and course of rheumatoid arthritis varies tients who have failed treatment with two conventional The treatment of rheumatoid arthritis during pregnancy
greatly between patients. Some have brief attacks with lit- DMARDs,17,19 but others permit earlier introduction, for presents its own problems; some of the most effective
tle or no disease progression, but the majority will have example after failure of the first conventional DMARDs such as methotrexate and leflunomide have ter-
slowly progressive joint destruction and deformity despite DMARD.8,16,20 Other classes of biological therapy are atogenic properties, and for others, including the biologi-
intermittent relapses and remissions; a few patients may likely to be reserved for patients in whom TNF-α inhibi- cal therapies, there is little evidence.33,34 Hydroxychloro-
have very severe and rapidly progressive disease. Because tors are ineffective or contra-indicated, as is currently the quine, and perhaps azathioprine and sulfasalazine, may be
irreversible joint damage occurs early in the course of dis- case with rituximab.18,21 relatively safe to use, but it is important to weigh benefit
ease, rapid diagnosis and institution of treatment aimed at There is also some evidence in favour of beginning thera- against risk for each individual case.33
preventing progression is crucial.1-3 Although there is no py with a combination of DMARDs, and subsequently 1. O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N
cure, remission or substantial slowing of the disease proc- Engl J Med 2004; 350: 2591–2602.
‘stepping down’ once control is achieved.1,4,5,8,9,22,23 The 2. Doan T, Massarotti E. Rheumatoid arthritis: an overview of new
ess is increasingly seen as an achievable goal in the major- large, multicentre BeSt study found that although initial and emerging therapies. J Clin Pharmacol 2005; 45: 751–62.
ity of patients.4,5 combination therapy (methotrexate and infliximab, or 3. Nurmohamed MT, Dijkmans BAC. Efficacy, tolerability and
cost effectiveness of disease-modifying antirheumatic drugs
The choice of drugs for relief of pain depends upon the methotrexate, sulfasalazine, and tapered high-dose pred- and biologic agents in rheumatoid arthritis. Drugs 2005; 65:
severity of symptoms. In mild cases an analgesic such as nisone) produced earlier clinical improvement and less 661–94.
4. Emery P. Treatment of rheumatoid arthritis. BMJ 2006; 332:
paracetamol (with codeine if needed) may be all that is re- progression of joint damage, the ultimate clinical improve- 152–5.
quired but most patients prefer an NSAID; although these ment was similar in patients assigned to sequential mono- 5. Smolen JS, et al. New therapies for treatment of rheumatoid ar-
are thought to have an advantage because of their anti-in- therapy or ‘step-up’ therapy.24 There is a concern that thritis. Lancet 2007; 370: 1861–74.
6. Wienecke T, Gøtzsche PC. Paracetamol versus nonsteroidal
flammatory effects, the clinical evidence for this has been combination therapy may expose patients to an increased anti-inflammatory drugs for rheumatoid arthritis. Available in
questioned.6 There is little apparent difference between the risk of toxicity,22 although the BeSt study did not find this The Cochrane Database of Systematic Reviews; Issue 1. Chich-
various NSAIDs in terms of anti-inflammatory activity, to be the case.24 Combinations of TNF-α inhibitors with ester: John Wiley; 2004 (accessed 23/06/08).
7. MHRA. Updated advice on the safety of selective COX-2 inhib-
but patient responses vary widely. When starting an other biological response modifiers such as anakinra or itors. Message from Professor G Duff, Chairman of Committee
NSAID the dose is gradually increased to the recommend- abatacept are not advisable, because of an increased risk of on Safety of Medicines (issued 17th February, 2005). Available
ed maximum over 1 to 2 weeks; if the response is inade- serious infection.5,16 at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_
FILE&dDocName=CON019458&RevisionSelectionMethod=
quate after a total of about 4 weeks, or if adverse effects are Since rheumatoid arthritis is a chronic disease, treatment LatestReleased (accessed 23/06/08)
intolerable, other NSAIDs are tried. In the light of con- may need to be very prolonged, but evidence of the long- 8. American College of Rheumatology Subcommittee on Rheuma-
cerns about cardiovascular safety, treatment with NSAIDs toid Arthritis. Guidelines for the management of rheumatoid ar-
term tolerability and efficacy of DMARDs is patchy. Stud- thritis. Arthritis Rheum 2002; 46: 328–46. Also available at:
such as celecoxib that are selective inhibitors of cyclo-oxy- ies have suggested that many DMARDs are stopped after http://www.rheumatology.org/publications/guidelines/
genase-2 (COX-2) is limited to those patients considered a few years, usually because of a decline in efficacy rather
raguidelines02.pdf (accessed 23/06/08)
to be at high risk of developing serious gastrointestinal 9. Luqmani R, et al. British Society for Rheumatology and British
than adverse events.25 Health Professionals in Rheumatology guideline for the man-
problems if given a non-selective NSAID and who do not agement of rheumatoid arthritis (the first two years). Rheuma-
have pre-existing cardiovascular risk factors7 (see p.97). Addition of corticosteroids to DMARD therapy may be tology (Oxford) 2006; 45: 1167–9. Full guideline available at:
Topical analgesics such as NSAIDs or capsaicin, or rube- useful in early disease to control synovitis, or as bridging http://rheumatology.oxfordjournals.org/cgi/data/kel215a/
DC1/1 (accessed 23/06/08)
facients may provide slight relief of pain but their role, if therapy when starting or increasing DMARDs, since they 10. Tugwell P. International consensus recommendations on cy-
any, is unclear. produce rapid symptomatic control.9 Although they pro- closporin use in rheumatoid arthritis. Drugs 1995; 50: 48–56.
duce bone loss, this may be outweighed (at least short- 11. Cush JJ, et al. US consensus guidelines for the use of cy-
Once the diagnosis is confirmed and severity and progres- closporin A in rheumatoid arthritis. J Rheumatol 1999; 26:
term) by their beneficial effects on the disease process: 1176–86.
sion of the disease have been assessed, introduction of a
there is good evidence that adding a corticosteroid to treat- 12. Felson DT, et al. The comparative efficacy and toxicity of sec-
disease-modifying antirheumatic drug (DMARD)
ment reduces the progression of joint erosion.26 Short-term ond-line drugs in rheumatoid arthritis. Arthritis Rheum 1990;
should take place as early as possible.1-4,8 Although opin- 33: 1449–61.
and moderate-term intermittent use of relatively low doses 13. Felson DT, et al. Use of short-term efficacy/toxicity tradeoffs to
ions vary, there is an increasing trend to aggressive man-
has therefore been suggested (not exceeding the equivalent select second-line drugs in rheumatoid arthritis: a metaanalysis
agement in early disease, with tight control of the disease of published clinical trials. Arthritis Rheum 1992; 35: 1117–25.
of 15 mg of prednisolone daily).27,28 However, prolonged
process.4,5,9 14. Capell HA, et al. Second line (disease modifying) treatment in
therapy is associated with significant adverse effects, and rheumatoid arthritis: which drug for which patient? Ann Rheum
Available DMARDs include antimalarials (hydroxychlo- long-term use is not considered justified.9 Intra-articular Dis 1993; 52: 423–8.
roquine), sulfasalazine, gold compounds (auranofin, sodi- injection is recommended for acute flares, and may be par- 15. Donahue KE, et al. Systematic review: comparative effective-
ness and harms of disease-modifying medications for rheuma-
um aurothiomalate), penicillamine, conventional immu- ticularly effective when combined with aggressive toid arthritis. Ann Intern Med 2008; 148: 124–34.
nosuppressants (methotrexate, azathioprine, ciclosporin, DMARD therapy.9 16. Furst DE, et al. Updated consensus statement on biological
cyclophosphamide, and leflunomide), and so-called bio- agents for the treatment of rheumatic diseases, 2007. Ann
There is little good evidence to support most other drugs Rheum Dis 2007; 66 (suppl 3): iii2–iii22. Correction. ibid. 2008;
logical therapies, including the tumour necrosis factor-α 67: 280.
tried in rheumatoid arthritis.8 Meta-analysis29 has con-
(TNF-α) inhibitors (adalimumab, etanercept, and inflixi- 17. NICE. Adalimumab, etanercept and infliximab for the treatment
firmed that tetracyclines, and in particular minocycline, of rheumatoid arthritis (issued October 2007). Available at:
mab), co-stimulation blockers (abatacept), interleukin-1
can produce some reduction in disease activity; effects on http://www.nice.org.uk/nicemedia/pdf/TA130guidance.pdf (ac-
receptor antagonists (anakinra), and B-cell-targeted anti- cessed 23/06/08)
serological markers appear to be more marked than clini-
bodies (rituximab). It is thought that most DMARDs in- 18. NICE. Rituximab for the treatment of rheumatoid arthritis (is-
cal improvements in tender and swollen joints. The effects sued August 2007). Available at: http://www.nice.org.uk/
hibit the release or activity of cytokines involved in main-
may be greater in patients with early disease. Much re- nicemedia/pdf/TA126guidance.pdf (accessed 23/06/08)
taining the inflammatory process, although other actions 19. Ledingham J, Deighton C. British Society for Rheumatology
search has been conducted into immunomodulators and
may also contribute. Since any therapeutic effect may not Standards, Guidelines and Audit Working Group. Update on the
immunotherapy. Although alternative immunosuppres- British Society for Rheumatology guidelines for prescribing
be apparent for 4 to 6 months, treatment should continue TNFα blockers in adults with rheumatoid arthritis (update of
sants such as mycophenolate mofetil and tacrolimus have
for at least 6 months before considered ineffective. previous guidelines of April 2001). Rheumatology (Oxford)
been tried, most interest in recent years has surrounded 2005; 44: 157–63. Also available at:
There is evidence of disease modifying effect for meth- new biological therapies. Matrix metalloproteinase inhibi- http://rheumatology.oxfordjournals.org/cgi/reprint/44/2/
otrexate, sulfasalazine, leflunomide, and intramuscular tors have proved disappointing, but new TNF-α inhibitors 157.pdf (accessed 23/06/08)
gold, with less compelling data for hydroxychloroquine, 20. Meyer O, et al. Clinical practice format for choosing a second-
such as certolizumab pegol and golimumab, the inter- line disease modifying anti-rheumatic drug in early rheumatoid
penicillamine, oral gold, ciclosporin, and azathioprine.9-15 leukin-6 receptor antagonist tocilizumab, and modulators arthritis after failure of 6 months’ first-line DMARD therapy.
Concerns about toxicity or effectiveness mean that gold of B-cell function such as atacicept, belimumab, and Joint Bone Spine 2007; 74: 73–8.
compounds and penicillamine seem now to be less widely 21. Smolen JS, et al. Working Group on the Rituximab Consensus
epratuzumab are under investigation. In addition, deno- Statement. Consensus statement on the use of rituximab in pa-
used. There is good evidence of the effectiveness of the sumab is of interest for its potential to control joint destruc- tients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:
TNF-α inhibitors,4,5,9,15-17 and some in favour of anakin- tion.5 Other methods of treatment that are being or have 143–50. Also available at: http://ard.bmj.com/cgi/reprint/66/2/
143.pdf (accessed 24/06/08)
ra,16 but good evidence of an effect of other biological been investigated include gene therapy and autologous 22. Anonymous. Combination therapy for early rheumatoid arthri-
therapies on disease progression is currently scanty, al- bone marrow transplantation. A rheumatoid arthritis vac- tis. Drug Ther Bull 2006; 44: 81–5.
though clinical benefit has been found with, for example, cine is also in clinical trials. Induction of tolerance with 23. Roberts LJ, et al. Early combination disease modifying
abatacept and rituximab.5,16,18 antirheumatic drug treatment for rheumatoid arthritis. Med J
collagen and other antigens given orally has also been Aust 2006; 184: 122–5.
The choice of DMARD to begin treatment is based on the tried, but results are reported to be variable.30 24. Goekoop-Ruiterman YPM, et al. Comparison of treatment strat-
egies in early rheumatoid arthritis: a randomized trial. Ann In-
risk/benefit ratio, with the antimalarial hydroxychloro- Some studies suggest that addition of fish oils31 and/or tern Med 2007; 146: 406–15.
quine an option in mild disease, and sulfasalazine or meth- evening primrose oil to standard antirheumatic therapy 25. Capell H. Longterm maintenance therapy with disease modify-
otrexate preferred in those with moderate to severe dis- ing antirheumatic drugs. J Rheumatol 2002; 29 (suppl 66):
might help to reduce pain and joint swelling. Many alter- 38–43.
ease, or judged likely to progress.9 Methotrexate has native and herbal therapies have been tried, although good 26. Kirwan JR, et al. Effects of glucocorticoids on radiological pro-
become the DMARD of first choice in the majority of pa- evidence of benefit is scanty. gression in rheumatoid arthritis. Available in The Cochrane Da-
tients.1,2,8,9 Subcutaneous or intramuscular methotrexate tabase of Systematic Reviews; Issue 1. Chichester: John Wiley;
may be an option in patients who cannot be satisfactorily There has been considerable interest in the possibility that 2007 (accessed 23/06/08).
27. Gotzsche PC, Johansen HK. Short-term low-dose corticoster-
managed with weekly oral dosage.1,9 Addition of sul- statins such as atorvastatin may produce clinical improve- oids vs placebo and nonsteroidal antiinflammatory drugs in
fasalazine, hydroxychloroquine, or both may be a suitable ments, albeit modest, in symptoms of rheumatoid arthri- rheumatoid arthritis. Available in The Cochrane Database of
option in patients refractory to optimal methotrexate ther- tis,32 as well as in any accompanying cardiovascular risk Systematic Reviews; Issue 1. Chichester: John Wiley; 2005 (ac-
cessed 23/06/08).
apy,1,9 and addition of corticosteroids or leflunomide are factors. 28. Criswell LA, et al. Moderate-term, low-dose corticosteroids for
rheumatoid arthritis. Available in The Cochrane Database of
also options, although evidence for combining methotrex- The importance of managing co-morbidity in patients with Systematic Reviews; Issue 3. Chichester: John Wiley; 1998 (ac-
ate with ciclosporin is not entirely convincing.9 At what rheumatoid arthritis has been emphasised;1 in particular cessed 23/06/08).
stage biological therapies are to be recommended remains infection (especially pulmonary infection), cardiovascular 29. Stone M, et al. Should tetracycline treatment be used more ex-
tensively for rheumatoid arthritis? Metaanalysis demonstrates
a matter of debate. In the UK, official recommendations disease, and osteoporosis require appropriate management clinical benefit with reduction in disease activity. J Rheumatol
are still that TNF-α inhibitors should be reserved for pa- and action to reduce risk factors. 2003; 30: 2112–22.
 Analgesics Anti-inflammatory Drugs and Antipyretics 13
30. Toussirot ÉA. Oral tolerance in the treatment of rheumatoid ar- 8. Goldenberg DL. Pharmacological treatment of fibromyalgia etanercept or adalimumab are preferred to infliximab, but
thritis. Curr Drug Targets Inflamm Allergy 2002; 1: 45–52. and other chronic musculoskeletal pain. Best Pract Res Clin
31. Cleland LG, et al. The role of fish oils in the treatment of rheu- Rheumatol 2007; 21: 499–511. treatment should be individualised; a monoclonal antibody
matoid arthritis. Drugs 2003; 63: 845–53. 9. Arroll B, Goodyear-Smith F. Corticosteroid injections for pain- such as adalimumab or infliximab is advocated by others
32. McCarey DW, et al. Trial of Atorvastatin in Rheumatoid Arthri- ful shoulder: a meta-analysis. Br J Gen Pract 2005; 55: 224–8. in patients who also have inflammatory bowel disease.
tis (TARA): double-blind, randomised placebo-controlled trial. 10. Buchbinder R, et al. Oral steroids for adhesive capsulitis. Avail-
Lancet 2004; 363: 2015–21. able in The Cochrane Database of Systematic Reviews; Issue 4.
There is some suggestion that alefacept may also be of
33. Vroom F, et al. Disease-modifying antirheumatic drugs in preg- Chichester: John Wiley; 2006 (accessed 23/06/08). benefit in psoriatic arthritis. Systemic corticosteroids have
nancy: current status and implications for the future. Drug Safe- 11. Bisset L, et al. Mobilisation with movement and exercise, corti- little or no place in the management of psoriatic arthritis.
ty 2006; 29: 845–63. costeroid injection, or wait and see for tennis elbow: ran-
34. Golding A, et al. Rheumatoid arthritis and reproduction. Rheum domised trial. Abridged version: BMJ 2006; 333: 939–41. Full Reactive arthritis is characterised by sterile synovitis fol-
Dis Clin North Am 2007; 33: 319–43, vi–vii. version: http://www.bmj.com/cgi/reprint/333/7575/939.pdf (ac- lowing 1 to 4 weeks after an infection, most commonly of
cessed 23/06/08) the gastrointestinal or genito-urinary tract. Extra-articular
12. Wong SM, et al. Treatment of lateral epicondylitis with botuli-
Soft-tissue rheumatism num toxin: a randomized, double-blind, placebo-controlled tri- features involving the skin, eyes, or genito-urinary tract
Soft-tissue rheumatism includes conditions such as: al. Ann Intern Med 2005; 143: 793–7. may or may not be present. Reactive arthritis is also a fea-
13. Qerama E, et al. A double-blind, controlled study of botulinum ture of Reiter’s syndrome. Reactive arthritis is treated with
• bursitis (e.g. housemaid’s knee) toxin A in chronic myofascial pain. Neurology 2006; 67: 241–5.
14. Murrell GAC. Using nitric oxide to treat tendinopathy. Br J physical therapy and NSAIDs and, if indicated, intra-artic-
• fasciitis ular injections of corticosteroids; the role of antibacterials
Sports Med 2007; 41: 227–31.
• fibromyalgia (fibrositis, muscular rheumatism, myofas- 15. Bland JDP. Carpal tunnel syndrome. BMJ 2007; 335: 343–6. is less certain (see Bone and Joint Infections, p.164).
cial pain) 16. O’Connor D, et al. Non-surgical treatment (other than steroid
References.
injection) for carpal tunnel syndrome. Available in The Co-
• frozen shoulder chrane Database of Systematic Reviews; Issue 1. Chichester: 1. Jones G, et al. Interventions for treating psoriatic arthritis.
• humeral epicondylitis (e.g. tennis or golfer’s elbow) John Wiley; 2003 (accessed 23/06/08). Available in The Cochrane Database of Systematic Reviews; Is-
17. Marshall S, et al. Local corticosteroid injection for carpal tunnel sue 3. Chichester: John Wiley; 2000 (accessed 23/06/08).
• sprains and strains syndrome. Available in The Cochrane Database of Systematic 2. Khan MA. Update on spondyloarthropathies. Ann Intern Med
• tendinitis Reviews; Issue 2. Chichester: John Wiley; 2007 (accessed 2002; 136: 896–907.
23/06/08). 3. Lee RZ, Veale DJ. Management of spondyloarthropathy: new
• tenosynovitis 18. Gooch CL, Mitten DJ. Treatment of carpal tunnel syndrome: is pharmacological treatment options. Drugs 2002; 62: 2349–59.
• Tietze’s syndrome there a role for local corticosteroid injection? Neurology 2005; 4. Sieper J, et al. Ankylosing spondylitis: an overview. Ann Rheum
64: 2006–7. Dis 2002; 61 (suppl III): iii8–iii18.
Inflamed or displaced tissue may also impinge on nearby 5. van der Horst-Bruinsma IE, et al. Treatment of ankylosing
nerves and produce compression neuropathies such as car- spondylitis with disease modifying antirheumatic drugs. Clin
pal tunnel syndrome. Spondyloarthropathies Exp Rheumatol 2002; 20 (suppl 28): S67–S70.
6. Brockbank J, Gladman D. Diagnosis and management of psori-
Some forms of soft-tissue rheumatism respond to selective The spondyloarthropathies are a group of seronegative ar- atic arthritis. Drugs 2002; 62: 2447–57.
rest of the affected region, massage, splinting, or applica- thritides which include ankylosing spondylitis, psoriatic 7. Kingsley G, Pugh N. Spondyloarthropathies. In: Snaith ML, ed.
arthritis, arthritis associated with inflammatory bowel dis- ABC of rheumatology. 3rd ed. London: BMJ Publishing Group,
tion of heat, cold, or rubefacients.1-3 Exercise is of value in 2004: 61–7.
neck pain,3,4 fibromyalgia,5,6 and frozen shoulder,7 but its orders (enteropathic arthritis), and arthritis associated with 8. Kyle S, et al. British Society for Rheumatology Standards
benefit in epicondylitis is unclear.4 infection as in reactive arthritis (aseptic arthritis). Guidelines Audit Working Group. Guideline for anti-TNF-α
therapy in psoriatic arthritis. Rheumatology (Oxford) 2005; 44:
For patients with epicondylitis oral or topical NSAIDs Ankylosing spondylitis is characterised by arthritis of the 390–7. Corrections. ibid.; 569 and 701. Also available at:
may offer short-term pain relief, but it is unclear if they are spine and sacroiliac joints and sometimes there is also http://rheumatology.oxfordjournals.org/cgi/reprint/44/3/390.pdf
asymmetrical peripheral involvement. Males under 40 (accessed 23/06/08)
effective in producing longer term benefit.4 They are of 9. Keat A, et al. British Society for Rheumatology Standards,
unknown benefit in frozen shoulder,7 and are not thought years of age are mainly affected. The aim of management Guidelines and Audit Working Group. BSR guidelines for pre-
to be helpful in fibromyalgia,5 although some benefit has of the disease is to reduce pain and stiffness and to prevent scribing TNF-α blockers in adults with ankylosing spondylitis.
spine and joint deformity, which is accomplished using a Rheumatology (Oxford) 2005; 44: 939–47. Also available at:
been reported with paracetamol and tramadol.8 http://www.rheumatology.org.uk/guidelines/guidelines_as/
Corticosteroid injections produce dose-dependent benefit combination of active physical therapy and drug therapy. tnfguideline_as (accessed 23/06/08)
for up to 9 months in shoulder pain such as that associated Exercises are used to strengthen muscles and to maintain a 10. Gladman DD. Traditional and newer therapeutic options for
good posture and range of movement in joints. NSAIDs psoriatic arthritis: an evidence-based review. Drugs 2005; 65:
with rotator cuff tendinitis or frozen shoulder,9 and oral 1223–38.
corticosteroids may be of benefit for up to 6 weeks al- are used to relieve pain and inflammation, thus allowing 11. Boulos P, et al. Pharmacological treatment of ankylosing spond-
though it is not clear that benefit is subsequently the exercises to be performed; they do not influence the ylitis: a systematic review. Drugs 2005; 65: 2111–27.
progression of the disease. Some patients may need to add 12. Reveille JD, Arnett FC. Spondyloarthritis: update on pathogen-
maintained10 (a study11 in patients with epicondylitis sug- esis and management. Am J Med 2005; 118: 592–603.
gested that benefits of corticosteroid injection in this group other non-opioid analgesics such as paracetamol for addi- 13. Petersel DL, Sigal LH. Reactive arthritis. Infect Dis Clin North
were paradoxically reversed after 6 weeks). Corticosteroid tional pain control. Systemic corticosteroids are rarely in- Am 2005; 19: 863–83.
dicated but intra-articular injections of corticosteroids may 14. Leirisalo-Repo M. Reactive arthritis. Scand J Rheumatol 2005;
injections are often combined with a local anaesthetic; in- 34: 251–9.
jection of a local anaesthetic alone has been shown to be of be beneficial when one or two peripheral joints are severe- 15. Gordon KB, Ruderman EM. The treatment of psoriasis and pso-
benefit in chronic neck pain.4 ly affected. The disease-modifying antirheumatic drug riatic arthritis: an interdisciplinary approach. J Am Acad Der-
(DMARD) sulfasalazine is of benefit for peripheral arthri- matol 2006; 54 (suppl 2): S85–S91.
Botulinum toxin has been tried in epicondylitis12 and myo- 16. McVeigh CM, Cairns AP. Diagnosis and management of anky-
tis, but not for spinal symptoms. The efficacy of most other
fascial pain.13 There is evidence that nitric oxide plays a losing spondylitis. BMJ 2006; 333: 581–5.
DMARDs used in rheumatoid arthritis (see above) re- 17. Zochling J, et al. ’ASsessment in AS’ International Working
role in healing in patients with tendinitis, and topical appli- Group. European League Against Rheumatism. ASAS/EULAR
mains to be demonstrated. However, the tumour necrosis
cation of a patch containing glyceryl trinitrate has proved recommendations for the management of ankylosing spondyli-
factor-α (TNF-α) inhibitors adalimumab, etanercept, and
of benefit in patients with epicondylitis or tendinitis.14 tis. Ann Rheum Dis 2006; 65: 442–52. Also available at:
infliximab improve spinal pain, function, and peripheral http://ard.bmj.com/cgi/reprint/65/4/442.pdf (accessed 23/06/08)
Fibromyalgia appears to be associated with abnormal pain joint disease. They produce rapid benefit (usually within 18. Anonymous. New drugs for peripheral joint psoriatic arthritis.
responses, and some consider it a central pain syndrome 12 weeks) although most patients relapse once they are
Drug Ther Bull 2006; 44: 1–5.
rather than a rheumatic syndrome. There is strong evi- 19. NICE. Etanercept and infliximab for the treatment of adults
withdrawn. Treatment with a TNF-α inhibitor should be with psoriatic arthritis (Technology Appraisal 104, issued July
dence that low-dose tricyclic antidepressants are of benefit considered in patients with active disease despite conven- 2006). Available at: http://www.nice.org.uk/nicemedia/pdf/
in many patients, as is the tricyclic compound cyclobenz- tional treatments. There is some evidence that early inter-
TA104guidance.pdf (accessed 23/06/08)
20. NICE. Adalimumab for the treatment of psoriatic arthritis
aprine. Combination of amitriptyline with the SSRI fluox- vention may produce better remission rates, but it is yet (Technology Appraisal 125, issued August 2007). Available at:
etine also appears beneficial, although SSRIs alone have unknown if this results in longer-lasting remission on http://www.nice.org.uk/nicemedia/pdf/TA125guidance.pdf (ac-
produced equivocal results; serotonin and noradrenaline cessed 23/06/08)
withdrawal. Evidence is mostly lacking for other biologi- 21. Furst DE, et al. Updated consensus statement on biological
reuptake inhibitors (SNRIs) such as duloxetine, milnacip- cal therapies, but no marked benefit has been seen in con- agents for the treatment of rheumatic diseases, 2007. Ann
ran, or venlafaxine have also been reported to be of value. flicting studies with the interleukin-1 receptor antagonist Rheum Dis 2007; 66 (suppl 3): iii2–iii22. Correction. ibid. 2008;
Pregabalin and gabapentin have been shown to be of ben- 67: 280.
anakinra. 22. Braun J, Sieper J. Ankylosing spondylitis. Lancet 2007; 369:
efit in controlled studies.5,6,8 1379–90.
Psoriatic arthritis (or psoriatic arthropathy) is an inflam-
Surgery may be of benefit in some conditions such as epi- matory seronegative arthritis occurring in patients with 23. Pham T, et al. Club Rhumatismes et Inflammation (CRI/SFR).
condylitis and possibly shoulder pain.4 Surgical decom- Recommendations of the French Society for Rheumatology re-
psoriasis. In some patients the spine may be involved garding TNFα antagonist therapy in patients with ankylosing
pression is also the definitive treatment for carpal tunnel when the condition may be indistinguishable from anky- spondylitis or psoriatic arthritis: 2007 update. Joint Bone Spine
syndrome,15 although there is also evidence of benefit losing spondylitis. Less frequently some patients have a
2007; 74: 638–46.
from splinting16 and local corticosteroid injection17 (al- 24. NICE. Adalimumab, etanercept and infliximab for ankylosing
form of symmetrical arthritis resembling rheumatoid ar- spondylitis: Technology Appraisal 143 (issued May 2008).
though benefit may not be long term, and the procedure thritis. The psoriasis (p.1583) and the arthritis usually re- Available at: ht tp:/ /www.nice.org.uk/nicemedia/pdf/
carries some risks18). Oral corticosteroids and ultrasound quire separate treatment. Treatment of the arthritis is ini-
TA143Guidance.pdf (accessed 22/07/08)
have also demonstrated benefit in patients with carpal tun- tially as for ankylosing spondylitis with NSAIDs and
nel syndrome.16 physical therapy. If these methods fail treatment with a Still’s disease
1. Reveille JD. Soft-tissue rheumatism: diagnosis and treatment. Adult-onset Still’s disease is a syndrome characterised by
Am J Med 1997; 102 (suppl 1A): 23S–29S. DMARD may be instituted, although chloroquine and hy-
2. Shipley MA. Pain in the wrist and hand. In: Snaith ML, ed. ABC droxychloroquine should be avoided since they may pre- high fever, with body temperature classically spiking daily
of rheumatology. 3rd ed. London: BMJ Publishing Group, 2004: cipitate skin reactions (see Psoriatic Arthritis, p.601). or twice daily, an evanescent pink maculopapular rash, and
4–9. arthritis (usually oligoarthritis initially). It is most common
3. Speed C. Pain in the neck, shoulder, and upper arm. In: Snaith There is most evidence to support the use of sulfasalazine
ML, ed. ABC of rheumatology. 3rd ed. London: BMJ Publishing or methotrexate. Leflunomide may be effective but is like- in patients aged 16 to 35 years.
Group, 2004: 10–14. ly to be restricted by its toxicity and prolonged half-life. Treatment has traditionally relied on NSAIDs, corticoster-
4. van Tulder M, et al. Repetitive strain injury. Lancet 2007; 369:
1815–22. Ciclosporin is also restricted by its toxicity. As in ankylos- oids, and immunosuppressants or other DMARDs similar
5. Forseth KØ, Gran JT. Management of fibromyalgia: what are ing spondylitis, however, significant benefit has now been to those used in rheumatoid arthritis (above).1-3 A trial of
the best treatment choices? Drugs 2002; 62: 577–92. found with the TNF-α inhibitors, and treatment with these NSAIDs is worthwhile in patients with mild disease, but
6. Goldenberg DL, et al. Management of fibromyalgia syndrome.
JAMA 2004; 292: 2388–95. is recommended in patients with active disease despite most patients cannot be managed with NSAIDs alone.2,3
7. Dias R, et al. Frozen shoulder. BMJ 2005; 331: 1453–6. treatment with NSAIDs and/or DMARDs. In the UK, Corticosteroids may be needed for initial therapy if mani-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
14 Analgesics Anti-inflammatory Drugs and Antipyretics
festations are severe, but will eventually be needed in In placebo-controlled studies the overall frequency of malignan- 7. Lundquist L. Abatacept: a novel therapy approved for the treat-
ment of patients with rheumatoid arthritis. Adv Therapy 2007;
about 80% of cases.2 DMARDs (generally methotrexate) cies in patients treated with abatacept compared to those that re-
24: 333–45.
are introduced when corticosteroid therapy fails to control ceived placebo was similar (1.4% and 1.1%, respectively). How-
8. Russell AS, et al. Abatacept improves both the physical and
the disease or when their adverse effects become problem- ever, there were more cases of lung cancer and lymphomas in mental health of patients with rheumatoid arthritis who have in-
those given abatacept. In animal studies in mice, increases in adequate response to methotrexate treatment. Ann Rheum Dis
atic. Most patients will respond to methotrexate although
lymphomas and mammary tumours have been noted, although 2007; 66: 189–94.
liver function must be closely monitored. The value of oth- these increases have not been seen in some studies with other 9. Bruce SP, Boyce EG. Update on abatacept: a selective costimu-
er DMARDs is uncertain. Intravenous immunoglobulin is mammals. lation modulator for rheumatoid arthritis. Ann Pharmacother
also frequently tried, although supporting evidence is lack- 2007; 41: 1153–62.
ing.2,3 Interactions Preparations
The TNF-α inhibitors have also been tried,2,3 but results Live vaccines should not be given with abatacept, or Proprietary Preparations (details are given in Part 3)
have been variable.2 There is, however, some evidence within 3 months of stopping it, as its effect on vaccine Arg.: Orencia; Cz.: Orencia; Fr.: Orencia; Port.: Orencia; UK: Orencia;
that interleukin-1 and interleukin-6 play a role in patho- USA: Orencia.
genesis of the condition, and there have been a few reports
efficacy or the risk of infection transmission is
of dramatic improvement with anakinra (an interleukin-1 unknown. The use of TNF inhibitors with abatacept
receptor antagonist) in resistant disease, while tocilizumab may increase the risk of serious infections (see p.71); Aceclofenac (BAN, rINN)
(an interleukin-6 receptor antagonist) has also been sug- such combinations are not recommended. Use with Acéclofénac; Aceclofenaco; Aceclofenacum; Aceklofenák; Acek-
gested as an investigational therapy.2,3 anakinra or rituximab is also not recommended be- lofenak; Aceklofenakas; Aseklofenaakki; Aseklofenak. [o-(2,6-
The name Still’s disease has also been used rather incon- cause of insufficient evidence to assess safety. Dichloroanilino)phenyl]acetate glycolic acid ester; 2-(2,6-Dichlo-
sistently to describe some types of juvenile idiopathic ar- roanalino)phenylacetoxyacetic acid.
thritis (above). Pharmacokinetics Ацеклофенак
1. Efthimiou P, Georgy S. Pathogenesis and management of adult- Abatacept is reported to have linear pharmacokinetics C 16 H 13Cl 2 NO 4 = 354.2.
onset Still’s disease. Semin Arthritis Rheum 2006; 36: 144–52. C AS — 89796-99-6.
2. Pouchot J. How can we improve the management of adult-onset at usual dosages. After repeated intravenous doses, its
ATC — M01AB16; M02AA25.
Still’s disease? Joint Bone Spine 2007; 74: 117–19. mean terminal half-life is about 13 days. ATC Vet — QM01AB16; QM02AA25.
3. Kontzias A, Efthimiou P. Adult-onset Still’s disease : pathogen-
esis, clinical manifestations and therapeutic advances. Drugs Studies in animals suggest that abatacept is distributed
2008; 68: 319–337. into breast milk.
O COOH
Uses and Administration
Abatacept, a fusion protein, is a co-stimulation blocker. O
Abatacept (BAN, USAN, rINN) NH
It prevents the activation of T-cells; activated T-cells
Abataceptum; BMS-188667; CTLA4-Ig. 1-25-oncostatin M (hu- Cl Cl
man precursor) fusion protein with CTLA-4 (antigen) (human)
have been found in the synovium of patients with rheu-
fusion protein with immunoglobulin G1 (human heavy chain frag- matoid arthritis. It is used in the treatment of moderate
ment), bimolecular (146→146′)-disulfide. to severe active rheumatoid arthritis to delay structural
Абатацепт damage and improve physical function. In the UK, it is
C AS — 332348-12-6. licensed for use in patients who have had an inadequate Pharmacopoeias. In Eur. (see p.vii).
ATC — L04AA24. response to standard disease-modifying antirheumatic Ph. Eur. 6.2 (Aceclofenac). A white or almost white, crystalline
ATC Vet — QL04AA24. drugs (DMARDs), including at least one TNF inhibi- powder. Practically insoluble in water; soluble in alcohol; freely
soluble in acetone. Store in airtight containers. Protect from light.
tor; in the USA, it may be used to reduce the signs and
Adverse Effects and Precautions symptoms of early disease. Adverse Effects and Treatment
Acute infusion reactions occurring within 1 hour of As for NSAIDs in general, p.96.
Abatacept is given by intravenous infusion over a peri-
starting an infusion are common with abatacept use. Hypersensitivity. Leukocytoclastic vasculitis, a type III hyper-
od of 30 minutes in the following doses, based on sensitivity reaction, has been reported after therapy with aceclo-
The most frequently reported infusion events are dizzi- body-weight: fenac.1,2 Anaphylaxis has also occurred.3
ness, headache, and hypertension; hypotension and
• 500 mg for patients weighing less than 60 kg 1. Epelde F, Boada L. Leukocytoclastic vasculitis and hemoptysis
dyspnoea occur less commonly. Other acute events in- after treatment with aceclofenac. Ann Pharmacother 1995; 29:
clude nausea, flushing, pruritus, rash, and wheezing. • 750 mg for those weighing 60 to 100 kg 1168.
• 1 g for those over 100 kg. 2. Morros R, et al. Hypersensitivity vasculitis related to ace-
Most events are usually mild to moderate although clofenac. Br J Rheumatol 1997; 36: 503–4.
stopping treatment may be necessary in a few patients. The dose is repeated at 2 and 4 weeks, then every 4 3. Rojas-Hijazo B, et al. Anaphylactic reaction after aceclofenac
intake. Allergy 2006; 61: 511.
Other common adverse effects include headache, na- weeks thereafter. If a response to treatment is not seen
sopharyngitis, nausea, dyspepsia, diarrhoea, dizziness, within 6 months, the benefits of continuing abatacept Precautions
As for NSAIDs in general, p.98.
back pain, fatigue, cough, and abnormal liver function may need to be considered. In the UK, abatacept is li-
Aceclofenac should be avoided in patients with moderate to se-
values. Antibodies to abatacept may develop and ana- censed for use with methotrexate; however, in the USA vere renal impairment.
phylaxis or anaphylactic reactions have been reported it may be given alone or with other DMARDs (but see
Interactions
rarely. Uncommon adverse reactions include paraes- Interactions, above). For interactions associated with NSAIDs, see p.99.
thesia, thrombocytopenia, and leucopenia. For the use of abatacept in children, and recommended Pharmacokinetics
Infections are frequent in patients treated with abata- doses, see below. Aceclofenac is well absorbed from the gastrointestinal tract;
cept and most often affect the respiratory and urinary Abatacept is also being studied for other auto-immune peak plasma concentrations are reached 1 to 3 hours after an oral
tracts. More serious infections such as pneumonia, sep- diseases such as inflammatory bowel disease, psoriatic dose. Aceclofenac is more than 99% bound to plasma proteins.
The plasma-elimination half-life is about 4 hours. About two-
sis, cellulitis, bronchitis, diverticulitis, and acute arthritis, and SLE. thirds of a dose is excreted in the urine, mainly as hydroxymetab-
pyelonephritis have also been rarely associated with Administration in children. In the USA, abatacept is li- olites. A small amount is converted to diclofenac.
abatacept treatment. Treatment should be stopped in censed in the treatment of moderate to severe, active juvenile id- ◊ It has been suggested1 that low concentrations of diclofenac, a
patients who develop a serious infection. Abatacept iopathic arthritis in children aged 6 years and above; it may be minor metabolite, may account for some of the actions of ace-
should not be given to patients with severe and uncon- used alone or with methotrexate. The dose is calculated accord- clofenac.
ing to body-weight and is given as an intravenous infusion over
trolled infections such as sepsis and opportunistic in- 30 minutes; those weighing less than 75 kg should be given
1. Hinz B, et al. Aceclofenac spares cyclooxygenase 1 as a result of
limited but sustained biotransformation to diclofenac. Clin Phar-
fections. It should be used with caution in patients with 10 mg/kg initially, while heavier children may receive the appro- macol Ther 2003; 74: 222–35.
a history of recurrent infections, with underlying con- priate adult dose (see above). Doses should be repeated at 2 and Uses and Administration
ditions that may predispose to infections, or with 4 weeks, and then every 4 weeks thereafter. Aceclofenac, a phenylacetic acid derivative, is an NSAID (see
chronic, latent, or localised infections. Patients should Rheumatoid arthritis. References to the use of abatacept in p.99) related to diclofenac (p.44). It is used in the management of
be screened for latent tuberculosis before starting treat- rheumatoid arthritis (p.11). osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis,
ment; those testing positive should be treated with 1. Kremer JM, et al. Treatment of rheumatoid arthritis by selective in usual oral doses of 100 mg twice daily. Reduced doses should
inhibition of T-cell activation with fusion protein CTLA4Ig. N be used in patients with hepatic impairment, see below.
standard chemoprophylaxis before beginning abata- Engl J Med 2003; 349: 1907–15.
cept. 2. Genovese MC, et al. Abatacept for rheumatoid arthritis refracto- ◊ Reviews.
ry to tumor necrosis factor α inhibition. N Engl J Med 2005; 353: 1. Dooley M, et al. Aceclofenac: a reappraisal of its use in the man-
Some disease-modifying antirheumatic drugs have 1114–23. Correction. ibid.; 2311. agement of pain and rheumatic disease. Drugs 2001; 61:
been associated with hepatitis B reactivation; licensed 3. Kremer JM, et al. Effects of abatacept in patients with meth- 1351–78.
otrexate-resistant active rheumatoid arthritis: a randomized trial. 2. Reginster JY, et al. Comment positionner l’acéclofénac au sein
product information for abatacept recommends screen- Ann Intern Med 2006; 144: 865–76. de l’arsenal thérapeutique des pathologies ostéo-articulaires
ing for viral hepatitis before starting treatment. 4. Weinblatt M, et al. Safety of the selective costimulation modula- chroniques? Rev Med Liege 2001; 56: 484–8.
tor abatacept in rheumatoid arthritis patients receiving back- 3. Legrand E. Aceclofenac in the management of inflammatory
Adverse effects of abatacept are more frequent in pa- ground biologic and nonbiologic disease-modifying antirheu- pain. Expert Opin Pharmacother 2004; 5: 1347–57.
tients with chronic obstructive pulmonary disease and matic drugs: a one-year randomized, placebo-controlled study. 4. Lee J, et al. Formulation of microemulsion systems for transder-
Arthritis Rheum 2006; 54: 2807–16. mal delivery of aceclofenac. Arch Pharm Res 2005; 28:
may include a worsening of their respiratory symp- 5. Nogid A, Pham DQ. Role of abatacept in the management of 1097–1102.
toms. rheumatoid arthritis. Clin Ther 2006; 28: 1764–78.
Administration in hepatic impairment. The initial oral
6. Pollard LC. Inhibiting costimulatory activation of T cells: a via-
Carcinogenicity. The role of abatacept in the onset of malig- ble treatment option for rheumatoid arthritis? Drugs 2007; 67: dose of aceclofenac should be reduced to 100 mg daily in pa-
nancies such as lymphoma in humans is not known. 1–9. tients with hepatic impairment.
 Abatacept/Adalimumab 15
Preparations Acetanilide concentrations are reached in about 3 to 8 days and bio-
Proprietary Preparations (details are given in Part 3) Acetanilida; Antifebrin. N-Phenylacetamide. availability is estimated to be 64%. The mean terminal
Arg.: Berlofen; Bristaflam†; Austria: Beofenac†; Belg.: Air-Tal; Biofenac; Антифебрин; Ацетанилид half-life is about 2 weeks.
Braz.: Aceflan†; Cecoflan†; Proflam; Chile: Airtal†; Bristaflam†; Denm.:
Barcan; Fin.: Barcan; Fr.: Cartrex; Ger.: Beofenac; Gr.: Aceclonac; Arlina;
C 8 H 9 NO = 135.2. ◊ References.
Biofenac; Sovipan; Hung.: Aflamin; India: Aceclo; Arrestin; Movon; Zero-
C AS — 103-84-4. 1. Nestorov I. Clinical pharmacokinetics of tumor necrosis factor
dol; Ital.: Airtal; Gladio; Kafenac; Mex.: Bristaflam; Neth.: Biofenac; Norw.: antagonists. J Rheumatol 2005; 74 (suppl): 13–18.
Barcan; Philipp.: Clanza; Port.: Airtal; Biofenac; Rus.: Airtal (Аэртал);
Spain: Airtal; Airtal Difucrem; Falcol; Gerbin; Sanein; Swed.: Barcan;
Switz.: Locomin†; UAE: Aceclofar; UK: Preservex; Venez.: Airtal†; Brista- O Uses and Administration
flam. Adalimumab is a recombinant human monoclonal
Multi-ingredient: India: Kinectine; Kinectine P; Kinectine-MR; Movon- N CH3 tumour necrosis factor (TNF) antibody that binds
MR; Movon-P†; Zerodol-MR; Zerodol-P. H specifically to TNF-α and blocks its interaction with
endogenous cell-surface TNF receptors. It also modu-
Pharmacopoeias. In Fr.
lates biological responses that are induced or regulated
Profile by TNF. Elevated levels of TNF have been found in the
Acemetacin (BAN, rINN) Acetanilide, a para-aminophenol derivative related to paraceta-
mol (p.108), has analgesic and antipyretic properties. It was re-
affected tissues and fluids of patients with rheumatoid
Acemetacina; Acémétacine; Acemetacinum; Asemetasin; Bay-f- arthritis, ankylosing spondylitis, psoriatic arthritis,
placed by safer analgesics.
4975; Indometasinin Glikolik Asit Esteri; TVX-1322. O-[(1-p- plaque psoriasis, and Crohn’s disease.
Chlorobenzoyl-5-methoxy-2-methylindol-3-yl)acetyl]glycolic ac-
id. Adalimumab is used in the treatment of moderate to
Actarit (rINN) severe, active rheumatoid arthritis and active and
Ацеметацин progressive psoriatic arthritis to delay structural
Actaritum; MS-932. (p-Acetamidophenyl)acetic acid.
C 21 H 18ClNO 6 = 415.8. damage and improve physical function. In the UK, it is
Актарит
C AS — 53164-05-9. C 10 H 11 NO 3 = 193.2. licensed for use in patients who have had an inadequate
ATC — M01AB11. C AS — 18699-02-0. response to standard disease-modifying antirheumatic
ATC Vet — QM01AB11. drugs (DMARDs), although in severe progressive
rheumatoid arthritis it may be used in patients not pre-
H viously treated with methotrexate; in the USA, it may
H 3C N
O be used to reduce the signs and symptoms of early dis-
O Cl ease. Adalimumab is also used in the treatment of
O
OH active ankylosing spondylitis: UK licensed product
N CH3 information recommends that it should only be used in
O Profile patients with severe disease who have had an inade-
Actarit is reported to be a disease-modifying antirheumatic drug. quate response to conventional treatment; however, in
H3CO O COOH It has been given in the treatment of rheumatoid arthritis in a usu- the USA it may be used to reduce signs and symptoms
al oral dose of 100 mg three times daily.
in early disease. For all the above indications, it is giv-
Pharmacopoeias. In Eur. (see p.vii). Adverse effects. A photosensitivity reaction developed in a en by subcutaneous injection in a dose of 40 mg every
Ph. Eur. 6.2 (Acemetacin). A yellow or greenish-yellow, crys- 52-year-old woman one month after starting actarit and doxycy-
cline.1 Photopatch tests for both drugs were only positive for the
other week. In the treatment of rheumatoid arthritis,
talline powder. It exhibits polymorphism. Practically insoluble in
water; slightly soluble in anhydrous alcohol; soluble in acetone. patches containing actarit. UK licensed product information recommends that
Protect from light. 1. Kawada A, et al. Photosensitivity due to actarit. Contact Derma- adalimumab should be given with methotrexate, al-
titis 1997; 36: 175–6. though monotherapy may be used where treatment
Adverse Effects, Treatment, and Precautions Use. References. with methotrexate would be inappropriate. When used
As for NSAIDs in general, p.96. 1. Nakamura H, et al. Clinical effects of actarit in rheumatoid ar- as monotherapy in rheumatoid arthritis, some patients
thritis: improvement of early disease activity mediated by reduc-
Interactions tion of serum concentrations of nitric oxide. Clin Exp Rheumatol
may benefit from increasing the dose to 40 mg every
For interactions associated with NSAIDs, see p.99. 2000; 18: 445–50. week. Clinical response is usually achieved within 12
Preparations weeks of treatment.
Pharmacokinetics
Acemetacin is well absorbed after oral dosage. Its major metab- Proprietary Preparations (details are given in Part 3) Adalimumab is also used in the treatment of moderate
olite is indometacin (p.66) which, after repeated doses, is present Jpn: Mover†; Orcl. to severe, active Crohn’s disease unresponsive to con-
at higher concentrations than those of acemetacin. Acemetacin is ventional treatment; it may also be used in patients who
bound to plasma proteins to a slightly lesser extent than indomet-
acin. It is eliminated via both the liver and the kidneys.
have relapsed while taking infliximab. Patients may be
Adalimumab (BAN, USAN, rINN) given an initial dose of 160 mg on day 1 (given as four
Uses and Administration 40-mg injections in one day or two 40-mg injections
Acemetacin, a glycolic acid ester of indometacin, is an NSAID Adalimumabum; D2E7; LU-200134. Immunoglobulin G1 (hu-
man monoclonal D2E7 heavy chain anti-human tumor necrosis daily for 2 consecutive days), followed by 80 mg two
(p.99). Its pharmacological activity is due to both acemetacin and
its major metabolite, indometacin (p.66). Acemetacin is used in factor), disulfide with human monoclonal D2E7κ-chain, dimer. weeks later (day 15). After a further two weeks (day
rheumatoid arthritis, osteoarthritis, and low back pain, and for Адалимумаб 29), a maintenance dose of 40 mg every other week
postoperative pain and inflammation. Usual oral doses are 120 to C AS — 331731-18-1. may be started. Alternatively, UK licensed product in-
180 mg daily in divided doses. Acemetacin is eliminated by both ATC — L04AB04. formation advises that patients at risk of adverse effects
hepatic and renal routes, although pharmacokinetics are not af- may be given 80 mg initially, followed by 40 mg 2
fected by moderate renal or hepatic impairment and appear to be ATC Vet — QL04AB04.
unchanged in the elderly. weeks later; thereafter, usual maintenance doses may
Adverse Effects and Precautions be given. A clinical response is usually seen within 12
◊ References. As for Infliximab, p.69. weeks of starting treatment; those patients who relapse
1. Jones RW, et al. Comparative pharmacokinetics of acemetacin in Injection site reactions including erythema, itching, while on adalimumab may benefit from increasing the
young subjects and elderly patients. Br J Clin Pharmacol 1991; maintenance dose to 40 mg every week.
31: 543–5. pain, and swelling are the most common adverse reac-
2. Hazleman B, Bernstein RM. Acemetacin in the long-term thera- tions with adalimumab; however, most reactions are In the treatment of moderate to severe chronic plaque
py of rheumatoid arthritis. Curr Med Res Opin 1993; 13: mild and do not result in drug withdrawal. Other com- psoriasis in patients unresponsive to, or intolerant of,
119–26. conventional systemic therapy including phototherapy,
mon reactions include headache, rashes, back pain, hy-
3. Chou CT, Tsai YY. A double-blind, randomized, controlled par- the recommended initial dose of adalimumab is 80 mg
allel group study evaluating the efficacy and safety of acemet- pertension, paraesthesias, increased alkaline phosphate
acin for the management of osteoarthritis. Int J Clin Pharmacol levels, and cough. subcutaneously; this may be followed by a mainte-
Res 2002; 22: 1–6.
Autoantibodies to adalimumab have been detected. nance dose of 40 mg subcutaneously on alternate
4. Leeb BF, et al. Behandlung der Gonarthrose: Wirksamkeit und weeks, starting 1 week after the initial dose. A clinical
Verträglichkeit von retardiertem Acemetacin im Vergleich zu
Celecoxib. Orthopade 2004; 33: 1032–41. Interactions response is usually seen within 16 weeks of starting
As for Infliximab, p.71. treatment.
Preparations
Methotrexate is reported to reduce the clearance of For the uses of adalimumab in children, and recom-
Proprietary Preparations (details are given in Part 3) mended doses, see below.
adalimumab by up to 44% but licensed product infor-
Austria: Rheutrop; Cz.: Rantudil; Ger.: Acemetadoc; Acephlogont†; Ran-
tudil; Gr.: Gamespir†; Rantutal; Hung.: Rantudil; Ital.: Acemix; Solart†; mation for the latter states that dosage adjustment for Administration in children. In the USA, adalimumab is li-
Jpn: Rantudil; Mex.: Rantudil; Philipp.: Rantudil; Pol.: Rantudil; Port.: either drug does not appear to be necessary. censed in the treatment of moderate to severe, active juvenile id-
Rantudil; Spain: Espledol; Oldan; Switz.: Tilur; Turk.: Rantudil; UK: Em- iopathic arthritis in children aged 4 years and above: it may be
flex; Venez.: Mostanol†; Pranex. used alone or with methotrexate. The dose is calculated accord-
Pharmacokinetics ing to weight and is given subcutaneously: those weighing 15 kg
Multi-ingredient: Arg.: Rucaten Forte; Rucaten Prednisolona.
Adalimumab is reported to have linear pharmacokinet- to less than 30 kg should be given 20 mg every other week, while
ics at usual dosages. After subcutaneous injection peak heavier children may receive 40 mg every other week.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
16 Analgesics Anti-inflammatory Drugs and Antipyretics
Inflammatory bowel disease. Adalimumab is used in the 12. Cvetković RS, Scott LJ. Adalimumab: a review of its use in
management of Crohn’s disease1-4 (p.1697), including in patients adult patients with rheumatoid arthritis. BioDrugs 2006; 20:
293–311.
who are intolerant of, or relapse on, infliximab treatment.5-8 It O
has also been tried in the treatment of ulcerative colitis (p.1697).9 13. Burmester GR, et al. Adalimumab alone and in combination CH3
with disease-modifying antirheumatic drugs for the treatment of
1. Hanauer SB, et al. Human anti-tumor necrosis factor monoclonal rheumatoid arthritis in clinical practice: the Research in Active N
antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Rheumatoid Arthritis (ReAct) trial. Ann Rheum Dis 2007; 66: O
Gastroenterology 2006; 130: 323–33. 732–9.
2. Sandborn WJ, et al. Adalimumab for maintenance treatment of 14. Bombardieri S, et al. Research in Active Rheumatoid Arthritis N
Crohn’s disease: results of the CLASSIC II trial. Gut 2007; 56: (ReAct) Study Group. Effectiveness of adalimumab for rheuma- H 3C N N OCH3
1232–9. toid arthritis in patients with a history of TNF-antagonist thera-
3. Colombel JF, et al. Adalimumab for maintenance of clinical re- py in clinical practice. Rheumatology (Oxford) 2007; 46: N N
sponse and remission in patients with Crohn’s disease: the 1191–9.
CHARM trial. Gastroenterology 2007; 132: 52–65. 15. NICE. Adalimumab, etanercept and infliximab for the treatment (alfentanil)
4. Plosker GL, Lyseng-Williamson KA. Adalimumab: in Crohn’s of rheumatoid arthritis: Technology Appraisal Guidance 130
disease. BioDrugs 2007; 21: 125–32. (issued October 2007). Available at: http://www.nice.org.uk/
5. Sandborn WJ, et al. An open-label study of the human anti-TNF nicemedia/pdf/TA130guidance.pdf (accessed 13/06/08) Pharmacopoeias. In Eur. (see p.vii) and US.
monoclonal antibody adalimumab in subjects with prior loss of Ph. Eur. 6.2 (Alfentanil Hydrochloride). A white or almost white
response or intolerance to infliximab for Crohn’s disease. Am J Spondyloarthropathies. References to the use of adalimum-
Gastroenterol 2004; 99: 1984–9.
powder. Freely soluble in water, in alcohol, and in methyl alco-
ab in ankylosing spondylitis and psoriatic arthritis (see Spondy-
6. Papadakis KA, et al. Safety and efficacy of adalimumab (D2E7) hol. Protect from light.
loarthropathies, p.13).
in Crohn’s disease patients with an attenuated response to inflix- USP 31 (Alfentanil Hydrochloride). A white to almost white
imab. Am J Gastroenterol 2005; 100: 75–9. 1. Chew A-L, et al. Successful treatment of severe psoriasis and powder. Soluble in water; freely soluble in alcohol, in chloro-
7. Peyrin-Biroulet L, et al. Adalimumab maintenance therapy for psoriatic arthritis with adalimumab. Br J Dermatol 2004; 151: form, and in methyl alcohol; sparingly soluble in acetone. Store
Crohn’s disease with intolerance or lost response to infliximab: 492–6.
in airtight containers.
an open-label study. Aliment Pharmacol Ther 2007; 25: 675–80. 2. Mease PJ, et al. Adalimumab for the treatment of patients with
8. Sandborn WJ, et al. Adalimumab induction therapy for Crohn moderately to severely active psoriatic arthritis: results of a dou-
disease previously treated with infliximab: a randomized trial. ble-blind, randomized, placebo-controlled trial. Arthritis Dependence and Withdrawal
Ann Intern Med 2007; 146: 829–38. Rheum 2005; 52: 3279–89.
As for Opioid Analgesics, p.101.
9. Peyrin-Biroulet L, et al. Adalimumab induction therapy for ul- 3. van der Heijde D, et al. Efficacy and safety of adalimumab in
cerative colitis with intolerance or lost response to infliximab: an patients with ankylosing spondylitis: results of a multicenter,
open-label study. World J Gastroenterol 2007; 13: 2328–32. randomized, double-blind, placebo-controlled trial. Arthritis Adverse Effects and Treatment
Rheum 2006; 54: 2136–46.
Psoriasis. Adalimumab is used in the treatment of plaque pso- As for Opioid Analgesics in general, p.102, and for
4. van der Heijde D, et al. ATLAS Study Group. Efficacy and safe-
riasis (p.1583). ty of adalimumab in patients with ankylosing spondylitis: re- Fentanyl, p.56.
References. sults of a multicenter, randomized, double-blind, placebo-con-
trolled trial. Arthritis Rheum 2006; 54: 2136–46. Effects on the cardiovascular system. Sinus arrest had
1. Gordon KB, et al. Clinical response to adalimumab treatment in
5. Simpson D, Scott LJ. Adalimumab: in psoriatic arthritis. Drugs
occurred1 during intubation in 2 patients given alfentanil
patients with moderate to severe psoriasis: double-blind, rand- 30 micrograms/kg.
omized controlled trial and open-label extension study. J Am 2006; 66: 1487–96.
Acad Dermatol 2006; 55: 598–606. 6. Gladman DD, et al. Adalimumab improves joint-related and 1. Maryniak JK, Bishop VA. Sinus arrest after alfentanil. Br J
2. Papoutsaki M, et al. Adalimumab for severe psoriasis and psori- skin-related functional impairment in patients with psoriatic ar- Anaesth 1987; 59: 390–1.
atic arthritis: an open-label study in 30 patients previously treat- thritis: patient-reported outcomes of the Adalimumab Effective- Effects on mental function. Like fentanyl, alfentanil 7.5 or
ed with other biologics. J Am Acad Dermatol 2007; 57: 269–75. ness in Psoriatic Arthritis Trial. Ann Rheum Dis 2007; 66:
163–8. 15 micrograms/kg intravenously had no effect on memory in
3. Menter A, et al. Adalimumab therapy for moderate to severe healthy subjects.1 In another study impairment of memory for
psoriasis: a randomized, controlled phase III trial. J Am Acad 7. Gladman DD, et al. Adalimumab for long-term treatment of
Dermatol 2008; 58: 106–15. psoriatic arthritis: forty-eight week data from the adalimumab new facts did occur 2 hours after operation in patients anaesthe-
4. Revicki D, et al. Impact of adalimumab treatment on health-re- effectiveness in psoriatic arthritis trial. Arthritis Rheum 2007; tised with alfentanil 7.5 micrograms/kg, but not in those given
lated quality of life and other patient-reported outcomes: results 56: 476–88. fentanyl;2 methohexital might have contributed to the impair-
from a 16-week randomized controlled trial in patients with 8. Genovese MC, et al. M02-570 Study Group. Safety and efficacy ment.
moderate to severe plaque psoriasis. Br J Dermatol 2008; 158: of adalimumab in treatment of patients with psoriatic arthritis 1. Scamman FL, et al. Ventilatory and mental effects of alfentanil
549–57. who had failed disease modifying antirheumatic drug therapy. J and fentanyl. Acta Anaesthesiol Scand 1984; 28: 63–7.
5. Saurat J-H, et al. CHAMPION Study Investigators. Efficacy and Rheumatol 2007; 34: 1040–50. Correction. ibid.; 1439.
2. Kennedy DJ, Ogg TW. Alfentanil and memory function: a com-
safety results from the randomized controlled comparative study 9. Davis JC, et al. Health-related quality of life outcomes in pa- parison with fentanyl for day case termination of pregnancy. An-
of adalimumab vs. methotrexate vs. placebo in patients with pso- tients with active ankylosing spondylitis treated with adalimu- aesthesia 1985; 40: 537–40.
riasis. Br J Dermatol 2008; 158: 558–66. mab: results from a randomized controlled study. Arthritis
6. NICE. Adalimumab for the treatment of adults with psoriasis: Rheum 2007; 57: 1050–7. Effects on the respiratory system. Alfentanil, like other
Technology Appraisal Guidance 146 (issued June 2008). Avail- 10. NICE. Adalimumab for the treatment of psoriatic arthritis: opioid agonists, causes dose-related respiratory depression; it is
a b l e a t : h t t p : / / w w w. n i c e . o r g . u k / n i c e m e d i a / p d f / Technology Appraisal Guidance 125 (issued August 2007). significant with doses of more than 1 mg. Recovery has been re-
TA146Guidance.pdf (accessed 25/07/08) Available at: http:// www.nice.org.uk/nicemedi a/pdf/ ported to be faster after alfentanil than after fentanyl (see p.56),1,2
TA125guidance.pdf (accessed 13/06/08) possibly reflecting the shorter elimination half-life of alfentanil.
Rheumatoid arthritis. References to the use of adalimumab
in rheumatoid arthritis (p.11). Uveitis. Adalimumab has been tried with some success in the Even so, accumulation of alfentanil is possible with large doses
1. den Broeder AA, et al. Long-term anti-tumour necrosis factor treatment of idiopathic uveitis (p.1515). Uveitis can also develop over a prolonged period. Profound analgesia is accompanied by
alpha monotherapy in rheumatoid arthritis: effect on radiologi- as a complication of other inflammatory disorders such as rheu- marked respiratory depression which may persist or recur post-
cal course and prognostic value of markers of cartilage turnover matoid arthritis; treatment with adalimumab may improve ocular operatively.
and endothelial activation. Ann Rheum Dis 2002; 61: 311–18.
2. Rau R. Adalimumab (a fully human anti-tumour necrosis factor symptoms in addition to its effect on the primary disorder. Sudden respiratory arrest usually within an hour after the end of
alpha monoclonal antibody) in the treatment of active rheuma- alfentanil infusion has been reported in patients who initially ap-
References.
toid arthritis: the initial results of five trials. Ann Rheum Dis peared to have made a rapid recovery from anaesthesia;3-5 all re-
2002; 61 (suppl 2): 70–3. 1. Vazquez-Cobian LB, et al. Adalimumab therapy for childhood sponded to treatment with naloxone. Close monitoring of respi-
3. Weinblatt ME, et al. Adalimumab, a fully human anti-tumor uveitis. J Pediatr 2006; 149: 572–5. ration in the initial postoperative period was recommended and
necrosis factor alpha monoclonal antibody, for the treatment of
rheumatoid arthritis in patients taking concomitant methotrex-
2. Biester S, et al. Adalimumab in the therapy of uveitis in child- this was reinforced by the manufacturers;6 factors such as hyper-
hood. Br J Ophthalmol 2007; 91: 319–24. ventilation and the use of opioid premedication might enhance or
ate: the ARMADA trial. Arthritis Rheum 2003; 48: 35–45.
4. Furst DE, et al. Adalimumab, a fully human anti tumor necrosis prolong the respiratory depressant effects of alfentanil.
factor-alpha monoclonal antibody, and concomitant standard Preparations 1. Andrews CJH, et al. Ventilatory effects during and after contin-
antirheumatic therapy for the treatment of rheumatoid arthritis: Proprietary Preparations (details are given in Part 3) uous infusion of fentanyl or alfentanil. Br J Anaesth 1983; 55:
results of STAR (Safety Trial of Adalimumab in Rheumatoid 211S–16S.
Arthritis). J Rheumatol 2003; 30: 2563–71. Arg.: Humira; Austral.: Humira; Belg.: Humira; Braz.: Humira; Canad.:
Humira; Chile: Humira; Cz.: Humira; Denm.: Humira; Fin.: Humira; Fr.: 2. Scamman FL, et al. Ventilatory and mental effects of alfentanil
5. van de Putte LB, et al. Efficacy and safety of adalimumab as and fentanyl. Acta Anaesthesiol Scand 1984; 28: 63–7.
monotherapy in patients with rheumatoid arthritis for whom Humira; Ger.: Humira; Gr.: Humira; Hong Kong: Humira; Hung.: Humira;
Irl.: Humira; Israel: Humira; Ital.: Humira; Malaysia: Humira; Mex.: Hu- 3. Sebel PS, et al. Respiratory depression after alfentanil infusion.
previous disease modifying antirheumatic drug treatment has BMJ 1984; 289: 1581–2.
failed. Ann Rheum Dis 2004; 63: 508–16. mira; Neth.: Humira; Trudexa; Norw.: Humira; NZ: Humira; Pol.: Humira;
Port.: Humira; Singapore: Humira; Spain: Humira; Swed.: Humira; 4. Krane BD, et al. Alfentanil and delayed respiratory depression:
6. Keystone EC, et al. Radiographic, clinical, and functional out- cases studies and review. Anesth Analg 1990; 70: 557–61.
comes of treatment with adalimumab (a human anti-tumor Switz.: Humira; UK: Humira; USA: Humira; Venez.: Humira.
necrosis factor monoclonal antibody) in patients with active 5. Sternlo JEG, Sandin RH. Recurrent respiratory depression after
rheumatoid arthritis receiving concomitant methotrexate thera- total intravenous anaesthesia with propofol and alfentanil. An-
py: a randomized, placebo-controlled, 52-week trial. Arthritis aesthesia 1998; 53: 378–81.
Rheum 2004; 50: 1400–11. 6. Waldron HA, Cookson RF. Respiratory depression after alfen-
7. Wick MC, et al. Adalimumab (Humira) restores clinical re- Alfentanil Hydrochloride tanil infusion. BMJ 1985; 290: 319.

(BANM, USAN, rINNM) ⊗

sponse in patients with secondary loss of efficacy from inflixi-
mab (Remicade) or etanercept (Enbrel): results from the Precautions
STURE registry at Karolinska University Hospital. Scand J
Rheumatol 2005; 34: 353–8. Alfentaniilihydrokloridi; Alfentanil, chlorhydrate d’; Alfentanil Hid- As for Opioid Analgesics in general, p.103.
8. Navarro-Sarabia F, et al. Adalimumab for treating rheumatoid roklorür; Alfentanil-hidroklorid; Alfentanil-hydrochlorid; Alfen-
arthritis. Available in The Cochrane Database of Systematic Re- Children. Alfentanil given to preterm infants undergoing paral-
views; Issue 3. Chichester: John Wiley; 2005 (accessed tanilhydroklorid; Alfentanili hydrochloridum; Alfentanilio hidro- ysis and mechanical ventilation for respiratory distress syndrome
13/06/08). chloridas; Hidrocloruro de alfentanilo; R-39209. N-{1-[2-(4- resulted in a rapid and significant fall in heart rate and blood pres-
9. Weinblatt ME, et al. Long term efficacy and safety of adalimu- Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-(methoxymethyl)-4-piper- sure, emphasising that proper evaluation of the pharmacological
mab plus methotrexate in patients with rheumatoid arthritis: and clinical effects was necessary.1
ARMADA 4 year extended study. Ann Rheum Dis 2006; 65: idyl}propionanilide hydrochloride.
753–9. The BNFC states that the half-life of alfentanil is prolonged in
Альфентанила Гидрохлорид
10. Breedveld FC, et al. The PREMIER study: a multicenter, rand- neonates and accumulation is likely with prolonged use; muscle
omized, double-blind clinical trial of combination therapy with C 21 H 32N 6 O 3 ,HCl = 453.0. rigidity may occur and the use of muscle relaxants may be re-
adalimumab plus methotrexate versus methotrexate alone or
adalimumab alone in patients with early, aggressive rheumatoid C AS — 71195-58-9 (alfentanil); 69049-06-5 (anhydrous quired.
arthritis who had not had previous methotrexate treatment. Ar- alfentanil hydrochloride); 70879-28-6 (alfentanil hydro- 1. Marlow N, et al. Hazards of analgesia for newborn infants. Arch
thritis Rheum 2006; 54: 26–37. Dis Child 1988; 63: 1293.
11. Heiberg MS, et al. Adalimumab and methotrexate is more effec- chloride monohydrate).
tive than adalimumab alone in patients with established rheuma-
The elderly. EEG changes suggested that elderly patients had
ATC — N01AH02. increased brain sensitivity to alfentanil,1 and that lower doses
toid arthritis: results from a 6-month longitudinal, observation-
al, multicentre study. Ann Rheum Dis 2006; 65: 1379–83. ATC Vet — QN01AH02. might be indicated in older patients for pharmacodynamic rather
 Alfentanil Hydrochloride 17
than pharmacokinetic reasons. See also under Pharmacokinetics, shorter. The manufacturers have given values for a three-com- 40 years and steady-state volume of distribution was enlarged
below. partment pharmacokinetic model with a distribution half-life of with increasing age; clearance did not correlate significantly with
1. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose re- 0.4 to 3.1 minutes, a redistribution half-life of 4.6 to 21.6 min- age and was thought to be more variable during a continuous in-
quirements with age: a simultaneous pharmacokinetic and phar- utes, and a terminal elimination half-life of 64.1 to 129.3 minutes fusion in long-term surgery than after a single bolus injection.
macodynamic evaluation. J Pharmacol Exp Ther 1987; 240: after single bolus injections of 50 or 125 micrograms/kg. Accu- Others have reported4 that the effects of age on alfentanil phar-
159–66. mulation is less likely than with fentanyl, but can occur after re- macokinetics are dependent on gender. In this study total plasma
Handling. Avoid contact with the skin and the inhalation of par- peated or continuous dosage especially in patients with reduced clearance decreased and terminal half-life increased with in-
ticles of alfentanil hydrochloride. clearance. The mean elimination half-life reported is usually creasing age in women, but not in men. It has been suggested that
about 90 minutes, but this is reduced in children and increased in this effect in women may be more dependent on menopausal sta-
Inflammatory bowel disease. Patients with Crohn’s disease
the elderly and neonates, in hepatic impairment, in the obese, and tus than on age.5
required higher doses of alfentanil than control patients1 al-
during cardiopulmonary bypass (see below). In a study6 in elderly patients plasma concentrations of alfentanil
though there were no differences in alfentanil pharmacokinetics
between the 2 groups of patients. ◊ Reviews. were greater and the maximum concentration occurred earlier
1. Gesink-van der Veer BJ, et al. Influence of Crohn’s disease on 1. Hull CJ. The pharmacokinetics of alfentanil in man. Br J Anaesth when alfentanil was injected into the deltoid muscle compared
the pharmacokinetics and pharmacodynamics of alfentanil. Br J 1983; 55 (suppl 2): 157S–164S. with injection into the gluteal muscle.
Anaesth 1993; 71: 827–34. 2. Mather LE. Clinical pharmacokinetics of fentanyl and its newer 1. Helmers H, et al. Alfentanil kinetics in the elderly. Clin Pharma-
derivatives. Clin Pharmacokinet 1983; 8: 422–46. col Ther 1984; 36: 239–43.
Pregnancy. UK licensed product information contra-indicates 3. Davis PJ, Cook DR. Clinical pharmacokinetics of the newer in- 2. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose re-
the use of alfentanil in labour, or before clamping of the cord travenous anaesthetic agents. Clin Pharmacokinet 1986; 11: quirements with age: a simultaneous pharmacokinetic and phar-
during caesarean section, because placental transfer means there 18–35. macodynamic evaluation. J Pharmacol Exp Ther 1987; 240:
is a risk of neonatal respiratory depression. 4. Bodenham A, Park GR. Alfentanil infusions in patients requiring 159–66.
intensive care. Clin Pharmacokinet 1988; 15: 216–26. 3. van Beem H, et al. Pharmacokinetics of alfentanil during and
5. Scholz J, et al. Clinical pharmacokinetics of alfentanil, fentanyl after a fixed rate infusion. Br J Anaesth 1989; 62: 610–15.
Interactions and sufentanil. Clin Pharmacokinet 1996; 31: 275–92. 4. Lemmens HJM, et al. Influence of age on the pharmacokinetics
For interactions associated with opioid analgesics, see of alfentanil: gender dependence. Clin Pharmacokinet 1990; 19:
Administration. CO NT IN UO US IN TR AVE NO U S I NF U SIO N.
p.103. Small studies of alfentanil by continuous intravenous
416–22.
5. Rubio A, Cox C. Sex, age and alfentanil pharmacokinetics. Clin
Drugs that depress the heart or increase vagal tone, infusion1-3 have found pharmacokinetic parameters to be sim- Pharmacokinet 1991; 21: 81.
such as beta blockers and anaesthetic drugs, may pre- ilar to those after a single bolus injection, but with some con- 6. Virkkilä M, et al. Pharmacokinetics and effects of i.m. alfentanil
flicting results. In 29 patients undergoing orthopaedic surgery as premedication for day-case ophthalmic surgery in elderly pa-
dispose patients given alfentanil to develop bradycar- an initial bolus intravenous injection of alfentanil tients. Br J Anaesth 1993; 71: 507–11.
dia and hypotension. Use of alfentanil with non-vago- 50 micrograms/kg was followed by intravenous infusion of Hepatic impairment. Total plasma clearance and protein
lytic neuromuscular blockers may produce 1 microgram/kg per minute, continued for 44 to 445 minutes; binding of alfentanil were decreased in patients with alcoholic
bradycardia and possibly asystole. a second bolus injection of 50 micrograms/kg was given im- cirrhosis when compared with control subjects. Elimination half-
mediately before incision and an additional bolus injection of life was prolonged from 90 to 219 minutes in the cirrhotic pa-
The metabolism of alfentanil via the cytochrome P450 1 mg given if necessary.4 The time course of the plasma-al-
isoenzyme CYP3A4 may be reduced by potent inhibi- tients following a single intravenous dose of 50 micrograms/kg
fentanil concentration fitted a two-compartmental model in and was attributed in part to alterations in binding sites of α1-acid
tors of this isoenzyme, resulting in a risk of prolonged 26 patients. Terminal half-lives varied widely from 56 to 226 glycoprotein.1 There might be different effects on alfentanil dis-
or delayed respiratory depression. Reduced doses of al- minutes (mean 106 minutes), the highest values being mainly position in patients with non-alcoholic cirrhosis or other liver
fentanil may be required if given with a CYP3A4 in- in patients over 60 years. There was no significant correlation disorders.2 The pharmacokinetics of alfentanil were apparently
between pharmacokinetic parameters and the duration of the not affected in children with cholestatic hepatic disease whereas
hibitor such as cimetidine, diltiazem, erythromycin, infusion or the total dose. Plasma clearance and volumes of
fluconazole, itraconazole, ketoconazole, or ritonavir. clearance was reduced postoperatively in 3 patients who had un-
distribution did not correlate significantly with body-weight dergone liver transplantation.3
Antibacterials. The elimination half-life of alfentanil was in- although steady-state volume of distribution was enlarged
1. Ferrier C, et al. Alfentanil pharmacokinetics in patients with cir-
creased and clearance decreased when given after a 7-day course with increasing age. The mean estimated steady-state con- rhosis. Anesthesiology 1985; 62: 480–4.
of oral erythromycin in healthy subjects.1 Prolonged respiratory c e n t rat i o n w a s 2 9 3 n a n o g ram s / m L ( ra n g e 1 4 7 t o 2. Bower S, et al. Effects of different hepatic pathologies on dispo-
depression has also occurred in a 32-year-old man given alfen- 636 nanograms/mL). sition of alfentanil in anaesthetized patients. Br J Anaesth 1992;
tanil during anaesthesia after three 1-g doses of erythromycin in 1. Fragen RJ, et al. Pharmacokinetics of the infusion of alfentanil 68: 462–5.
in man. Br J Anaesth 1983; 55: 1077–81. 3. Davis PJ, et al. Effects of cholestatic hepatic disease and chronic
the 24 hours before surgery.2 In another study of healthy subjects, 2. Shafer A, et al. Pharmacokinetics and pharmacodynamics of al- renal failure on alfentanil pharmacokinetics in children. Anesth
the clearance (three-compartment model) of alfentanil was re- fentanil infusions during general anesthesia. Anesth Analg 1986; Analg 1989; 68: 579–83.
duced by 70% in those given oral troleandomycin.3 65: 1021–8.
Other hepatic enzyme inhibitors and drugs interfering with he- 3. Reitz JA, et al. The pharmacokinetics of alfentanil in gynecolog- Obesity. The pharmacokinetics of alfentanil are reportedly al-
patic blood flow might also affect the clearance of alfentanil. ic surgical patients. J Clin Pharmacol 1986; 26: 60–4. tered in obesity.1 Elimination half-life was 172 minutes in 6
4. van Beem H, et al. Pharmacokinetics of alfentanil during and obese patients compared with 92 minutes in 7 who were not
1. Bartkowski RR, et al. Inhibition of alfentanil metabolism by after a fixed rate infusion. Br J Anaesth 1989; 62: 610–15.
erythromycin. Clin Pharmacol Ther 1989; 46: 99–102. obese. Plasma clearance of alfentanil was also decreased, al-
2. Bartkowski RR, McDonnell TE. Prolonged alfentanil effect fol- INTRAMUSCULAR. See The Elderly, below. though others2 found that obesity had no effect on clearance, but
lowing erythromycin administration. Anesthesiology 1990; 73: it did have a direct relationship with the volume of the central
566–8. Burns. The volume of distribution and total clearance of alfen- compartment.
3. Kharasch ED, et al. The role of cytochrome P450 3A4 in alfen- tanil were reduced and its elimination half-life prolonged in pa- 1. Bentley JB, et al. Obesity and alfentanil pharmacokinetics. An-
tanil clearance: implications for interindividual variability in dis- tients with burns.1 This was due, in part, to raised concentrations esth Analg 1983; 62: 251.
position and perioperative drug interactions. Anesthesiology of α1-acid glycoprotein leading to increased protein binding. 2. Maitre PO, et al. Population pharmacokinetics of alfentanil: the
1997; 87: 36–50.
1. Macfie AG, et al. Disposition of alfentanil in burns patients. Br average dose-plasma concentration relationship and interindi-
Antifungals. Azole antifungals such as fluconazole, ketocona- J Anaesth 1992; 69: 447–50. vidual variability in patients. Anesthesiology 1987; 66: 3–12.
zole, or voriconazole can inhibit the metabolism of alfentanil. In Cardiopulmonary bypass. The elimination half-life of alfen- Renal impairment. The pharmacokinetics of alfentanil were
a study,1 giving alfentanil 1 hour after intravenous or oral fluco- tanil increased from 72 minutes before cardiopulmonary bypass not affected significantly in adults1 or children2 with chronic re-
nazole decreased the clearance of alfentanil by 60 and 55%, re- to 195 minutes afterwards in 5 patients.1 This was attributed to an nal failure. In another study3 increased volume of distribution of
spectively and increased the mean half-life of alfentanil from 1.5 increase in volume of distribution, based in part on a dilution- alfentanil at steady state was associated with decreased plasma
hours to 2.7 and 2.5 hours, respectively. Similarly, another study2 induced decrease in plasma protein binding. Others2,3 found that protein binding in patients with chronic renal failure.
found that giving alfentanil 1 hour after oral voriconazole de- on starting cardiopulmonary bypass total serum concentrations 1. Van Peer A, et al. Alfentanil kinetics in renal insufficiency. Eur
creased the clearance of alfentanil by 85% and increased the of alfentanil were halved, mainly because of dilution of α1-acid J Clin Pharmacol 1986; 30: 245–7.
mean half-life of alfentanil to 6.6 hours. glycoprotein and an increase in unbound alfentanil. 2. Davis PJ, et al. Effects of cholestatic hepatic disease and chronic
1. Palkama VJ, et al. The effect of intravenous and oral fluconazole 1. Hug CC, et al. Alfentanil pharmacokinetics in patients before renal failure on alfentanil pharmacokinetics in children. Anesth
on the pharmacokinetics and pharmacodynamics of intravenous and after cardiopulmonary bypass. Anesth Analg 1983; 62: 266. Analg 1989; 68: 579–83.
alfentanil. Anesth Analg 1998; 87: 190–4. 3. Chauvin M, et al. Pharmacokinetics of alfentanil in chronic renal
2. Kumar K, et al. The effect of cardiopulmonary bypass on plasma
2. Saari TI, et al. Voriconazole, but not terbinafine, markedly re- protein binding of alfentanil. Eur J Clin Pharmacol 1988; 35: failure. Anesth Analg 1987; 66: 53–6.
duces alfentanil clearance and prolongs its half-life. Clin Phar- 47–52.
macol Ther 2006; 80: 502–8.
3. Hynynen M, et al. Plasma concentration and protein binding of Uses and Administration
alfentanil during high-dose infusion for cardiac surgery. Br J
Pharmacokinetics Anaesth 1994; 72: 571–6. Alfentanil is a short-acting opioid analgesic (p.104) re-
After parenteral doses alfentanil hydrochloride has a Children. Alfentanil has been shown to have a shorter elimina-
lated to fentanyl (p.58).
rapid onset and short duration of action. Alfentanil is tion half-life (about 40 minutes) and a smaller volume of distri- Alfentanil is used in surgical procedures as an analge-
about 90% protein bound and has a small volume of bution in children than in adults.1 However, the half-life of alfen- sic and adjunct to general anaesthetics or as a primary
tanil is prolonged in neonates. See also Hepatic Impairment, anaesthetic. It is also used as an analgesic and respira-
distribution. Its terminal elimination half-life is about 1 below.
to 2 hours. It is metabolised in the liver; oxidative N- 1. Meistelman C, et al. A comparison of alfentanil pharmacokinet-
tory depressant in the management of mechanically
and O-dealkylation by the cytochrome P450 isoen- ics in children and adults. Anesthesiology 1987; 66: 13–16. ventilated patients under intensive care.
zyme CYP3A4 leads to inactive metabolites, which are The elderly. Plasma clearance of alfentanil after a single intra- Alfentanil is given intravenously as the hydrochloride
excreted in the urine. Alfentanil crosses the blood- venous dose of 50 micrograms/kg was reduced in patients more although doses are expressed in terms of the base. Al-
brain barrier and the placenta and has been detected in than 65 years old when compared with that in healthy young fentanil hydrochloride 108.8 micrograms is equivalent
colostrum. adults.1 Mean elimination half-life was 137 minutes in the elder-
ly and 83 minutes in the young adults. Volumes of distribution to about 100 micrograms of alfentanil. A peak effect
◊ Alfentanil is less lipid-soluble than fentanyl, but more so than were similar and it was considered that reduced clearance might may be seen within 1.5 to 2 minutes of an injection and
morphine. It is highly bound to plasma proteins, mainly to α1- be due to decreased hepatic metabolism in the elderly. In a study analgesia can be expected to last for up to 10 minutes;
acid glycoprotein. Decreased lipid solubility can be expected to in male patients the terminal elimination half-life of alfentanil dose supplements are therefore required if it is to be
limit penetration of the blood-brain barrier when compared with increased with age, although clearance was not significantly af-
fentanyl, but the majority of unbound alfentanil is unionised and fected.2 In patients given alfentanil 1 microgram/kg per minute
used for more prolonged surgical procedures. It may be
can rapidly gain access to the CNS. Alfentanil has a smaller vol- by continuous intravenous infusion during orthopaedic surgery,3 given by continuous intravenous infusion in ventilated
ume of distribution than fentanyl and its elimination half-life is terminal half-life increased linearly with age in those older than patients.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
18 Analgesics Anti-inflammatory Drugs and Antipyretics
The dosage of alfentanil used depends on whether the 2. Virkkilä M, et al. Pharmacokinetics and effects of i.m. alfentanil minutes). However, some considered that there was no over-
as premedication for day-case ophthalmic surgery in elderly pa- all advantage of epidural over intravenous alfentanil either as
patient has spontaneous respiration or assisted ventila- tients. Br J Anaesth 1993; 71: 507–11. patient-controlled analgesia2 or by continuous infusion.3
tion and on the expected duration of anaesthesia. Doses 3. Hughes DA, Hill DA. Intrathecal alfentanil with and without
1. Chrubasik J, et al. Relative analgesic potency of epidural fenta-
are adjusted according to the needs of the patient. Chil- bupivacaine for analgesia in labour. Anaesthesia 2000; 55:
1116–21. nyl, alfentanil, and morphine in treatment of postoperative pain.
dren may require higher or more frequent doses than Anesthesiology 1988; 68: 929–33.
Administration in children. Alfentanil is licensed in the UK 2. Chauvin M, et al. Equivalence of postoperative analgesia with
adults, whereas the elderly or debilitated patients may for use in ventilated children during surgical procedures as an patient-controlled intravenous or epidural alfentanil. Anesth An-
require lower or less frequent doses. Obese patients analgesic and adjunct to general anaesthetics or as a primary an- alg 1993; 76: 1251–8.
may require doses based on their ideal (lean) body- aesthetic. When used as an adjunct in the maintenance of gen- 3. van den Nieuwenhuyzen MCO, et al. Epidural vs intravenous
infusion of alfentanil in the management of postoperative pain
weight. eral anaesthesia licensed product information states that venti- following laparotomies. Acta Anaesthesiol Scand 1996; 40:
lated children may be given the usual intravenous injection doses 1112–18.
When used as an adjunct in the maintenance of gen- as for ventilated adults (see above). However, the BNFC sug-
eral anaesthesia the initial licensed dose in the UK is gests that neonates may be given 5 to 20 micrograms/kg initially Preparations
as follows: and children aged from 1 month to 18 years, 10 to USP 31: Alfentanil Injection.
20 micrograms/kg initially; supplementary doses of up to Proprietary Preparations (details are given in Part 3)
• in patients with spontaneous respiration, up to 10 micrograms/kg may be given. When given by infusion the Arg.: Brevafen; Austral.: Rapifen; Austria: Rapifen; Belg.: Rapifen; Braz.:
500 micrograms may be given slowly over about BNF states that ventilated children may be given the usual doses Alfast; Rapifen; Canad.: Alfenta; Chile: Rapifen; Cz.: Rapifen; Denm.:
as for ventilated adults (see above); the BNFC suggests that usual Rapifen; Fin.: Rapifen; Fr.: Rapifen; Ger.: Rapifen; Gr.: Rapifen; Hong Kong:
30 seconds with supplementary doses of Rapifen; Hung.: Rapifen; Irl.: Rapifen; Israel: Rapifen; Ital.: Fentalim; Ma-
adult doses may be given to those aged as young as 1 month. The laysia: Rapifen†; Mex.: Rapifen; Neth.: Rapifen; Norw.: Rapifen; NZ:
250 micrograms BNFC also suggests that neonates may be given an initial loading Rapifen; S.Afr.: Rapifen; Spain: Fanaxal; Limifen; Swed.: Rapifen; Switz.:
• ventilated patients may be given 30 to dose of 10 to 50 micrograms/kg over 10 minutes followed by in- Rapifen; Turk.: Rapifen; UK: Rapifen; USA: Alfenta; Venez.: Rapifen.
fusion at a rate of 0.5 to 1 microgram/kg per minute.
50 micrograms/kg with supplements of
15 micrograms/kg. When given by infusion to venti- Anaesthesia. Alfentanil, like fentanyl (p.59), appears to pro-
lated patients there is an initial loading dose of 50 to duce fewer circulatory changes than morphine and may be pre- Alminoprofen (rINN)
ferred for anaesthetic use, especially in cardiovascular surgery. It Alminoprofène; Alminoprofeno; Alminoprofenum. 4-[(2-Methy-
100 micrograms/kg given as a bolus or by infusion is generally considered to have a shorter duration of action than
over 10 minutes, followed by infusion at a rate of 0.5 lallyl)amino]hydratropic acid.
fentanyl. It has been used with propofol to facilitate intubation,
to 1 microgram/kg per minute and for total intravenous anaesthesia. Альминопрофен
For a discussion of the drugs used to facilitate intubation and of C 13 H 17NO 2 = 219.3.
Typical doses that have been used in the USA are as opioids such as alfentanil used to control the pressor response C AS — 39718-89-3.
follows: and the rise of intra-ocular pressure associated with intubation, ATC — M01AE16.
see Anaesthesia, p.1900. For reference to a study indicating that ATC Vet — QM01AE16.
• for short surgical procedures of less than 1 hour in
pretreatment with alfentanil can reduce the pain associated with
patients with spontaneous respiration or assisted injection of propofol, see p.1791.
ventilation, the dose is 8 to 20 micrograms/kg; this HO
CAESAREAN SECTION. UK licensed product information contra-
may be followed by supplementary doses of 3 to indicates the use of alfentanil before clamping the cord during O
5 micrograms/kg every 5 to 20 minutes or an infu- caesarean section because of the risk of respiratory depression H3C HN
sion of 0.5 to 1 microgram/kg per minute. Alterna- in the neonate. A study of alfentanil 30 micrograms/kg in
tively patients with assisted or controlled vent- women undergoing caesarean section was abandoned after CH3
ilation may be given an initial dose of 20 to massive respiratory depression had occurred in 4 of 5 neo- H2C
nates.1 Another study2 in patients undergoing elective caesar-
50 micrograms/kg, followed by supplementary dos- ean section found that although maternal haemodynamic re-
es of 5 to 15 micrograms/kg every 5 to 20 minutes sponses to intubation were minimised when alfentanil Profile
10 micrograms/kg was given intravenously immediately be- Alminoprofen, a propionic acid derivative related to ibuprofen
• in general surgical procedures in patients with as- fore induction, neonates in the alfentanil group had lower Ap- (p.64), is an NSAID (p.96). It has been used in inflammatory and
sisted or controlled ventilation, an initial dose of 50 gar scores compared with those in the placebo group. rheumatic disorders in oral doses of up to 900 mg daily.
to 75 micrograms/kg may be followed by an infu- However, alfentanil has been used successfully to minimise Preparations
sion of 0.5 to 3 micrograms/kg per minute. If alfen- haemodynamic responses to intubation and surgery in patients Proprietary Preparations (details are given in Part 3)
tanil has been given in anaesthetic doses (see below) with severe cardiovascular disorders undergoing caesarean sec- Fr.: Minalfene.
for the induction of anaesthesia, infusion rates may tion.3,4 A baby delivered after the successful use of alfentanil
35 micrograms/kg in a mother with severe aortic stenosis3 was
need to be reduced by 30 to 50% during the first hour apnoeic and unresponsive with poor muscle tone; the baby re-
of maintenance sponded rapidly to naloxone. Alfentanil 10 micrograms/kg im- Aloxiprin (BAN, rINN)
mediately before induction attenuated the cardiovascular re- Acetilsalicilato de polioxoaluminio; Aloksipriini; Aloxiprina;
Maintenance infusions of alfentanil should be stopped sponse to intubation in patients with severe pregnancy-induced Aloxiprine; Aloxiprinum.
10 to 30 minutes before the anticipated end of surgery. hypertension4 and was considered a suitable alternative to fenta- Алоксиприн
For details of doses in children, see below. nyl 2.5 micrograms/kg; no effect on neonatal mortality could be
C AS — 9014-67-9.
attributed to anaesthetic technique. However, it has been sug-
ATC — B01AC15; N02BA02.
The dose for the induction of anaesthesia in patients gested that the use of smaller doses of alfentanil of
ATC Vet — QB01AC15; QN02BA02.
with assisted ventilation undergoing procedures of at 7.5 micrograms/kg with magnesium sulfate 30 mg/kg may pro-
least 45 minutes is 130 to 245 micrograms/kg, fol- vide better cardiovascular control.5
1. Leuwer M, et al. Pharmacokinetics and pharmacodynamics of an
lowed by an inhalation anaesthetic or maintenance equipotent fentanyl and alfentanil dose in mother and infant dur- COOH
doses of alfentanil of 0.5 to 1.5 micrograms/kg per ing caesarean section. Br J Anaesth 1990; 64: 398P–9P.
Al2O2
minute. 2. Gin T, et al. Alfentanil given immediately before the induction
of anesthesia for elective cesarean delivery. Anesth Analg 2000;
90: 1167–72. O
In the UK, ventilated patients in intensive care may be
3. Redfern N, et al. Alfentanil for caesarean section complicated by
given alfentanil initially at an infusion rate of severe aortic stenosis: a case report. Br J Anaesth 1987; 59:
2 mg/hour or a loading dose of 5 mg may be given in 1309–12. O CH3
4. Rout CC, Rocke DA. Effects of alfentanil and fentanyl on induc-
divided doses over 10 minutes or more slowly if hypo- tion of anaesthesia in patients with severe pregnancy-induced Pharmacopoeias. In Br.
tension or bradycardia occur. Thereafter a suitable rate hypertension. Br J Anaesth 1990; 65: 468–74. BP 2008 (Aloxiprin). A polymeric condensation product of alu-
of infusion should be determined for each patient (rates 5. Ashton WB, et al. Attenuation of the pressor response to tracheal
intubation by magnesium sulphate with and without alfentanil in minium oxide and aspirin. A fine, white or slightly pink powder,
of 0.5 to 10 mg/hour have been used); patients should hypertensive proteinuric patients undergoing caesarean section. odourless or almost odourless. It contains not less than 7.5% and
be carefully monitored and the duration of treatment Br J Anaesth 1991; 67: 741–7. not more than 8.5% of aluminium and not less than 79.0% and
should not generally exceed 4 days. During continuous not more than 87.4% of total salicylates, calculated as aspirin,
PHAEOCHROMOCYTOMA. Alfentanil does not release histamine
and was of value in the anaesthetic management of patients C9H8O4, both calculated with reference to the dried substance.
infusion additional bolus injections of 0.5 to 1 mg may Practically insoluble in water, in alcohol, and in ether; slightly
be given if required to provide analgesia for short pain- with phaeochromocytoma.1 It has a very rapid onset of action,
good vasodilating properties, and a relatively short elimina- soluble in chloroform.
ful procedures that may be carried out in intensive care. tion half-life. These patients are often very somnolent for the Profile
Alfentanil is also used as an analgesic in patients with first 48 hours after surgery and postoperative opioid dosage Aloxiprin, a polymeric condensation product of aluminium ox-
spontaneous respiration receiving monitored anaes- requirements may be less than expected. Alfentanil infusion ide and aspirin, has actions similar to those of aspirin (p.20);
continued into the postoperative period allows careful titra- aloxiprin 600 mg is equivalent to about 500 mg of aspirin.
thesia care; in the USA, an initial dose of 3 to tion of dosage. Aloxiprin has been used as an analgesic and anti-inflammatory
8 micrograms/kg may be followed by supplementary 1. Hull CJ. Phaeochromocytoma: diagnosis, preoperative prepara- in musculoskeletal and joint disorders. It has also been used in
doses of 3 to 5 micrograms/kg every 5 to 20 minutes or tion and anaesthetic management. Br J Anaesth 1986; 58: the treatment and prevention of thromboembolic disorders.
1453–68.
an infusion of 0.25 to 1 microgram/kg per minute. Preparations
Pain. POSTOPERATIVE ANALGESIA. Continuous on-demand epi- BP 2008: Aloxiprin Tablets.
Administration. Alfentanil is usually given by intravenous in- dural infusions of alfentanil 200 micrograms/hour or fentanyl
jection or infusion, but has also been given intramuscularly,1,2 20 micrograms/hour provided comparable analgesia to mor- Proprietary Preparations (details are given in Part 3)
intrathecally,3 or epidurally (see Pain, below). Cz.: Superpyrin.
phine 200 micrograms/hour in the early postoperative peri-
od;1 alfentanil (16 minutes) and fentanyl (13 minutes) had the Multi-ingredient: UK: Askit.
1. Arendt-Nielsen L, et al. Analgesic efficacy of im alfentanil. Br J
Anaesth 1990; 65: 164–8. advantage of more rapid onset of analgesia than morphine (44
 Alminoprofen/Anakinra 19
Aluminium Aspirin
Acetilsalicilato de aluminio; Aluminum Acetylsalicylate; Alumi-
num Aspirin; Aluminum Bis(acetylsalicylate); Aspirin Aluminium. H 3C CH3 H 3C
O
Bis(2-acetoxybenzoato-O′)hydroxyaluminium. H 3C N
Алюминий Аспирина; Аспирин Алюминий N H 3C O
N H
C 18 H 15AlO 9 = 402.3. N H N
H 3C N
C AS — 23413-80-1. CH3 O O
O O OCH3

O O O O Profile
Al Aminopropylone is an NSAID (p.96) that has been used in topi- Profile
cal preparations, for the local treatment of pain and inflammatory Amtolmetin guacil is an NSAID (p.96) that is an ester prodrug of
H3C O OH O CH3 conditions. The hydrochloride has been used similarly. tolmetin (p.130). It is used in painful and inflammatory disorders
Preparations in oral doses of 600 to 1200 mg daily.
O O Proprietary Preparations (details are given in Part 3) ◊ References.
1. Biasi G, Marcolongo R. Efficacia e tollerabilità dell’amtolmetina
Multi-ingredient: Ital.: Vessiflex†.
guacil nel trattamento dell’artrosi in fase di riacutizzazione. Min-
Pharmacopoeias. In Jpn. erva Med 2001; 92: 315–24.
2. Jajic Z, et al. Gastrointestinal safety of amtolmetin guacyl in
Profile comparison with celecoxib in patients with rheumatoid arthritis.
Aluminium aspirin is a salicylic acid derivative (see Aspirin, Ammonium Salicylate Clin Exp Rheumatol 2005; 23: 809–18.
p.20) that has been given orally in the management of fever, pain, Salicilato de amonio. Preparations
and musculoskeletal and joint disorders. Аммоний Салицилат Proprietary Preparations (details are given in Part 3)
Preparations C 7 H 9 NO 3 = 155.2. Ital.: Artricol; Artromed; Eufans.
Proprietary Preparations (details are given in Part 3) C AS — 528-94-9.
Multi-ingredient: Indon.: Remasal; S.Afr.: Analgen-SA†.
Amyl Salicylate
HO Isoamyl Salicylate; Isopentyl Salicylate; Salicilato de isoamilo; Sali-
NH4+ -O cilato de isopentilo. 3-Methylbutyl 2-hydroxybenzoate.
Aminophenazone (rINN) Амилсалицилат
Amidazofen; Amidopyrine; Amidopyrine-Pyramidon; Amino- C 12 H 16 O 3 = 208.3.
fenatsoni; Aminofenazon; Aminofenazona; Aminophénazone; O C AS — 87-20-7.
Aminophenazonum; Aminopyrine; Dimethylaminoantipyrine;
Dimethylaminophenazone. 4-Dimethylamino-1,5-dimethyl-2- Profile
phenyl-4-pyrazolin-3-one. Ammonium salicylate is a salicylic acid derivative used topically
Аминофеназон in rubefacient preparations similarly to methyl salicylate (p.85)
for the relief of pain in musculoskeletal and joint disorders. O CH3
C 13 H 17N 3 O = 231.3.
C AS — 58-15-1. Preparations
ATC — N02BB03. Proprietary Preparations (details are given in Part 3) OH O CH3
ATC Vet — QN02BB03. Multi-ingredient: Austral.: Radian-B†; Irl.: Radian-B†; UK: Radian-B.
Pharmacopoeias. In Fr.
Profile
Ampiroxicam (BAN, rINN) Amyl salicylate is a salicylic acid derivative used topically in ru-
befacient preparations similarly to methyl salicylate (p.85) for its
Ampiroxicamum; CP-65703. 4-[1-(Ethoxycarbonyloxy)ethoxy]- analgesic and anti-inflammatory actions. It has also been used in
2-methyl-N2-pyridyl-2H-1,2-benzothiazine-3-carboxamide 1,1- perfumery.
dioxide.
N CH3 Preparations
O Ампироксикам
N Proprietary Preparations (details are given in Part 3)
C 20 H 21 N 3 O 7 S = 447.5.
H 3C C AS — 99464-64-9.
Multi-ingredient: Arg.: Atomo Desinflamante; Atomo Desinflamante C;
N CH3 Atomo Desinflamante Familiar; Rati Salil Crema; Fr.: Sedartryl†; Spain: Lin-
imento Klari†.

CH3 O O
Pharmacopoeias. In It. S CH3 Anakinra (BAN, USAN, rINN)
N Anakinrum; rhIL-1ra; r-metHuIL-1ra. N2-L-methionylinterleukin 1
Profile H receptor antagonist (human isoform x reduced).
Aminophenazone, a pyrazolone derivative, is an NSAID (p.96), N
Анакинра
but the risk of agranulocytosis is sufficiently great to render it
unsuitable for systemic use. Onset of agranulocytosis may be C AS — 143090-92-0.
H 3C O O O O N ATC — L04AC03.
sudden and unpredictable. Aminophenazone has been used as
salts or complexes, including topically as the salicylate. ATC Vet — QL04AC03.
O CH3
Precautions. CARCINOGENICITY. Some1 consider that amino-
phenazone should be regarded as a potential carcinogen be- M
cause it reacted readily with nitrous acid to form dimethylni- Profile RPSGRKSSKM QAFRIWDVNQ KTFYLRNNQL VAGYLQGPNV NLEEKIDVVP
trosamine. The reaction was catalysed by thiocyanate present Ampiroxicam is an NSAID (p.96) that is reported to be metabo- IEPHALFLGI HGGKMCLSCV KSGDETRLQL EAVNITDLSE NRKQDKRFAF
in the saliva particularly in smokers. lised to piroxicam (p.117). It has been given orally for the relief
IRSDSGPTTS FESAACPGWF LCTAMEADQP VSLTNMPDEG VMVTKFYFQE
of pain and inflammation particularly in musculoskeletal disor-
1. Boyland E, Walker SA. Catalysis of the reaction of aminopyrine DE
and nitrite by thiocyanate. Arzneimittelforschung 1974; 24: ders such as rheumatoid arthritis and osteoarthritis.
1181–4. Adverse effects. Photosensitivity reactions have occurred dur-
ing ampiroxicam treatment.1-3 Adverse Effects and Precautions
PORPHYRIA. Aminophenazone has been associated with acute Mild to moderate injection site reactions with symptoms of ery-
attacks of porphyria and is considered unsafe in porphyric pa- 1. Kurumaji Y. Ampiroxicam-induced photosensitivity. Contact
thema, bruising, swelling, and pain are common with anakinra
tients. Dermatitis 1996; 34: 298–9.
2. Toyohara A, et al. Ampiroxicam-induced photosensitivity. Con- particularly in the first month of treatment. Other common reac-
Preparations tact Dermatitis 1996; 35: 101–2. tions include headache, nausea, diarrhoea, and abdominal pain.
3. Chishiki M, et al. Photosensitivity due to ampiroxicam. Derma- Antibodies to anakinra may develop. Allergic reactions such as
Proprietary Preparations (details are given in Part 3)
tology 1997; 195: 409–10. rashes have been reported rarely; if a severe allergic reaction oc-
Multi-ingredient: Braz.: Gineburno†; Cz.: Dinyl†; Eunalgit†; Hung.: An- curs, anakinra should be stopped and appropriate treatment giv-
tineuralgica; Demalgon; Demalgonil; Dolor; Germicid-C; Germicid†; Kefal- Preparations
gin; Meristin; Ital.: Virdex; Mex.: Flumil; Switz.: Thermocutan†; Venez.: en.
Proprietary Preparations (details are given in Part 3)
Flexidone†.
Jpn: Flucam†.
Serious infections have been reported with anakinra, particularly
in patients with asthma. These infections are mainly bacterial,
such as cellulitis, pneumonia, and bone and joint infections.
More rarely, opportunistic infections involving fungal, mycobac-
Aminopropylone Amtolmetin Guacil (rINN) terial, and viral pathogens have also been seen. Anakinra should
Aminopropilona; Aminopropylon. N-(2,3-Dihydro-1,5-dimethyl- Amtolmetina guacilo; Amtolmétine Guacil; Amtolmetinum be stopped in those who develop a serious infection. In addition,
3-oxo-2-phenyl-1H-pyrazol-4-yl)-2-(dimethylamino)propana- therapy should not be started in patients with active infections,
Guacilum; MED-15; ST-679. N-[(1-Methyl-5-p-toluoylpyrrol-2-
mide. including chronic or localised infections; caution is recommend-
yl)acetyl]glycine o-methoxyphenyl ester. ed in those with a history of recurrent infections or with underly-
Аминопропилон Амтолметин Гуацил ing conditions that may predispose to infections.
C 16 H 22N 4 O 2 = 302.4. C 24 H 24 N 2 O 5 = 420.5. A small decrease in absolute neutrophil count (ANC) is com-
C AS — 3690-04-8. C AS — 87344-06-7. monly seen with anakinra treatment; however, true neutropenia
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
20 Analgesics Anti-inflammatory Drugs and Antipyretics
(ANC <1500 cells/mm3) is rare. Licensed product information 2. Cohen S, et al. Treatment of rheumatoid arthritis with anakinra,
Aspirin (BAN)
recommends that neutrophil counts should be taken before start- a recombinant human interleukin-1 receptor antagonist, in com-
bination with methotrexate: results of a twenty-four-week, mul- _
ing anakinra and periodically throughout treatment. UK licensed ticenter, randomized, double-blind, placebo-controlled trial. Ar- Acetilsalicílico, ácido; Acetilsalicilo ru gštis; Acetilszalicilsav; Ace-
information recommends monthly monitoring during the first 6 thritis Rheum 2002; 46: 614–24. tylsal. Acid; Acetylsalicylic Acid; Acetylsalicylsyra; Acide acétylsal-
months and then quarterly thereafter; US licensed information 3. Nuki G, et al. Long-term safety and maintenance of clinical im- icylique; Acidum acetylsalicylicum; Asetilsalisilik Asit; Asetyylisal-
requires monthly monitoring for the first 3 months and then quar- provement following treatment with anakinra (recombinant hu-
man interleukin-1 receptor antagonist) in patients with rheuma-
isyylihappo; Kwas acetylosalicylowy; Kyselina acetylsalicylová; Pol-
terly monitoring for a period of up to 1 year. Anakinra should not opiryna; Salicylic Acid Acetate. O-Acetylsalicylic acid; 2-Acetoxy-
toid arthritis: extension phase of a randomized, double-blind,
be started in patients with neutropenia. Small reductions in the placebo-controlled trial. Arthritis Rheum 2002; 46: 2838–46. benzoic acid.
total white blood cell and platelets counts and a small increase in 4. Fleischmann RM, et al. Anakinra, a recombinant human inter-
eosinophils have also been noted. Anakinra is also associated leukin-1 receptor antagonist (r-metHuIL-1ra), in patients with Аспирин
with an increased incidence of lymphoma in patients with rheu- rheumatoid arthritis: a large, international, multicenter, placebo- C 9 H 8 O 4 = 180.2.
controlled trial. Arthritis Rheum 2003; 48: 927–34.
matoid arthritis. C AS — 50-78-2.
5. NICE. Anakinra for rheumatoid arthritis: Technology Appraisal
For caution in patients with renal impairment see under Uses and Guidance 72 (issued November 2003). Available at: ATC — A01AD05; B01AC06; N02BA01.
Administration, below. http://www.nice.org.uk/nicemedia/pdf/TA072guidance.pdf (ac-
cessed 22/06/07) ATC Vet — QA01AD05; QB01AC06; QN02BA01.
Effects on the cardiovascular system. A 29-year-old wom- 6. Schiff MH. Durability and rapidity of response to anakinra in
an with refractory adult-onset Still’s disease developed shortness patients with rheumatoid arthritis. Drugs 2004; 64: 2493–2501.
of breath, which progressed to cardiorespiratory failure, 3 7. Waugh J, Perry CM. Anakinra: a review of its use in the man- COOH
agement of rheumatoid arthritis. BioDrugs 2005; 19: 189–202.
months after being started on anakinra;1 although resuscitation 8. Reiff A. The use of anakinra in juvenile arthritis. Curr Rheuma-
was tried, the patient died. The authors considered that the role of O CH3
tol Rep 2005; 7: 434–40.
anakinra in this event was unclear, particularly as the patient had 9. den Broeder AA, et al. Observational study on efficacy, safety,
shown some evidence of myocardial or pulmonary dysfunction and drug survival of anakinra in rheumatoid arthritis patients in O
before starting the drug. clinical practice. Ann Rheum Dis 2006; 65: 760–2.
10. Burger D, et al. Is IL-1 a good therapeutic target in the treatment
1. Ruiz PJ, et al. Cardiac death in a patient with adult-onset Still’s of arthritis? Best Pract Res Clin Rheumatol 2006; 20: 879–96.
disease treated with the interleukin 1 receptor inhibitor anakinra. NOTE. The use of the name Aspirin is limited; in some countries
Ann Rheum Dis 2007; 66: 422–3. Preparations it is a trade-mark.
Proprietary Preparations (details are given in Part 3) Compounded preparations of aspirin may be represented by the
Effects on the skin. Inflammatory lesions at injection sites following names:
Austral.: Kineret; Canad.: Kineret; Cz.: Kineret; Denm.: Kineret; Fin.: Ki-
were reported in 5 patients after anakinra use.1 The lesions were neret; Fr.: Kineret; Ger.: Kineret; Gr.: Kineret; Irl.: Kineret; Ital.: Kineret;
erythematous, oedematous, painful, and itchy plaques, and were Neth.: Kineret; Norw.: Kineret; Pol.: Kineret; Port.: Kineret; Spain: Kiner- • Co-codaprin (BAN)—aspirin 50 parts and codeine phosphate
seen within 16 days of starting treatment. Treatment with anak- et; Swed.: Kineret; UK: Kineret; USA: Kineret. 1 part (w/w)
inra was completely stopped in 1 patient and interrupted in 2 oth- • Co-codaprin (PEN)—aspirin and codeine phosphate.
er patients; when reintroduced, one patient developed abdominal
pain, dyspnoea, and facial and abdominal erythema with pruri- Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
tus. Anileridine (BAN, rINN) Viet.
Anileridiini; Anileridin; Anileridina; Aniléridine; Anileridinum. Ethyl Ph. Eur. 6.2 (Acetylsalicylic Acid; Aspirin BP 2008). White or al-
1. Vila AT, et al. Adverse cutaneous reactions to anakinra in pa-
tients with rheumatoid arthritis: clinicopathological study of five 1-(4-aminophenethyl)-4-phenylpiperidine-4-carboxylate. most white, crystalline powder or colourless crystals. Slightly
patients. Br J Dermatol 2005; 153: 417–23. soluble in water; freely soluble in alcohol. Store in airtight con-
Анилеридин tainers.
Interactions C 22 H 28N 2 O 2 = 352.5. USP 31 (Aspirin). White crystals, commonly tubular or needle-
Live vaccines should not be given with anakinra as its effect on C AS — 144-14-9. like, or white crystalline powder; odourless or has a faint odour.
vaccine efficacy or the risk of infection transmission is unknown. ATC — N01AH05. Is stable in dry air; in moist air it gradually hydrolyses to salicylic
The risk of serious infection and neutropenia is increased when ATC Vet — QN01AH05. and acetic acids. Soluble 1 in 300 of water, 1 in 5 of alcohol, 1 in
anakinra and etanercept are used together (see under Infliximab, 17 of chloroform, and 1 in 10 to 15 of ether; sparingly soluble in
p.71); a similar effect may occur with other TNF antagonists. absolute ether. Store in airtight containers.
The use of anakinra with etanercept or other TNF inhibitors is O CH3
not recommended. O Adverse Effects and Treatment
Pharmacokinetics Aspirin has many properties in common with the non-
After subcutaneous doses, peak plasma concentrations of anak- aspirin NSAIDs, the adverse effects of which are de-
inra are reached in 3 to 7 hours. Its terminal half-life is about 4 to N
6 hours. Anakinra is excreted mainly in the urine. scribed on p.96.
Uses and Administration The most common adverse effects of therapeutic doses
Anakinra is a recombinant receptor antagonist of interleukin-1 H 2N of aspirin are gastrointestinal disturbances such as nau-
(p.2325), an inflammatory mediator found in the plasma and sea, dyspepsia, and vomiting. Gastrointestinal symp-
synovial fluid of patients with rheumatoid arthritis. Pharmacopoeias. In US. toms may be minimised by giving aspirin with food.
Anakinra is used for the treatment of the signs and symptoms of USP 31 (Anileridine). A white to yellowish-white, odourless or Irritation of the gastric mucosa with erosion, ulcera-
moderate to severely active rheumatoid arthritis in patients who practically odourless, crystalline powder. When exposed to light
and air it oxidises and darkens in colour. It exhibits polymor- tion, haematemesis, and melaena may occur. Hista-
have had an inadequate response to methotrexate or another dis-
ease-modifying antirheumatic drug (DMARD) alone (but see phism, and of two crystalline forms observed, one melts at about mine H2-antagonists, proton pump inhibitors, and
below). In the UK, it is only licensed for use with methotrexate; 80° and the other at about 89°. Very slightly soluble in water; sol- prostaglandin analogues such as misoprostol may be
however, in the USA, it may be given either alone or with anoth- uble 1 in 2 of alcohol and 1 in 1 of chloroform; soluble in ether used in the management of NSAID-induced ulceration
er DMARD, although not one that inhibits TNF (see Interac- but solutions may be turbid. Store in airtight containers. Protect (see Peptic Ulcer Disease, p.1702), including that
tions, above). The usual dose in adults is 100 mg once daily by from light.
caused by aspirin. Slight blood loss, which is often
subcutaneous injection. The dose should be given at about the
same time each day. Anileridine Hydrochloride (BANM, rINNM) asymptomatic, may occur in about 70% of patients; it
Anakinra has been tried in septic shock and graft-versus-host dis- Aniléridine, Chlorhydrate d’; Anileridini Hydrochloridum; Hidro-
is not usually of clinical significance but may, in a few
ease in transplant recipients, but results were disappointing. cloruro de anileridina. patients, cause iron-deficiency anaemia during long-
Administration in renal impairment. Caution may be ad- Анилеридина Гидрохлорид
term therapy. Such occult blood loss is not affected by
visable if anakinra is used in patients with renal impairment. A C 22 H 28N 2 O 2 ,2HCl = 425.4. giving aspirin with food but may be reduced by use of
study1 in patients with varying degrees of renal function indicat- C AS — 126-12-5. enteric-coated or other modified-release tablets, H2-
ed that no dosage adjustment was needed for anakinra in patients antagonists, or high doses of antacids. Major upper
Pharmacopoeias. In US.
with mild or moderate renal impairment but dosage on alternate gastrointestinal bleeding occurs rarely.
USP 31 (Anileridine Hydrochloride). A white or nearly white
days appeared advisable in those with severe renal impairment.
odourless crystalline powder. Soluble 1 in 5 of water and 1 in 80 Some persons, especially those with asthma, chronic
US licensed product information also recommends alternate-day
of alcohol; practically insoluble in chloroform and in ether. pH of
dosing in patients with severe impairment or end-stage disease
a 5% solution in water is 2.5 to 3.0. Store in airtight containers. urticaria, or chronic rhinitis, exhibit notable hypersen-
(creatinine clearance less than 30 mL/minute). However, in the sitivity to aspirin (see also below), which may provoke
UK, licensed product information contra-indicates use in those Protect from light.
with this degree of impairment.
reactions including urticaria and other skin eruptions,
Dialysis does not affect anakinra concentrations to any signifi- Anileridine Phosphate (BANM, rINNM) angioedema, rhinitis, and severe, even fatal, paroxys-
cant degree. Aniléridine, Phosphate d’; Anileridini Phosphas; Fosfato de anile- mal bronchospasm and dyspnoea. Persons sensitive to
1. Yang B-B, et al. Pharmacokinetics of anakinra in subjects with ridina. aspirin often exhibit cross-sensitivity to other NSAIDs.
different levels of renal function. Clin Pharmacol Ther 2003; 74: Анилеридина Фосфат Aspirin increases bleeding time, decreases platelet ad-
85–94.
C 22 H 28N 2 O 2 ,H 3 PO 4 = 450.5. hesiveness, and, in large doses, can cause hypopro-
Familial Mediterranean fever. For mention of anakinra hav- C AS — 4268-37-5.
ing been tried in familial Mediterranean fever, see p.557.
thrombinaemia. It may cause other blood disorders, in-
Profile cluding thrombocytopenia.
Rheumatoid arthritis. In the UK, anakinra is licensed for the Anileridine, a phenylpiperidine derivative, is an opioid analgesic
treatment of rheumatoid arthritis (p.11) in patients with an inad- (p.101) chemically related to pethidine (p.113) and with similar Aspirin and other salicylates may cause hepatotoxicity,
equate response to methotrexate alone; however, NICE does not actions. It has been used as the hydrochloride in the management particularly in patients with juvenile idiopathic arthritis
recommend its use except in the context of a controlled, long- of moderate to severe pain. Anileridine has also been given by or other connective tissue disorders. In children the use
term clinical study. injection as the phosphate. of aspirin has been implicated in some cases of Reye’s
References. Preparations syndrome, leading to severe restrictions on the indica-
1. Bresnihan B, et al. Treatment of rheumatoid arthritis with re- USP 31: Anileridine Hydrochloride Tablets; Anileridine Injection. tions for aspirin therapy in children. For further details
combinant human interleukin-1 receptor antagonist. Arthritis
Rheum 1998; 41: 2196–2204. see under Reye’s Syndrome, below.
 Anileridine/Aspirin 21
Aspirin given rectally may cause local irritation; Effects on the cardiovascular system. Salicylate poisoning Effects on the kidneys. Although abuse of combined analge-
anorectal stenosis has been reported. may result in cardiovascular collapse but details of such cases sic preparations containing aspirin has been implicated in the de-
have not been widely reported. In 2 patients with salicylate intox- velopment of analgesic nephropathy, kidney damage associated
Mild chronic salicylate intoxication, or salicylism, usu- ication asystole developed after intravenous diazepam.1 It was with the therapeutic use of aspirin alone appears to be compara-
ally occurs only after repeated use of large doses. Sali- suggested that diazepam-induced respiratory depression affected tively rare. Many studies have failed to find an increased risk of
cylism can also occur following excessive topical ap- the acid–base balance so that the concentration of non-ionised renal damage in patients taking aspirin.1-9
plication of salicylates. Symptoms include dizziness, membrane-penetrating fraction of salicylate was increased. Fatal 1. New Zealand Rheumatism Association Study. Aspirin and the
aspirin intoxication in a 5-year-old child was marked by hypo- kidney. BMJ 1974; 1: 593–6.
tinnitus, deafness, sweating, nausea and vomiting, tension and rapidly progressive cardiac symptoms including 2. Walker BR, et al. Aspirin and renal function. N Engl J Med 1977;
headache, and confusion, and may be controlled by re- ventricular tachycardia and AV block.2 Extensive myocardial 297: 1405.
3. Akyol SM, et al. Renal function after prolonged consumption of
ducing the dosage. Tinnitus can occur at the plasma necrosis was found at autopsy. aspirin. BMJ 1982; 284: 631–2.
concentrations of 150 to 300 micrograms/mL required For reference to the effects of aspirin on blood pressure com- 4. Bonney SL, et al. Renal safety of two analgesics used over the
for optimal anti-inflammatory activity; more serious pared with other NSAIDs, see p.96. counter: ibuprofen and aspirin. Clin Pharmacol Ther 1986; 40:
1. Berk WA, Andersen JC. Salicylate-associated asystole: report of 373–7.
adverse effects occur at concentrations above two cases. Am J Med 1989; 86: 505–6. 5. Sandler DP, et al. Analgesic use and chronic renal disease. N
300 micrograms/mL. Symptoms of more severe intox- 2. Peña-Alonso YR, et al. Aspirin intoxication in a child associated Engl J Med 1989; 320: 1238–43.
with myocardial necrosis: is this a drug-related lesion? Pediatr 6. Pommer W, et al. Regular analgesic intake and the risk of end-
ication or of acute poisoning following overdosage in- Dev Pathol 2003; 6: 342–7. stage renal failure. Am J Nephrol 1989; 9: 403–12.
clude hyperventilation, fever, restlessness, ketosis, and 7. Dubach UC, et al. An epidemiologic study of abuse of analgesic
Effects on the gastrointestinal tract. Clinical and epidemi- drugs: effects of phenacetin and salicylate on mortality and car-
respiratory alkalosis and metabolic acidosis. Depres- ological evidence suggests that aspirin produces dose-related diovascular morbidity (1968 to 1987). N Engl J Med 1991; 324:
sion of the CNS may lead to coma; cardiovascular col- gastrointestinal toxicity1,2 that is sometimes, but rarely, fatal.2 155–60.
lapse and respiratory failure may also occur. In chil- Meta-analysis3 suggests that the risk of gastrointestinal bleeding 8. Perneger TV, et al. Risk of kidney failure associated with the use
of acetaminophen, aspirin, and nonsteroidal antiinflammatory
dren drowsiness and metabolic acidosis commonly is not significantly lowered with the use of oral low-dose aspirin drugs. N Engl J Med 1994; 331: 1675–9.
(less than 300 mg daily). A systematic review4 of observational
occur; hypoglycaemia may be severe. epidemiologic studies also concurred with this finding. More re-
9. Rexrode K, et al. Analgesic use and renal function in men. JAMA
2001; 286: 315–21.
In acute oral salicylate overdosage the UK National cently, a systematic review5 of randomised, controlled studies
Effects on the liver. Aspirin-induced hepatic injury is general-
Poisons Information Service recommends that repeat- found that although low-dose aspirin (up to 325 mg daily) in-
ly mild and manifests as a mild to moderate elevation in ami-
ed oral doses of activated charcoal be given if the pa- creased the risk of major bleeding including gastrointestinal
notransferase values; however, there is a risk of severe liver inju-
bleeding by twofold when compared to placebo, the actual risk
tient is suspected of ingesting more than 125 mg/kg of ry.1 One review2 reported an increase in aminotransferase values
of bleeding was modest; for every 833 patients taking low-dose
salicylate within 1 hour of presentation. Activated in 59 of 439 patients given aspirin; the increase was considered
aspirin for cardiovascular prophylaxis only 1 additional major
charcoal not only prevents the absorption of any sali- to be probably related to aspirin in 23. Hepatotoxicity appears to
bleeding episode will occur annually. In another, population-
be correlated with serum-salicylate concentrations greater than
cylate remaining in the stomach but also aids the elim- based study,6 the annual excess risk of upper gastrointestinal
150 micrograms/mL and with active rheumatoid disease. Aspi-
ination of any that has been absorbed. complications was about an extra 5 cases per 1000 patients; how-
rin-induced liver injury is usually reversible on stopping the
ever, the excess risk varied with underlying gastrointestinal risk
Measurement of plasma-salicylate concentration drug.2
factors such as old age and might exceed an extra 10 cases per
should be carried out in patients who have ingested 1000 patients in a higher risk group comprising over 10% of as- See also under Reye’s Syndrome, below.
pirin users. It has been suggested that very small doses of aspirin 1. Lewis JH. Hepatic toxicity of nonsteroidal anti-inflammatory
more than 125 mg/kg of salicylate, although the sever- drugs. Clin Pharm 1984; 3: 128–38.
ity of poisoning cannot be estimated from plasma con- can produce prophylactic benefits in cardiovascular disease 2. Freeland GR, et al. Hepatic safety of two analgesics used over
without the risk of gastrointestinal toxicity,7 although others have the counter: ibuprofen and aspirin. Clin Pharmacol Ther 1988;
centrations alone. Absorption of aspirin can be delayed reported gastric injury even with doses of 10 mg daily.8 43: 473–9.
by reduced gastric emptying, formation of concretions There appears to be no convincing evidence that the risk of major Effects on the mouth. Aspirin burn (ulceration of the mucosal
in the stomach, or as a result of ingestion of enteric- gastrointestinal bleeding associated with a 75-mg dose is re- layer of the lips) developed in a 26-year-old woman after taking
coated preparations. In consequence, plasma concen- duced by using enteric-coated or modified-release formulations an aspirin-containing powder for a migraine.1 The woman had
trations should be measured at least 2 hours (sympto- rather than soluble aspirin,3,4,9 although individual studies have swallowed the powder undissolved rather than adding to water.
reported a reduction in acute mucosal injury with enteric coat-
matic patients) or 4 hours (asymptomatic patients) after ing.10 All known NSAIDs have the potential for causing acute
1. Dellinger TM, Livingston HM. Aspirin burn of the oral cavity.
Ann Pharmacother 1998; 32: 1107.
ingestion and repeated 2 hours later. Patients who over- damage to the gastric mucosa (see p.97), and comparative stud-
dose with enteric preparations require continual moni- ies of acute gastric mucosal damage caused by such drugs con- Hypersensitivity. The main clinical features of patients who
sistently associate aspirin with the most severe lesions.1 Gastric have aspirin hypersensitivity include middle-age, female sex, di-
toring of plasma concentrations. agnoses of asthma or rhinitis, a personal or family history of ato-
mucosal injury can occur even with cutaneous application.11
Fluid and electrolyte management is essential to cor- 1. Graham DY, Smith JL. Aspirin and the stomach. Ann Intern py, and a history of nasal polyps.1,2 Aspirin sensitivity occurring
rect acidosis, hyperpyrexia, hypokalaemia, and dehy- Med 1986; 104: 390–8. with asthma and nasal polyps has been referred to in some re-
dration. Intravenous sodium bicarbonate is given to 2. Roderick PJ, et al. The gastrointestinal toxicity of aspirin: an ports as the ‘aspirin triad’. Other sensitivities often found con-
overview of randomised controlled trials. Br J Clin Pharmacol comitantly include allergy to food dyes such as tartrazine and to
enhance urinary salicylate excretion if plasma salicy- 1993; 35: 219–26. drugs such as other NSAIDs.
late concentrations exceed 500 micrograms/mL 3. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with
long term use of aspirin: meta-analysis. BMJ 2000; 321: The prevalence of aspirin-induced asthma can vary according to
(350 micrograms/mL in children under 5 years). 1183–7. the method used to measure it. A systematic review3 calculated
Haemodialysis or haemoperfusion are also effective 4. Garcia Rodríguez LA, et al. Association between aspirin and the prevalence of aspirin-induced asthma to be 21% in the gen-
upper gastrointestinal complications: systematic review of epi-
methods of removing salicylate from the plasma. The demiologic studies. Br J Clin Pharmacol 2001; 52: 563–71. eral adult asthma population and 5% in children when deter-
5. McQuaid KR, Laine L. Systematic review and meta-analysis of mined by oral provocation testing. However, when based on
BNF considers haemodialysis the method of choice in adverse events of low-dose aspirin and clopidogrel in rand- medical history alone it was only 2.7% in adults and 2% in chil-
severe poisoning; it should be seriously considered omized controlled trials. Am J Med 2006; 119: 624–38. dren. In another study4 using data from patient questionnaires the
when the plasma salicylate concentration is more than 6. Hernández-Díaz S, García Rodríguez LA. Cardioprotective as- prevalence of aspirin-induced asthma was 10 to 11% in patients
pirin users and their excess risk of upper gastrointestinal com-
700 micrograms/mL or if there is severe metabolic plications. BMC Med 2006; 4: 22. Available at: with asthma and 2.5% in non-asthmatics.
acidosis. Vulnerable patients such as children or the http://www.biomedcentral.com/content/pdf/1741-7015-4-22.pdf There is considerable cross-reactivity between aspirin and other
(accessed 11/12/06) NSAIDs and it is generally recommended that patients who have
elderly may require dialysis at an earlier stage. 7. Lee M, et al. Dose effects of aspirin on gastric prostaglandins
had a hypersensitivity reaction to aspirin or any other NSAID
and stomach mucosal injury. Ann Intern Med 1994; 120: 184–9.
◊ References to salicylate toxicity and its management. 8. Cryer B, Feldman M. Effects of very low dose daily, long-term should avoid all NSAIDs. In a systematic review3 cross-sensitiv-
1. Notarianni L. A reassessment of the treatment of salicylate poi- aspirin therapy on gastric, duodenal, and rectal prostaglandin ity to other NSAIDs (ibuprofen, diclofenac, and naproxen) oc-
soning. Drug Safety 1992; 7: 292–303. levels and on mucosal injury in healthy humans. Gastroenterol- curred in over 90% of those patients with aspirin-induced asth-
2. Woods D, et al. Acute toxicity of drugs: salicylates. Pharm J ogy 1999; 117: 17–25. ma. Paracetamol is usually safe in patients sensitive to aspirin
1993; 250: 576–8. 9. Anonymous. Which prophylactic aspirin? Drug Ther Bull 1997;
3. Collee GG, Hanson GC. The management of acute poisoning. Br 35: 7–8. and cross-sensitivity to paracetamol has been calculated as about
J Anaesth 1993; 70: 562–73. 10. Cole AT, et al. Protection of human gastric mucosa against as- 7%.3 Based on these figures, it is considered that less than 2% of
4. Watson JE, Tagupa ET. Suicide attempt by means of aspirin en- pirin—enteric coating or dose reduction? Aliment Pharmacol asthmatic patients would be likely to react to both paracetamol
ema. Ann Pharmacother 1994; 28: 467–9. Ther 1999; 13: 187–93. and aspirin.
5. Dargan PI, et al. An evidence based flowchart to guide the man- 11. Cryer B, et al. Effects of cutaneous aspirin on the human stom-
ach and duodenum. Proc Assoc Am Physicians 1999; 111: The response to individual NSAIDs is believed to be closely
agement of acute salicylate (aspirin) overdose. Emerg Med J
2002; 19: 206–9. 448–56. linked to the extent to which they inhibit prostaglandin synthe-
6. Rivera W, et al. Delayed salicylate toxicity at 35 hours without Effects on hearing. Studies have shown that tinnitus develops sis.5,6 There may be a dose threshold below which no detectable
early manifestations following a single salicylate ingestion. Ann at serum-salicylate concentrations above 200 micrograms/mL.1 symptoms occur and patients who may be tolerant of regular
Pharmacother 2004; 38: 1186–8. Correction. ibid. 2006; 40: However, there appears to be considerable intersubject variation low-dose aspirin can develop symptoms when they take larger
999.
in the response of the ear to salicylate;2 tinnitus may occur at doses.6 Some6 use a formal challenge with a 300-mg oral dose of
Effects on the blood. Although it has beneficial effects on lower concentrations, whereas patients with pre-existing hearing aspirin to confirm a diagnosis of NSAID sensitivity but others7
platelets, aspirin can cause adverse blood effects. An indication loss may not experience tinnitus despite serum-salicylate con- consider this to be a dangerous technique and use inhalation of
of this toxicity is given by an early reference1 to reports submit- centrations of 311 to 677 micrograms/mL.1 A graded increase in lysine aspirin which they consider to be a safer and more predict-
ted to the UK CSM. There were 787 reports of adverse reactions intensity of ototoxicity with increasing salicylate dose and able alternative. Intranasal challenge with lysine aspirin has also
to aspirin reported to the CSM between June 1964 and January plasma concentration has been demonstrated.2 For example, at been used.8,9
1973. These included 95 reports of blood disorders (17 fatal) in- an average total plasma-salicylate concentration of 1. Kwoh CK, Feinstein AR. Rates of sensitivity reactions to aspi-
cluding thrombocytopenia (26; 2 fatal), aplastic anaemia (13; 7 rin: problems in interpreting the data. Clin Pharmacol Ther
110 micrograms/mL, the hearing loss at any given frequency 1986; 40: 494–505.
fatal), and agranulocytosis or pancytopenia (10; 2 fatal). Aspirin was about 12 decibels; such a deficit might be relevant to patients 2. Schiavino D, et al. The aspirin disease. Thorax 2000; 55 (suppl
has also been associated with haemolytic anaemia in patients with pre-existing hearing impairment.2 2): S66–S69.
with G6PD deficiency.2 1. Mongan E, et al. Tinnitus as an indication of therapeutic serum 3. Jenkins C, et al. Systematic review of prevalence of aspirin in-
1. Cuthbert MF. Adverse reactions to non-steroidal antirheumatic salicylate levels. JAMA 1973; 226: 142–5. duced asthma and its implications for clinical practice. BMJ
drugs. Curr Med Res Opin 1974; 2: 600–9. 2. Day RO, et al. Concentration-response relationships for sali- 2004; 328: 434–7.
2. Magee P, Beeley L. Drug-induced blood dyscrasias. Pharm J cylate-induced ototoxicity in normal volunteers. Br J Clin Phar- 4. Vally H, et al. The prevalence of aspirin intolerant asthma (AIA)
1991; 246: 396–7. macol 1989; 28: 695–702. in Australian asthmatic patients. Thorax 2002; 57: 569–74.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
22 Analgesics Anti-inflammatory Drugs and Antipyretics
5. Power I. Aspirin-induced asthma. Br J Anaesth 1993; 71: 8. Casteels-Van Daele M, Eggermont E. Reye’s syndrome. BMJ oping, is not associated with an increased risk of cardiac defects.5
619–21. 1994; 308: 919–20. The ability of aspirin, however, to alter platelet function may be
6. Frew A. Selected side-effects: 13. non-steroidal anti-inflamma- 9. Hall SM. Reye’s syndrome. BMJ 1994; 309: 411.
10. Orlowski JP, et al. Is aspirin a cause of Reye’s syndrome? A a potential risk. There have been a few reports of haemorrhagic
tory drugs and asthma. Prescribers’ J 1994; 34: 74–7. disorders in infants whose mothers had consumed aspirin during
case against. Drug Safety 2002; 25: 225–31.
7. Davies BH. NSAIDs and asthma. Prescribers’ J 1994; 34: 11. Waller P, Suvarna R. Is aspirin a cause of Reye’s syndrome? pregnancy6 and of salicylate-associated haemorrhagic complica-
163–4. Drug Safety 2004; 27: 71–3. tions in mothers.7 However, no clinically significant adverse ef-
8. Casadevall J et al. Intranasal challenge with aspirin in the diag-
nosis of aspirin intolerant asthma: evaluation of nasal response
fects on maternal or neonatal bleeding or on fetal ductus flow
by acoustic rhinometry. Thorax 2000; 55: 921–4. Precautions were reported in a meta-analysis8 of 6 controlled studies which
9. Alonso-Llamazares A, et al. Nasal provocation test (NPT) with Aspirin has many properties in common with the non- evaluated low-dose aspirin (less than 325 mg daily) in pregnan-
aspirin: a sensitive and safe method to diagnose aspirin-induced aspirin NSAIDs, the precautions of which are de- cy-induced hypertension. Two more recent placebo-controlled
asthma (AIA). Allergy 2002; 57: 632–5. studies9,10 have also observed no clinically significant adverse
scribed on p.98. effects on neonatal bleeding with low-dose aspirin. It appeared
Successful desensitisation has been
D E S E N S I T I S AT I O N .
achieved using oral aspirin challenge protocols.1-5 Incremen-
Aspirin should be used cautiously, if at all, in patients that the degree of cyclo-oxygenase inhibition produced by aspi-
prone to dyspepsia or known to have a lesion of the rin was unlikely to be great enough to cause premature closure of
tal doses of aspirin (traditionally starting at 30 mg) are given
gastric mucosa. It should not be given to patients with the ductus arteriosus or to affect the pulmonary blood vessels.1
until an allergic response occurs; aspirin is readministered at
See also under Surgical Procedures, below. However, in some
the dose that caused the response and again incremental doses haemophilia or other haemorrhagic disorders, nor to studies in patients considered to have high-risk pregnancies the
are given until finally a 650-mg dose is tolerated.1,2 After treat patients with gout (since low doses increase urate risk of abruptio placentae11 or consequent perinatal death12 was
desensitisation, an interruption of continuous aspirin dosage
results in the reappearance of sensitivity. concentrations). increased by maternal dosage with aspirin. For reference to a
possible association between aspirin and other NSAIDs and per-
1. Asad SI, et al. Effect of aspirin in "aspirin sensitive" patients. Aspirin should be used with caution in patients with sistent pulmonary hypertension of the newborn, see under
BMJ 1984; 288: 745–8. asthma or allergic disorders. It should not be given to NSAIDs, p.99.
2. Stevenson DD. Desensitization of aspirin-sensitive asthmatics: a patients with a history of sensitivity reactions to aspirin
therapeutic alternative? J Asthma 1983; 20: 31–8. Although aspirin has the potential to inhibit uterine contractions
3. Gollapudi RR, et al. Aspirin sensitivity: implications for patients or other NSAIDs, including those in whom attacks of of labour it was considered that intermittent or low-dose aspirin
with coronary artery disease. JAMA 2004; 292: 3017–23. asthma, angioedema, urticaria, or rhinitis have been was unlikely to inhibit cyclo-oxygenase for long enough to pro-
4. Cormican LJ, et al. Improvements in an oral aspirin challenge precipitated by such drugs (for further details of risk long pregnancy or labour.1
protocol for the diagnosis of aspirin hypersensitivity. Clin Exp 1. de Swiet M, Fryers G. The use of aspirin in pregnancy. J Obstet
Allergy 2005; 35: 717–22. factors see Hypersensitivity under Adverse Effects, Gynaecol 1990; 10: 467–82.
5. Pfaar O, Klimek L. Aspirin desensitization in aspirin intoler- above). 2. Slone D, et al. Aspirin and congenital malformations. Lancet
ance: update on current standards and recent improvements. 1976; 1: 1373–5.
Curr Opin Allergy Clin Immunol 2006; 6: 161–6.
Caution is necessary when renal or hepatic function is 3. Shapiro S, et al. Perinatal mortality and birth-weight in relation
impaired; aspirin should be avoided in severe renal or to aspirin taken during pregnancy. Lancet 1976; i: 1375–6.
Hypoglycaemia. A review of the literature1 on drug-induced 4. Winship KA, et al. Maternal drug histories and central nervous
hepatic impairment. Aspirin should be used cautiously system anomalies. Arch Dis Child 1984; 59: 1052–60.
hypoglycaemia highlighted the fact that overdosage with sali- 5. Werler MM, et al. The relation of aspirin use during the first
cylates could produce hypoglycaemia in children. Although in dehydrated patients and in the presence of uncon- trimester of pregnancy to congenital cardiac defects. N Engl J
therapeutic doses of salicylates in adults can lower blood-glucose trolled hypertension. Med 1989; 321: 1639–42.
concentrations in diabetic and non-diabetic subjects alike, opin- 6. Bleyer WA, Breckenridge RT. Studies on the detection of ad-
High doses may precipitate acute haemolytic anaemia verse drug reactions in the newborn II: the effects of prenatal
ion on the clinical significance of this effect varies. Salicylates
have been implicated in a few cases of hypoglycaemia in adults1
in patients with G6PD deficiency. Aspirin may inter- aspirin on newborn hemostasis. JAMA 1970; 213: 2049–53.
7. Collins E, Turner G. Maternal effects of regular salicylate inges-
and some2 suggest that patients with renal impairment or those fere with insulin and glucagon control in diabetics (see tion in pregnancy. Lancet 1975; ii: 335–7.
receiving large doses, such as in the treatment of rheumatoid ar- Hypoglycaemia under Adverse Effects, above). 8. Imperiale TF, Petrulis AS. A meta-analysis of low-dose aspirin
thritis, may be at risk. Hypoglycaemia has been reported in a pa- for the prevention of pregnancy-induced hypertensive disease.
The use of aspirin in children is extremely limited be- JAMA 1991; 266: 261–4.
tient with renal failure after excessive application of a topical 9. Louden KA, et al. Neonatal platelet reactivity and serum throm-
preparation containing salicylic acid.3
cause of the risk of Reye’s syndrome (see under Ad- boxane B production in whole blood: the effect of maternal low
1. Seltzer HS. Drug-induced hypoglycemia: a review of 1418 cas-
verse Effects, above, and under Uses and Administra- dose aspirin. Br J Obstet Gynaecol 1994; 101: 203–8.
tion, below). 10. Dasari R, et al. Effect of maternal low dose aspirin on neonatal
es. Endocrinol Metab Clin North Am 1989; 18: 163–83. platelet function. Indian Pediatr 1998; 35: 507–11.
2. Pandit MK, et al. Drug-induced disorders of glucose tolerance. Although low-dose aspirin might be used in some 11. Sibai BM, et al. Prevention of preeclampsia with low-dose as-
Ann Intern Med 1993; 118: 529–39. pirin in healthy, nulliparous pregnant women. N Engl J Med
3. Raschke R, et al. Refractory hypoglycemia secondary to topical
pregnant patients, analgesic doses of aspirin should not 1993; 329: 1213–18.
salicylate intoxication. Arch Intern Med 1991; 151: 591–3. be used at term as they may be associated with delayed 12. Hamid R, et al. Low dose aspirin in women with raised maternal
serum alpha-fetoprotein and abnormal Doppler waveform pat-
Reye’s syndrome. Reye’s syndrome is a disorder characterised onset and prolongation of labour and with maternal and terns from the uteroplacental circulation. Br J Obstet Gynaecol
by acute encephalopathy and fatty degeneration of the liver. It neonatal bleeding. High doses may cause closure of fe- 1994; 101: 481–4.
occurs almost exclusively in young children although cases have tal ductus arteriosus in utero and possibly persistent Resistance. Some patients given aspirin for the management of
been seen1 in patients over the age of 12. Many factors may be pulmonary hypertension in the newborn (but see Preg- cardiovascular disease do not respond to treatment, a phenome-
involved in its aetiology but it typically occurs after a viral infec- nancy, below); kernicterus may occur in jaundiced neo- non that has been described as aspirin resistance. At present, as-
tion such as chickenpox or influenza and may be precipitated by pirin resistance is poorly understood and further studies are need-
a chemical trigger. Several large studies, as well as individual nates. ed to define it.
case reports, have found a link between Reye’s syndrome and the Continuous prolonged use of aspirin should be avoided References
prior ingestion of aspirin.2-6 The evidence for other salicylates in the elderly because of the risk of gastrointestinal 1. Sanderson S, et al. Narrative review: aspirin resistance and its
could not be adequately evaluated.4 Although the role of aspirin clinical implications. Ann Intern Med 2005; 142: 370–80.
and possibly other salicylates in the pathogenesis of Reye’s syn-
bleeding. 2. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006;
drome remains to be determined, the use of aspirin and other Aspirin should be stopped several days before sched- 367: 606–17.
3. Michos ED, et al. Aspirin and clopidogrel resistance. Mayo Clin
acetylated salicylates as analgesics or antipyretics is generally uled surgical procedures (see below). Proc 2006; 81: 518–26.
considered contra-indicated in children under the age of 12 years
and, in some countries, in teenagers. For example, the UK CSM
Aspirin and other salicylates can interfere with thyroid 4. Undas A, et al. Antithrombotic properties of aspirin and resist-
ance to aspirin: beyond strictly antiplatelet actions. Blood 2007;
has recommended that all children under 16 should not take as- function tests. 109: 2285–92.
pirin.7 (This advice superseded their earlier recommendations to Breast feeding. The American Academy of Pediatrics1 consid- 5. Dalen JE. Aspirin resistance: is it real? Is it clinically signifi-
avoid aspirin during fever or viral infection in children under 16 cant? Am J Med 2007; 120: 1–4.
ers that salicylates should be given with caution to breast-feeding
years; the Committee felt that this advice was too complex for mothers, since aspirin has been associated with metabolic acido- Surgical procedures. Aspirin prolongs bleeding time, mainly
products on general sale and, given the wide availability of other sis in the infant.2 The BNF also recommends that aspirin should by inhibiting platelet aggregation. This effect is irreversible and
analgesic preparations, there was no need to expose this age be avoided in breast-feeding mothers because of the possible risk new platelets must be released into the circulation before bleed-
group to any risk.) Some countries also extend these recommen- of Reye’s syndrome in nursing infants; they also advise that in- ing time can return to normal. Therefore aspirin therapy should
dations to non-acetylated salicylates. One group of workers8 who fants with neonatal vitamin K deficiency may be at risk of hypo- be stopped several days before surgical procedures. In some clin-
re-examined some of the original studies suggested that there prothrombinaemia after the regular use of high doses of aspirin ical situations, aspirin may have been given shortly before a sur-
might also be a link between Reye’s syndrome and the use of in breast-feeding mothers. However, a prospective study3 found gical procedure. When emergency coronary bypass surgery is re-
antiemetics, phenothiazines, and some other antihistamines, but no adverse effects in 15 breast-fed infants whose mothers were quired for myocardial infarction, most patients would have
their conclusions have been criticised.9 More recently, others10 receiving aspirin. received aspirin as part of the initial treatment for infarction.
have suggested that Reye’s syndrome was caused by a viral mu- 1. American Academy of Pediatrics. The transfer of drugs and oth- Perioperative bleeding, transfusion requirements, and surgical
tation or the result of misdiagnoses of metabolic disorders but er chemicals into human milk. Pediatrics 2001; 108: 776–89. re-exploration rates may be increased when aspirin is given.1
again these conclusions have been questioned.6,11 Correction. ibid.; 1029. Also available at: However, some studies2,3 have shown that the increase in bleed-
h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l / ing is not significant; in addition, there have been reports that
1. Hall SM, Lynn R. Reye’s syndrome. N Engl J Med 1999; 341:
845–6. pediatrics%3b108/3/776 (accessed 23/11/06) pre-operative aspirin may reduce the rate of perioperative myo-
2. Clark JH, Wilson WG. A 16-day-old breast-fed infant with met-
2. Waldman RJ, et al. Aspirin as a risk factor in Reye’s syndrome. abolic acidosis caused by salicylate. Clin Pediatr (Phila) 1981; cardial infarction (with aprotinin),4 improve oxygenation,5 and
JAMA 1982; 247: 3089–94. 20: 53–4. even decrease mortality.3,6 Desmopressin may reduce the risk of
3. Halpin TJ, et al. Reye’s syndrome and medication use. JAMA 3. Ito S, et al. Prospective follow-up of adverse reactions in breast- perioperative bleeding (see under Haemorrhagic Disorders,
1982; 248: 687–91. fed infants exposed to maternal medication. Am J Obstet Gyne- p.2187).
4. Hurwitz ES, et al. Public health service study of Reye’s syn- col 1993; 168: 1393–9.
drome and medications: report of the main study. JAMA 1987; Aspirin is sometimes given during the second and third trimester
257: 1905–11. Pregnancy. The potential adverse effects of aspirin when used for the prevention of pregnancy-induced hypertensive disease
5. Hall SM, et al. Preadmission antipyretics in Reye’s syndrome. during pregnancy have been reviewed.1 Salicylates readily cross (see under Hypertension, p.1171). Studies indicate that when
Arch Dis Child 1988; 63: 857–66. the placenta and have been shown to be teratogenic in animals. given in a dose of 325 mg daily or less, clinically significant ef-
6. Glasgow JFT. Reye’s syndrome: the case for a causal link with Although some studies and anecdotal reports have implicated as- fects on maternal or neonatal bleeding do not occur.7 Some have
aspirin. Drug Safety 2006; 29: 1111–21. pirin in the formation of congenital abnormalities, most large suggested that aspirin therapy may increase the risk of formation
7. MHRA. Aspirin and Reye’s syndrome: questions and answers studies2-4 have failed to find any significant risk or evidence of of extradural haematoma thus making epidural anaesthesia
(issued 4th April, 2003). Available at: teratogenicity. Analysis of data collected by the Slone Epidemi- inadvisable8 but a subsequent study9 found that low-dose aspirin
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_
FILE&dDocName=CON019512&RevisionSelectionMethod= ology Unit Birth Defects Study suggests that use of aspirin dur- during pregnancy did not increase the risk of bleeding complica-
LatestReleased (accessed 29/11/06) ing the early months of pregnancy, when the fetal heart is devel- tions during epidural anaesthesia.
 Aspirin 23
Patients on low-dose aspirin, in whom tourniquets are used for 2. Abebe W. Herbal medication: potential for adverse interactions bound to plasma proteins and is widely distributed; its
nerve blocks or other procedures, may be at increased risk of de- with analgesic drugs. J Clin Pharm Ther 2002; 27: 391–401.
3. Gaziano JM, Gibson CM. Potential for drug-drug interactions in volume of distribution is reported to be 170 mL/kg in
veloping purpuric rash.10 patients taking analgesics for mild-to-moderate pain and low- adults. As plasma-drug concentrations increase, the
It has been suggested that in patients undergoing dermatologi- dose aspirin for cardioprotection. Am J Cardiol 2006; 97: 23–9.
cal,11 or minor dental12 surgery, aspirin need only be stopped be-
binding sites on the proteins become saturated and the
ACE inhibitors. For a discussion of aspirin and other NSAIDs volume of distribution increases. Both aspirin and sal-
fore surgery in those patients with a prolonged bleeding time, reducing the activity of ACE inhibitors, see p.1197.
whereas patients with a normal bleeding time could continue icylate have pharmacological activity although only
therapy. Antiepileptics. Aspirin may inhibit the metabolism of val- aspirin has an anti-platelet effect. Salicylate is exten-
1. Goldman S, et al. Improvement in early saphenous vein graft proate; for further details, see Analgesics, p.510.
sively bound to plasma proteins and is rapidly distrib-
patency after coronary artery bypass surgery with antiplatelet Antifungals. Plasma-salicylate concentrations in an 8-year-old
therapy: results of a Veterans Administration Cooperative uted to all body parts. Salicylate appears in breast milk
Study. Circulation 1988; 77: 1324–32. child receiving long-term aspirin therapy for rheumatic heart dis-
ease were markedly reduced when treatment with griseofulvin and crosses the placenta.
2. Reich DL, et al. Aspirin does not increase homologous blood
requirements in elective coronary bypass surgery Anesth Analg was started.1 It was suggested that griseofulvin might interfere Salicylate is mainly eliminated by hepatic metabolism;
1994; 79: 4–8. with absorption of aspirin. the metabolites include salicyluric acid, salicyl phenol-
3. Dacey LJ, et al. Effect of preoperative aspirin use on mortality 1. Phillips KR, et al. Griseofulvin significantly decreases serum
in coronary artery bypass grafting patients. Ann Thorac Surg salicylate concentrations. Pediatr Infect Dis J 1993; 12: 350–2.
ic glucuronide, salicylic acyl glucuronide, gentisic
2000; 70: 1986–90.
Calcium-channel blockers. The antiplatelet effects of aspirin
acid, and gentisuric acid. The formation of the major
4. Klein M, et al. Aprotinin counterbalances an increased risk of
peri-operative hemorrhage in CABG patients pre-treated with and calcium-channel blockers may be increased when they are metabolites, salicyluric acid and salicyl phenolic glu-
aspirin. Eur J Cardiothorac Surg 1998; 14: 360–6. used together; there have been isolated reports1,2 of disturbed curonide, is easily saturated and follows Michaelis-
5. Gerrah R, et al. Preoperative aspirin administration improves haemostasis including abnormal bruising, prolonged bleeding Menten kinetics; the other metabolic routes are first-
oxygenation in patients undergoing coronary artery bypass times and ecchymosis in patients taking aspirin and verapamil
grafting. Chest 2005; 127: 1622–6. order processes. As a result, steady-state plasma-sali-
concurrently.
6. Bybee KA, et al. Preoperative aspirin therapy is associated with
1. Ring ME, et al. Clinically significant antiplatelet effects of cal-
cylate concentrations increase disproportionately with
improved postoperative outcomes in patients undergoing coro-
nary artery bypass grafting. Circulation 2005; 112 (suppl I): cium-channel blockers. J Clin Pharmacol 1986; 26: 719–20. dose. After a 325-mg aspirin dose, elimination is a
I286–I292. 2. Verzino E, et al. Verapamil-aspirin interaction. Ann Pharmaco- first-order process and the plasma-salicylate half-life is
7. Imperiale TF, Petrulis AS. A meta-analysis of low-dose aspirin ther 1994; 28: 536–7.
for the prevention of pregnancy-induced hypertensive disease. about 2 to 3 hours; at high aspirin doses, the half-life
General anaesthetics. For the effect of aspirin on thiopental
JAMA 1991; 266: 260–4.
anaesthesia, see p.1796.
increases to 15 to 30 hours. Salicylate is also excreted
8. Macdonald R. Aspirin and extradural blocks. Br J Anaesth unchanged in the urine; the amount excreted by this
1991; 66: 1–3. NSAIDs. It has been suggested that ibuprofen and possibly oth-
9. Sibai BM, et al. Low-dose aspirin in nulliparous women: safety er NSAIDs may reduce the cardioprotective effect of aspirin. A
route increases with increasing dose and also depends
of continuous epidural block and correlation between bleeding on urinary pH, about 30% of a dose being excreted in
time and maternal-neonatal bleeding complications. Am J Ob- study1 involving 7107 patients found that cardiovascular mortal-
stet Gynecol 1995; 172: 1553–7. ity was increased in patients taking low-dose aspirin for cardio- alkaline urine compared with 2% of a dose in acidic
10. Runcie CJ, et al. Aspirin and intravenous regional blocks. Br J vascular disease when also taking ibuprofen (adjusted hazard ra- urine. Renal excretion involves glomerular filtration,
Hosp Med 1990; 43: 229–30. tio 1.73 times that of patients not taking ibuprofen). Another active renal tubular secretion, and passive tubular rea-
11. Lawrence C, et al. Effect of aspirin and nonsteroidal antiinflam- study2 found that although taking low-dose aspirin or NSAIDs
matory drug therapy on bleeding complications in dermatologic alone decreased the incidence of myocardial infarction, there bsorption.
surgical patients. J Am Acad Dermatol 1994; 31: 988–92.
12. Madan GA, et al. Minor oral surgery without stopping daily
was a non-significant increase in the risk of myocardial infarc- Salicylate is removed by haemodialysis.
tion when both were taken. Another large study also found the
low-dose aspirin therapy: a study of 51 patients. J Oral Maxil-
lofac Surg 2005; 63: 1262–5. risk to be increased in those taking regular rather than intermit- ◊ References.
tent NSAID treatment with aspirin.3 However, a study4 involving 1. Needs CJ, Brooks PM. Clinical pharmacokinetics of the sali-
cylates. Clin Pharmacokinet 1985; 10: 164–77.
Interactions 14 098 patients concluded that the risk of myocardial infarction
was reduced in patients taking ibuprofen with aspirin when com-
Aspirin has many properties in common with the non- pared to those taking aspirin alone. Furthermore, a study5 in Uses and Administration
aspirin NSAIDs, the interactions of which are de- 70 316 patients found that the risk of death in patients prescribed Aspirin is a salicylate NSAID and has many properties
scribed on p.99. aspirin and ibuprofen was comparable to that of patients pre- in common with non-aspirin NSAIDs (p.99). Aspirin
Some of the effects of aspirin on the gastrointestinal scribed aspirin alone or with another NSAID. and other salicylates have analgesic, anti-inflammato-
The timing of doses may be important; a study6 has shown that ry, and antipyretic properties; they act as inhibitors of
tract are enhanced by alcohol. Use of gold compounds irreversible platelet aggregation occurred when a single daily
with aspirin may exacerbate aspirin-induced liver dam- dose of ibuprofen was given 2 hours after aspirin; however, when the enzyme cyclo-oxygenase, which results in the di-
age. ibuprofen was given before aspirin as a single daily dose or given rect inhibition of the biosynthesis of prostaglandins
Use of aspirin with dipyridamole may result in an in- three times daily, platelet aggregation was reversible which may and thromboxanes from arachidonic acid (see p.2374).
limit the cardioprotective effects of aspirin. Aspirin also inhibits platelet aggregation; non-acetylat-
crease in plasma-salicylate concentrations. Drugs such There are limitations to all these studies and further studies are
as metoclopramide in patients with migraine headache ed salicylates do not.
needed before any recommendations can be made.7-11
result in earlier absorption of aspirin and higher peak 1. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective Aspirin is used for the relief of mild to moderate pain
plasma-salicylate concentrations. Metoprolol may also effect of aspirin. Lancet 2003; 361: 573–4. such as headache, dysmenorrhoea, myalgias, and den-
2. Kimmel SE, et al. The effects of nonselective non-aspirin non-
increase peak plasma-salicylate concentrations. Sali- steroidal anti-inflammatory medications on the risk of nonfatal tal pain. It has also been used in the management of
cylate intoxication has occurred in patients on high- myocardial infarction and their interaction with aspirin. J Am pain and inflammation in acute and chronic rheumatic
Coll Cardiol 2004; 43: 985–90.
dose salicylate regimens and carbonic anhydrase inhib- 3. Kurth T, et al. Inhibition of clinical benefits of aspirin on first disorders such as rheumatoid arthritis, juvenile idio-
itors. myocardial infarction by nonsteroidal antiinflammatory drugs. pathic arthritis, osteoarthritis, and ankylosing spond-
Circulation 2003; 108: 1191–5.
Plasma-salicylate concentrations may be reduced by 4. Patel TN, Goldberg KC. Use of aspirin and ibuprofen compared ylitis. In the treatment of minor febrile conditions, such
with aspirin alone and the risk of myocardial infarction. Arch as colds or influenza, aspirin can reduce temperature
corticosteroids. This interaction is likely to be impor- Intern Med 2004; 164: 852–6.
tant in patients receiving high-dose long-term sali- 5. Curtis JP, et al. Aspirin, ibuprofen, and mortality after myocar- and relieve headache and joint and muscle pains.
dial infarction: retrospective cohort study. BMJ 2003; 327: Aspirin is also used for its antiplatelet activity in the
cylate treatment. Conversely, salicylate toxicity may 1322–3.
occur if corticosteroids are withdrawn. Also the risk of 6. Catella-Lawson F, et al. Cyclooxygenase inhibitors and the an- initial treatment of cardiovascular disorders such as
tiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809–17. angina pectoris and myocardial infarction and for the
gastrointestinal bleeding and ulceration associated 7. Etminan M, Samii A. Effect of ibuprofen on cardioprotective
with aspirin is increased when used with corticoster- effect of aspirin. Lancet 2003; 361: 1558–9. prevention of cardiovascular events in patients at risk.
8. Kimmel SE, Strom BL. Giving aspirin and ibuprofen after my- Other such uses include the treatment and prevention
oids. Antacids may increase the excretion of aspirin in ocardial infarction. BMJ 2003; 327: 1298–9.
alkaline urine. 9. Curtis JP, Krumholz HM. The case for an adverse interaction of cerebrovascular disorders such as stroke. For further
between aspirin and non-steroidal anti-inflammatory drugs: is it details see under Antiplatelet Therapy, below.
Aspirin may increase the activity of coumarin antico- time to believe the hype? J Am Coll Cardiol 2004; 43: 991–3.
agulants, sulfonylurea hypoglycaemic drugs, zafirlu- 10. Cheema AA. Should people on aspirin avoid ibuprofen? A re- Aspirin is usually taken by mouth. Gastric irritation
view of the literature. Cardiol Rev 2004; 12: 174–6.
kast, methotrexate, phenytoin, and valproate. Aspirin 11. Corman SL, et al. Impact of nonsteroidal antiinflammatory may be reduced by taking doses after food. Various
diminishes the effects of uricosurics such as probene- drugs on the cardioprotective effects of aspirin. Ann Pharmaco- dosage forms are available including plain uncoated
ther 2005; 39: 1073–9.
cid and sulfinpyrazone. The manufacturer of mifepris- tablets, buffered tablets, dispersible tablets, enteric-
Spironolactone. For the effect of aspirin in patients taking
tone advises of a theoretical risk that prostaglandin spironolactone, see p.1401.
coated tablets, and modified-release tablets. In some
synthetase inhibition by aspirin or NSAIDs may alter instances aspirin may be given rectally by suppository.
the efficacy of mifepristone. Pharmacokinetics The usual oral dose of aspirin as an analgesic and anti-
Use of aspirin with other NSAIDs should be avoided Aspirin and other salicylates are absorbed rapidly from pyretic is 300 to 900 mg, repeated every 4 to 6 hours
because of the increased risk of adverse effects; the car- the gastrointestinal tract when taken orally but absorp- according to clinical needs, to a maximum of 4 g daily.
dioprotective effects of aspirin may be abolished by tion after rectal doses is less reliable. Aspirin and other The dose as suppositories is 450 to 900 mg every 4
ibuprofen and possibly other NSAIDS. Aspirin may salicylates can also be absorbed through the skin. hours to a maximum of 3.6 g daily.
decrease the plasma concentration of some other After oral doses, absorption of non-ionised aspirin oc- Plasma-salicylate concentrations of 150 to
NSAIDs, for example, fenbufen, indometacin, and curs in the stomach and intestine. Some aspirin is hy- 300 micrograms/mL are required for optimal anti-in-
piroxicam. drolysed to salicylate in the gut wall. Once absorbed, flammatory activity (but see also Adverse Effects,
◊ References.
aspirin is rapidly converted to salicylate, but during the above). Doses need to be adjusted individually to
1. Miners JO. Drug interactions involving aspirin (acetylsalicylic
first 20 minutes after an oral dose aspirin is the main achieve optimum concentrations. Generally doses of
acid) and salicylic acid. Clin Pharmacokinet 1989; 17: 327–44. form of the drug in the plasma. Aspirin is 80 to 90% about 4 to 8 g daily in divided doses are used for acute
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
24 Analgesics Anti-inflammatory Drugs and Antipyretics
rheumatic disorders such as rheumatoid arthritis or os- prevent postoperative complications. It may have some effect 12. British Cardiac Society, British Hypertension Society, Diabetes
in delaying disease progression and reducing vascular events UK, HEART UK, Primary Care Cardiovascular Society, The
teoarthritis. Doses of up to 5.4 g daily in divided doses Stroke Association. JBS 2: Joint British Societies’ guidelines on
in patients with peripheral arterial disease (p.1178) but an
may be sufficient in chronic conditions. analysis10 concluded that there was insufficient evidence to
prevention of cardiovascular disease in clinical practice. Heart
2005; 91 (suppl V): v1–v52. Also available at:
Indications for aspirin therapy in children are extreme- support its prophylactic use in patients with intermittent clau- http://www.diabetes.org.uk/Documents/Reports/DiabetesUk_
ly limited because of the risk of Reye’s syndrome (see dication but no additional cardiovascular risk factors. cardiovascular.pdf (accessed 08/12/06)
13. Patrignani P, et al. Selective cumulative inhibition of platelet
under Adverse Effects, above), but include Kawasaki The benefit of aspirin for the primary prevention of cardiovas- thromboxane production by low-dose aspirin in healthy sub-
disease (see below), and juvenile idiopathic arthritis cular events in patients with diabetes mellitus (see under Dia- jects. J Clin Invest 1982; 69: 1366–72.
betic Complications, p.433) and who have no other cardiovas- 14. Weksler BB, et al. Differential inhibition by aspirin of vascular
and Still’s disease (see Rheumatic Disorders, below). cular risk factors remains to be determined. 8 Use is
and platelet prostaglandin synthesis in atherosclerotic patients.
N Engl J Med 1983; 308: 800–5.
Sodium aspirin has also been used for the treatment of recommended in all those at increased risk, which includes (in 15. McLeod LJ, et al. The effects of different doses of some acetyl-
pain and fever. the USA) all diabetics over 40 years of age,11 or those aged 50 salicylic acid formulations on platelet function and bleeding
and over or with existing atherosclerosis or hypertension or a times in healthy subjects. Scand J Haematol 1986; 36: 379–84.
Administration in children. Indications for aspirin therapy in 16. Hirsh J, et al. Aspirin and other platelet active drugs: relation-
history of diabetes for over 10 years (in the UK).12 ship among dose, effectiveness, and side effects. Chest 1989; 95
children are extremely limited because of the risk of Reye’s syn-
The value of adding aspirin to anticoagulants for the prophy- (suppl 2): 12S–18S.
drome (see under Adverse Effects, above). For further informa- 17. Campbell CL, et al. Aspirin dose for the prevention of cardio-
tion, including some doses, see Antiplatelet Therapy, Kawasaki laxis of thromboembolism in patients with prosthetic heart
vascular disease: a systematic review. JAMA 2007; 297:
Disease, and Rheumatic Disorders, below. valves (see p.1187) is also still to be firmly established. It is 2018–24.
usually recommended as an adjunct in patients with other risk 18. Dalen JE. Aspirin to prevent heart attack and stroke: what’s the
Antiplatelet therapy. Aspirin is an inhibitor of the enzyme cy- factors. Aspirin alone may be considered in patients with bio- right dose? Am J Med 2006; 119: 198–202.
clo-oxygenase, the action being considered to be due to an irre- prosthetic valves who do not require anticoagulation. Behçet’s syndrome. For reference to the use of aspirin in the
versible acetylation process. management of vasculitic symptoms of Behçet’s syndrome, see
Several pharmacological studies have attempted to find a dose of
• In blood platelets such enzyme inhibition prevents the synthe- aspirin that would inhibit synthesis of platelet thromboxane A2 p.1499.
sis of thromboxane A2, a compound which is a vasoconstric- while sparing the effect on prostacyclin production13-15 but it has
tor, causes platelet aggregation, and is thus potentially throm- Cataract. Evidence to support or disprove the hypothesis that
been pointed out3 that in patients with vascular disease accompa- aspirin has a protective effect against cataract formation is con-
botic. nying or caused by endothelial dysfunction, such as in athero- sidered inconclusive. A study in the US in over 22 000 males
• In blood vessel walls the enzyme inhibition prevents the syn- sclerosis, a selective sparing of vascular prostacyclin production concluded that low-dose aspirin (325 mg on alternate days) for 5
thesis of prostacyclin, which is a vasodilator, has anti-aggre- may not be obtained at any effective antiplatelet dose. However, years was unlikely to have a major effect on cataract formation
gating properties, and is thus potentially anti-thrombotic. the clinical relevance of inhibiting the synthesis of prostacyclin but that a slightly decreased risk for cataract extraction could not
Aspirin therefore appears to have paradoxical biological effects. may have been exaggerated.16 Experimental evidence indicates be excluded.1 In a later study2 in the UK ophthalmic examination
The duration of these effects, however, may differ, with the ef- that aspirin is thrombogenic only at extremely high doses of over 1800 patients who were receiving 300 mg to 1.2 g of as-
fects on the vascular tissue generally being shorter than the ef- (200 mg/kg), far exceeding the minimum dose required to inhibit pirin daily for transient ischaemic attacks failed to confirm any
fects on the platelets (although the animal species studied, the prostacyclin production. Also aspirin is clinically effective as an protective effect. Re-analysis3 of the results of the original US
type of blood vessel used, and the prevailing experimental con- antithrombotic drug at doses that inhibit the synthesis of prosta- study identified additional cases of cataract formation or extrac-
ditions may alter the results). The difference may be explained cyclin. Further support for the lack of importance of inhibition of tion although these cases did not affect the overall conclusions of
by the fact that vascular cells regain the ability to regenerate pros- prostacyclin synthesis comes from epidemiological studies in the original study. However, when the study patients were fol-
tacyclin in a few hours but platelets are unable to re-synthesise patients with arthritis given large doses of aspirin and patients lowed up over 15 years, observational data4 suggested that the
cyclo-oxygenase, which results in no new thromboxane A2 being with congenital cyclo-oxygenase deficiency; neither of these use of low-dose aspirin may, in fact, increase the risk of cataract
produced for about 24 hours until more platelets are released by groups of patients have experienced an excess of thrombotic ep- development. It was considered that further trials were needed to
the bone marrow; as platelet activity in bone marrow may also be isodes. establish the role of long-term aspirin in cataract prevention.
affected by aspirin it is generally considered that aspirin only In a meta-analysis conducted by the Antithrombotic Trialists’ 1. Seddon JM, et al. Low dose aspirin and risks of cataract in a
needs to be given once daily for inhibition of platelet aggregation Collaboration8 daily doses of 75 to 325 mg appeared to be equal- randomised trial of US physicians. Arch Ophthalmol 1991; 109:
to occur. The inhibitory effect on thromboxane is rapid and unre- ly effective for their antiplatelet effect; doses greater than 500 mg 252–5.
lated to serum concentrations of aspirin, probably because of the did not appear to be superior and caused more gastrointestinal 2. UK-TIA Study Group. Does aspirin affect the rate of cataract
inactivation of cyclo-oxygenase in platelets in the presystemic formation? Cross-sectional results during a randomised double-
adverse effects. Whether doses less than 75 mg offer the same blind placebo controlled trial to prevent serious vascular events.
circulation. Since the effect is unrelated to systemic bioavailabil- efficacy with reduced gastrointestinal toxicity remains to be de- Br J Ophthalmol 1992; 76: 259–61.
ity, modified-release and dermal delivery preparations which do termined (see Effects on the Gastrointestinal Tract, above). The 3. Christen WG, et al. Low-dose aspirin and risk of cataract and
not achieve high systemic concentrations of aspirin are being de- meta-analysis concluded that for the long-term prevention of se- subtypes in a randomized trial of U.S. physicians. Ophthalmic
veloped to limit extraplatelet effects of aspirin. Inhibition is cu- rious vascular events in high-risk patients, a daily dose of aspirin Epidemiol 1998; 5: 133–42.
mulative on repeated dosage, and it has been estimated that a 4. Christen WG, et al. Aspirin use and risk of cataract in posttrial
in the range of 75 to 150 mg should be effective; if an immediate follow-up of Physicians’ Health Study I. Arch Ophthalmol 2001;
daily dose of 20 to 50 mg will result in virtually complete sup- effect is required as in the initial treatment of acute myocardial 119: 405–12.
pression of platelet thromboxane synthesis within a few days. infarction, acute ischaemic stroke, or unstable angina, a loading
Large doses of 150 to 300 mg can produce maximum suppres- dose of 150 to 300 mg may be given. Other analyses10,17 have Dysmenorrhoea. Drugs such as aspirin and other NSAIDs
sion almost instantaneously. made similar dose recommendations. However, another that inhibit prostaglandin production through inhibition of cyclo-
Uses. Aspirin’s antiplatelet activity has led to its use for the treat- review18 has suggested that doses as low as 75 or 80 mg daily oxygenase are effective drugs in the treatment of dysmenorrhoea
ment or prevention of a variety of disorders.1-6 may be inadequate for the primary prevention of stroke and myo- (p.6).
• It is used as part of the initial treatment of unstable angina cardial infarction; it was considered that the most appropriate Fever. Methods for controlling fever (see p.10) include the use
(p.1157) and is given in the early treatment of myocardial inf- dose of aspirin for primary prevention was 160 mg daily. Aspirin of antipyretics and/or physical cooling methods (although the
arction (p.1175); it is also of benefit in the initial treatment of should be chewed or dispersed in water; chewing a tablet of as- value of the latter is questionable). Paracetamol, salicylates such
acute ischaemic stroke (p.1185). pirin ensures that some buccal absorption occurs. as aspirin, and some other NSAIDs are the main antipyretics
• Aspirin is used for its combination of anti-inflammatory, anti- The use of aspirin in children is limited because of the risk of used. However, salicylates are generally contra-indicated for the
pyretic, and antiplatelet activity in the treatment of Kawasaki Reye’s syndrome (see under Adverse Effects, above); however, management of fever in children because of the possible link be-
disease (see below). It is also used to treat thrombotic symp- it may be specifically indicated in those at risk of clot formation tween their use and the development of Reye’s syndrome (see
toms associated with antiphospholipid syndrome, such as after cardiac surgery or for the prophylaxis of stroke in high-risk under Adverse Effects, above).
occurs in patients with SLE (p.1513), and has been recom- children. The BNFC has suggested oral doses of 1 to 5 mg/kg (up Headache. Aspirin is often used for the symptomatic treatment
mended for prophylactic use in pregnant patients with anti- to a usual maximum of 75 mg) once daily in neonates and chil- of various types of headache including migraine (see p.616) and
phospholipid antibodies who are at risk of fetal loss. The dren up to 12 years of age; older children may be given 75 mg tension-type headache (see p.617). Aspirin given at the onset of
thrombolytic action of aspirin has also led to its use in throm- daily. symptoms can successfully treat an acute attack of migraine.
botic thrombocytopenic purpura (see Thrombotic Microangi- 1. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; However, absorption may be poor due to gastric stasis which is
opathies, p.1076). Aspirin has been tried in pregnancy-in- 330: 1287–94. commonly present in migraine. For this reason dispersible and
duced hypertension (see under Hypertension, p.1171) for the 2. Lutomski DM, et al. Pharmacokinetic optimisation of the treat- effervescent preparations and compound preparations containing
prevention of pre-eclampsia and intra-uterine growth retarda- ment of embolic disorders. Clin Pharmacokinet 1995; 28: drugs such as metoclopramide which relieve gastric stasis have
tion and may provide a small to moderate benefit in some 67–92.
been advocated.
women. 3. Schrör K. Antiplatelet drugs: a comparative review. Drugs
1995; 50: 7–28. References.
• It is of value for the prevention of cardiovascular events in 4. Hung J. Aspirin for cardiovascular disease prevention. Med J 1. Tfelt-Hansen P, Olesen J. Effervescent metoclopramide and as-
patients at high risk, including those with stable or unstable Aust 2003; 179: 147–52. pirin (Migravess) versus effervescent aspirin or placebo for mi-
angina, current or previous myocardial infarction, ischaemic 5. Saseen JJ. ASHP therapeutic position statement on the daily use graine attacks: a double-blind study. Cephalalgia 1984; 4:
stroke, or transient ischaemic attack (see Cardiovascular Risk of aspirin for preventing cardiovascular events. Am J Health- 107–11.
Syst Pharm 2005; 62: 1398–1405. 2. Buring JE, et al. Low-dose aspirin for migraine prophylaxis.
Reduction, p.1164). It has also been used in the long-term JAMA 1990; 264: 1711–13.
management of atrial fibrillation (see under Cardiac Arrhyth- 6. Patrono C, et al. Low-dose aspirin for the prevention of athero- 3. MacGregor EA, et al. Mouth-dispersible aspirin in the treatment
mias, p.1160) for the prevention of stroke in patients with con- thrombosis. N Engl J Med 2005; 353: 2373–83.
of migraine: a placebo-controlled study. Headache 2002; 42:
tra-indications to warfarin or if there are no other risk factors 7. Sanmuganathan PS, et al. Aspirin for primary prevention of cor- 249–55.
onary heart disease: safety and absolute benefit related to coro- 4. Steiner TJ, et al. Aspirin in episodic tension-type headache: pla-
for stroke. nary risk derived from meta-analysis of randomised trials. cebo-controlled dose-ranging comparison with paracetamol. Ce-
• The value of aspirin for primary prevention of cardiovascu- Heart 2001; 85: 265–71. phalalgia 2003; 23: 59–66.
lar events, particularly myocardial infarction and stroke de- 8. Antithrombotic Trialists’ Collaboration. Collaborative meta- 5. Lipton RB, et al. Aspirin is efficacious for the treatment of acute
pends upon the accurate estimation of overall cardiovascular analysis of randomised trials of antiplatelet therapy for preven- migraine. Headache 2005; 45: 283–92.
tion of death, myocardial infarction, and stroke in high risk pa-
risk but is probably not justified in healthy individuals.7-9 tients. BMJ 2002; 324: 71–86. Correction. ibid.; 141.
6. Diener HC, et al. Aspirin in the treatment of acute migraine at-
tacks. Expert Rev Neurother 2006; 6: 563–73.
Although aspirin may prevent venous thromboembolism 9. Collaborative Group of the Primary Prevention Project. Low-
(p.1189) after surgery, other treatments have been preferred. dose aspirin and vitamin E in people at cardiovascular risk: a Kawasaki disease. Aspirin has been given in regimens with
However, it is recommended for use in preventing thrombotic randomised trial in general practice. Lancet 2001; 357: 89–95. normal immunoglobulins to children with Kawasaki disease
complications associated with procedures such as angioplasty 10. Eccles M, et al. North of England evidence based guideline de- (p.2228) because of its anti-inflammatory, antipyretic, and an-
and coronary bypass grafting (see under Reperfusion and velopment project: guideline on the use of aspirin as secondary tiplatelet activity.1-4
prophylaxis for vascular disease in primary care. BMJ 1998;
Revascularisation Procedures, p.1181). Aspirin is often given 316: 1303–9. The usual practice is to use an anti-inflammatory regimen until
as an adjunct to patients with peripheral arterial thromboem- 11. American Diabetes Association. Aspirin therapy in diabetes. the fever has settled and then convert to an antithrombotic regi-
bolism (p.1178) to prevent propagation of the clot and also to Diabetes Care 2004; 27 (suppl 1): S72–S73. men. The BNFC recommends an oral dose of 30 to 50 mg/kg
 Aspirin/Auranofin 25
daily in 4 divided doses in children aged 1 month and over (neo-
nates may be given 32 mg/kg daily in 4 divided doses); this
2. Hersch EV, et al. Over-the-counter analgesics and antipyretics: a
critical assessment. Clin Ther 2000; 22: 500–48.
Auranofin (BAN, USAN, rINN)
should be continued until the patient is afebrile or for the first 14 Auranofiini; Auranofina; Auranofine; Auranofinum; Oranofin;
3. Vergne P, et al. Aspirine, douleurs et inflammation. Rev Med In-
days after the onset of symptoms. Once fever and signs of in- terne 2000; 21 (Suppl 1): 89s–96s.
SKF-39162; SKF-D-39162. (1-Thio-β-D-glucopyranosato)(tri-
flammatory disease resolve, the aspirin dose is reduced to 2 to ethylphosphine)gold 2,3,4,6-tetra-acetate.
5 mg/kg daily (neonates may be given 5 mg/kg daily) as a single Ауранофин
dose for its antiplatelet effect. Aspirin may be stopped 6 to 8 Rheumatic disorders. Aspirin was once widely used in the
treatment of rheumatoid arthritis (p.11) but has been superseded C 20 H 34 AuO 9 PS = 678.5.
weeks after the onset of illness but is usually continued for at
least one year if coronary abnormalities are present and is contin- by better tolerated NSAIDs; however, juvenile idiopathic arthri- C AS — 34031-32-8.
ued indefinitely if coronary aneurysms persist. Similar tis including Still’s disease (p.10) are among the limited number ATC — M01CB03.
regimens3,4 are used in the USA although the initial dose of aspi- of indications for aspirin use in children. The American Hospital ATC Vet — QM01CB03.
rin is more usually 80 to 100 mg/kg daily. Service Formulary suggests that children weighing 25 kg or less
Despite this widespread use the optimum dose and duration of may be given an initial oral dose of 60 to 130 mg/kg daily in
treatment have not been clearly established, and the value of as- divided doses; heavier children should be started on 2.4 to 3.6 g O
pirin in the initial management of Kawasaki disease has been daily. The usual maintenance dose is 80 to 100 mg/kg daily al- CH3
questioned. In a meta-analysis5 fever duration was significantly though up to 130 mg/kg daily may be required in some children; H 3C O
shorter in those on high-dose aspirin; however, other studies6
however, because of the risk of toxicity, it is recommended that P CH3
have not shown such a benefit. Meta-analyses5,7 have also shown O S
that the incidence of coronary artery abnormalities is not signifi- children weighing over 25 kg should not receive doses of O Au
cantly different for regimens using high (over 80 mg/kg daily) or 100 mg/kg daily or above.
CH3
low doses of aspirin. Furthermore, a retrospective study8 sug-
H3C O O
gested that aspirin use (irrespective of dose) in the acute phase of Preparations
the disease may be unnecessary as its addition to immunoglobu- H3 C O
lin treatment had no effect on the rate of coronary artery abnor- BP 2008: Aspirin and Caffeine Tablets; Aspirin Tablets; Co-codaprin Tab- H3 C O
malities. A more recent review9 found that evidence from com- lets; Dispersible Aspirin Tablets; Dispersible Co-codaprin Tablets; Efferves-
parative studies failed to show that aspirin reduced the rate of cent Soluble Aspirin Tablets; Gastro-resistant Aspirin Tablets; O
coronary artery abnormalities; a lack of good quality randomised USP 31: Acetaminophen and Aspirin Tablets; Acetaminophen, Aspirin, and
controlled trials prevented any recommendations on the use of Caffeine Tablets; Aspirin and Codeine Phosphate Tablets; Aspirin Capsules;
aspirin in the treatment of Kawasaki disease. Aspirin Delayed-release Capsules; Aspirin Delayed-release Tablets; Aspirin Adverse Effects and Treatment
Effervescent Tablets for Oral Solution; Aspirin Extended-release Tablets; As-
1. Williams RV, et al. Pharmacological therapy for patients with
pirin Suppositories; Aspirin Tablets; Aspirin, Alumina, and Magnesia Tablets;
The most common adverse effects of auranofin involve
Kawasaki disease. Paediatr Drugs 2001; 3: 649–60. the gastrointestinal tract and include nausea, abdomi-
2. Brogan PA, et al. Kawasaki disease: an evidence based approach Aspirin, Alumina, and Magnesium Oxide Tablets; Buffered Aspirin Tablets;
to diagnosis, treatment, and proposals for future research. Arch Butalbital and Aspirin Tablets; Butalbital, Aspirin, and Caffeine Capsules; nal pain, and sometimes vomiting, but most often diar-
Butalbital, Aspirin, and Caffeine Tablets; Butalbital, Aspirin, Caffeine, and Co-
Dis Child 2002; 86: 286–90.
deine Phosphate Capsules; Carisoprodol and Aspirin Tablets; Carisoprodol,
rhoea, which can affect up to 50% of patients and may
3. Newburger JW, et al. Diagnosis, treatment, and long-term man-
agement of Kawasaki disease: a statement for health profession- Aspirin, and Codeine Phosphate Tablets; Oxycodone and Aspirin Tablets; be severe enough to cause patients to withdraw from
als from the Committee on Rheumatic Fever, Endocarditis, and Pentazocine and Aspirin Tablets; Propoxyphene Hydrochloride, Aspirin, treatment. Other adverse effects are similar to those ex-
Kawasaki Disease, Council on Cardiovascular Disease in the and Caffeine Capsules; Propoxyphene Napsylate and Aspirin Tablets.
Young, American Heart Association. Pediatrics 2004; 114:
perienced with sodium aurothiomalate (p.122), al-
1708–33. Correction. ibid. 2005; 115: 1118. Also available at: Proprietary Preparations (details are given in Part 3) though they appear to be less troublesome since fewer
http://pediatrics.aappublications.org/cgi/reprint/114/6/1708.pdf patients stop treatment with auranofin than with inject-
(accessed 12/04/07) Also published in Circulation 2004; 110: Arg.: Adiro†; Aspimed†; Aspirina; Aspirinetas; Ball†; Bayaspirina; Bufferin†;
2747–71. Also available at: http://circ.ahajournals.org/cgi/ Cardioaspirina; Desenfriolito; Ecotrin; Geniol AP†; Geniol Prevencion; Ge-
able gold. As with other gold salts, treatment of ad-
reprint/110/17/2747.pdf (accessed 12/04/07) niol SC sin Cafeina; Geniolito†; Lacefal†; Lafeaspirina; Nuevapina; Austral.: verse effects is generally symptomatic (see p.123).
4. Freeman AF, Shulman ST. Kawasaki disease: summary of the
American Heart Association guidelines. Am Fam Physician
Aspro; Astrix; Bex†; Cardiprin; Cartia; Disprin; Disprin Direct; Ecotrin†; Sol- Modifying the diet to increase bulk, use of a bulking
prin; Spren†; Vincent’s Powders†; Austria: Acekapton; Aspiricor; Aspro;
2006; 74: 1141–8.
ASS; Herz ASS; Herzschutz ASS; Salimont; Thrombo ASS; Thrombostad;
agent such as bran, or a temporary reduction in au-
5. Terai M, Shulman ST. Prevalence of coronary artery abnormali-
ties in Kawasaki disease is highly dependent on gamma globulin Togal Mono; Belg.: Acenterine; Asaflow; Asarid†; Aspirine; Aspro; Cardio- ranofin dosage, may help the diarrhoea (but see Effects
dose but independent of salicylate dose. J Pediatr 1997; 131: aspirine; Cardiphar; Dispril; Sedergine; Therasa†; Braz.: AAS; Aasedatil†; on the Gastrointestinal Tract, below).
888–93. Aceticil; Analgesin; Antifebrin†; Ascedor†; Asetisin†; Aspirina; Bufferin;
6. Saulsbury FT. Comparison of high-dose and low-dose aspirin Caas†; Cardio AAS; Cimaas; Ecasil†; Hipotermal; Salicil; Salicin; Salitil; Soma- ◊ Reviews.
plus intravenous immunoglobulin in the treatment of Kawasaki lgin; Canad.: Asaphen; Aspergum; Aspirin with Stomach Guard; Bufferin; 1. Tozman ECS, Gottlieb NL. Adverse reactions with oral and
syndrome. Clin Pediatr (Phila) 2002; 41: 597–601. Entrophen; Equate; Novasen; Rivasa; Tri-Buffered ASA; Chile: Aspirina; parenteral gold preparations. Med Toxicol 1987; 2: 177–89.
7. Durongpisitkul K, et al. The prevention of coronary artery aneu- Cardioaspirina; Disgren; Ecotrin; Fluicor; Hassapirin Puro; Thrombo AS;
rysm in Kawasaki disease: a meta-analysis on the efficacy of as- Cz.: Acylpyrin; Anopyrin; Apo-Asa†; Aspro†; Godasal; Upsarin†; Denm.:
Effects on the gastrointestinal tract. Diarrhoea and abdom-
pirin and immunoglobulin treatment. Pediatrics 1995; 96: Hjerdyl; Hjertemagnyl; Idotyl; Magnyl; Fin.: Aspirin Cardio; Aspirin Zipp; inal pain are common with auranofin. The mechanism of gas-
1057–61. Disperin; Primaspan; Fr.: Aspirine; Aspirine pH8†; Aspirisucre; Aspro; Cat- trointestinal toxicity has not been established but may be associ-
8. Hsieh K-S, et al. Treatment of acute Kawasaki disease: aspirin’s algine†; Claragine; Ger.: Acesal; Acetylin†; Aspro; ASS; Godamed; Her- ated with a reversible defect in intestinal permeability.1 Although
role in the febrile stage revisited. Pediatrics 2004; 114: 689. Full zASS; Miniasal; Santasal N; Thomapyrin akut†; Togal ASS; Gr.: Salospir; Up- some have suggested that diarrhoea may occur in up to 50% of
version: http://pediatrics.aappublications.org/cgi/reprint/114/6/ patients taking auranofin, a study in 269 patients given the drug
salgin-N; Hong Kong: Aspilets; Astrix; Bokey; Cardiprin; Cartia; Disprin;
e689 (accessed 27/11/06)
9. Baumer JH, et al. Salicylate for the treatment of Kawasaki dis- Ecotrin; Glyprin; LAsprin; Propirin; Hung.: Aspirin Protect; Astrix; Colfarit; for rheumatoid arthritis found that only about 15% experienced
ease in children. Available in The Cochrane Database of System- Istopirin†; Kalmopyrin; India: ASA; Aspicot; Colsprin; CV-Sprin; Delisprin; loose and watery stools over a six-month period.2 Although bulk-
atic Reviews; Issue 4. Chichester: John Wiley; 2006 (accessed Disprin; Ecosprin; Indon.: Aptor; Ascardia; Aspilets; Astika; Bodrexin; Car- ing agents have been recommended in the management of au-
27/11/06). dio Aspirin; Contrexyn; Farmasal; Inzana; Minigrip; Naspro; Procardin; Res- ranofin-induced diarrhoea, no overall difference in incidence
tor; Rheumapill; Thrombo Aspilets; Irl.: Aspro; Caprin; Disprin; Lowasa; was seen between patients given prophylactic psyllium and those
Leg ulcers. A 4-month placebo-controlled study1 in 20 patients Nu-Seals; Resprin; Israel: Acetosal; Alka-Seltzer; Ascriptin†; Buffered Pirin;
suggested that aspirin 300 mg daily aided healing of chronic ve- Cartia; Ecoprin; Godamed; Micropirin; Tevapirin; Ital.: Acesal†; ASA-ratio;
given placebo; however, patients given psyllium had slightly
nous leg ulcers; the mechanism of action was unclear.2 However, Ascriptin; Aspiglicina; Aspirina; Aspirina 03; Aspirinetta; Aspro; Bufferin†; fewer days with loose and watery stools.
the validity of the findings has been challenged.3 The manage- Cardioaspirin; Cemirit; Kilios†; Malaysia: Aceprin; Bufferin Low Dose†; Gold-induced colitis has also been reported in patients taking au-
ment of leg ulcers is discussed on p.1585. Cardiprin; Casprin; Disprin; Dusil†; Glyprin; Mex.: Acetil-A; Acetin; Acitab; ranofin.3,4
1. Layton AM, et al. Randomised trial of oral aspirin for chronic Adiro†; Antacsal; ASA; Ascriptin; Aspirina Protect; Axal†; Disprina; Dolo- 1. Behrens R, et al. Investigation of auranofin-induced diarrhoea.
venous leg ulcers. Lancet 1994; 344: 164–5. quim; Ecotrin; Midolen; Vastecel; Neth.: Asacard; Aspirine Protect; Aspro; Gut 1986; 27: 59–65.
2. Ibbotson SH, et al. The effect of aspirin on haemostatic activity Bisolgripin†; Darosal; Togal; Norw.: Albyl-E; Dispril; Globoid; NZ: Aspec; 2. van Beusekom HJ, et al. The moderate intestinal side effects of
in the treatment of chronic venous leg ulceration. Br J Dermatol Aspro; Cardiprin†; Cartia; Disprin; Ecotrin; Solprin; Philipp.: Anthrom; As- auranofin do not require prophylactic therapy with a bulkform-
1995; 132: 422–6. aprim; Aspec; Aspilets; Cor-30, Cor-80; Cortal; Enteroprin; Tromcor; Pol.: ing agent. Dutch Ridaura Study Group. Clin Rheumatol 1997;
3. Ruckley CV, Prescott RJ. Treatment of chronic leg ulcers. Lancet Acard; Acesan; Alka-Prim; Alka-Seltzer; ASA; Aspimag; Aspirin Protect; As- 16: 471–6.
1994; 344: 1512–13. procard; Asprocol; Bestpirin; Calcipiryna; Cardiofil; Encopirin; Galocard; Ni- 3. Michet CJ, et al. Auranofin-associated colitis and eosinophilia.
pas; Polocard; Polopiryna; Polopiryna S; Proficar; Upsarin; Port.: AAS; Asac- Mayo Clin Proc 1987; 62: 142–4.
Malignant neoplasms. For references to studies suggesting 4. Langer HE, et al. Gold colitis induced by auranofin treatment of
ard; ASP; Aspirina; Aspro†; Car tia; Melhoral Infantil†; Migraspirina;
that regular use of aspirin and other NSAIDs may reduce the risk rheumatoid arthritis: case report and review of the literature. Ann
Salycilina†; Toldex; Tromalyt; Rus.: Aspinat Cardio (Аспинат Кардио); As-
of developing malignant neoplasms of the gastrointestinal tract, pirin Cardio (Аспирин Кардио); CardiASK (КардиАСК); Thrombo ASS
Rheum Dis 1987; 46: 787–92.
see under NSAIDs, p.100. (Тромбо АСС); S.Afr.: Disprin; Ecotrin; Myoprin; Singapore: Aspro; As- Effects on the kidneys. In a retrospective review1 of 1283 pa-
Myeloproliferative disorders. Aspirin in low doses may be trix†; Bokey; Bufferin†; Cardiprin; Disprin; Dusil; Glyprin; Spain: AAS; Adi- tients who had received auranofin for treatment of rheumatoid
used to provide symptomatic relief for erythromelalgia (burning ro; Aspinfantil†; Aspirina; Bioplak; Helver Sal†; Mejoral†; Okal; Orravina†; arthritis 41 (3.2%) were found to have developed proteinuria. In
pain and erythema of the hands and feet) in patients with poly- Rhonal; Saspryl†; Sedergine; Tromalyt; Swed.: Albyl minor; Bamycor†; most cases proteinuria was treated by stopping auranofin thera-
Bamyl; Bamyl S; Emotpin†; Magnecyl; Trombyl; Switz.: ASA; Asperivo†; As- py. Long-term follow-up of 36 patients indicated that proteinuria
cythaemia vera (p.654) and primary thrombocythaemia (p.654). pirine Cardio; Aspro; ASS; Juridin; Thrombace Neo; Tiatral 100 SR; Togal
had resolved in 31 within 2 years and in 29 within 1 year. Seven
Pain. Aspirin, along with other NSAIDs and paracetamol, may ASS; Thai.: Actorin; Anassa; Asatab; Ascot†; Aspent; Aspilets; Asrina; Ca-
of 8 patients later rechallenged with auranofin had no relapses. In
be used for treating mild or moderate pain (see Choice of parin; Cardiprin; Comoprin†; Entrarin; Seferin; V-AS; Turk.: Algo; Algo
Bebe; Asabrin; Asinpirine; Aspapirine; Aspinal; Ataspin; Babyprin; Coraspin; a further review of 2 comparative double-blind studies using
Analgesic, p.2) and is also used in moderate or severe pain to gold compounds in the treatment of rheumatoid arthritis, pro-
potentiate the effects of opioids. It is suitable for use in acute or Dispril; Ecopirin; Notras; Opon; UAE: Jusprin; UK: Alka; Angettes; Aspro;
Caprin; Disprin; Disprin Direct; Enprin; Micropirin; Nu-Seals; PostMI†; Pure teinuria was found to have developed in 27% (23 of 85) of pa-
chronic pain. Aspirin should not be used for pain relief in chil- tients treated with sodium aurothiomalate, in 17% (42 of 247) of
Health; USA: Adprin-B; Arthritis Pain Formula; Ascriptin; Aspergum; Aspri-
dren because of its association with Reye’s syndrome (see under mox†; Bayer Low Adult Strength; Bufferin; Buffex; Cama Arthritis Pain Re- those treated with auranofin, and in 17% (36 of 210) of those
Adverse Effects, above). liever; Easprin; Ecotrin; Empirin; Extra Strength Bayer Plus; Genprin; Half- receiving placebo. All patients were receiving NSAIDs.
Dependence and tolerance are not a problem with non-opioid prin; Magnaprin†; Norwich Extra Strength; Norwich Regular Strength; 1. Katz WA, et al. Proteinuria in gold-treated rheumatoid arthritis.
analgesics such as aspirin, but there is a ceiling of efficacy, above Regular Strength Bayer; St. Joseph Adult Chewable; ZORprin; Venez.: As- Ann Intern Med 1984; 101: 176–9.
which increasing the dose has no further therapeutic effect. aprol; Ascriptin; Aspiretina†; Azacard; Cardipirina; Coraspirina.
References. Precautions
Multi-ingredient: numerous preparations are listed in Part 3.
1. Edwards JE, et al. Single dose oral aspirin for acute pain. Avail- As for Sodium Aurothiomalate, p.123. Urine and
able in The Cochrane Database of Systematic Reviews; Issue 4.
Chichester: John Wiley; 1999 (accessed 27/11/06). blood tests should be carried out before starting au-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
26 Analgesics Anti-inflammatory Drugs and Antipyretics
ranofin and monthly thereafter; licensed product infor- tions, such as contact dermatitis, was thought to outweigh any Aurotioprol
mation advises that auranofin should be withdrawn if benefit. Sodium 3-aurothio-2-hydroxypropane-1-sulphonate.
the platelet count falls below 100 000 cells/mm3 or if 1. Helm KF, et al. Topical auranofin ointment for the treatment of Ауротиопрол
plaque psoriasis. J Am Acad Dermatol 1995; 33: 517–19.
signs and symptoms suggestive of thrombocytopenia, C 3 H 6 AuNaO 4 S 2 = 390.2.
leucopenia or aplastic anaemia occur. US licensed Rheumatic disorders. Gold compounds are among the dis- C AS — 27279-43-2.
product information states that baseline renal and liver ease-modifying antirheumatic drugs (DMARDs) that may be ATC — M01CB05.
used in the treatment of rheumatoid arthritis (p.11). Oral gold is ATC Vet — QM01CB05.
function levels should also be established before start- less toxic than intramuscular gold but is also much less effective.
ing auranofin therapy. Auranofin should be used with Profile
Gold compounds may also be of benefit in psoriatic arthritis (see
Aurotioprol is a gold compound with a gold content of about
caution in patients with inflammatory bowel disease. under Spondyloarthropathies, p.13) and have been used in juve-
50%; it has similar actions and uses to those of sodium aurothi-
nile idiopathic arthritis (p.10).
Porphyria. Auranofin has been associated with acute attacks of omalate (p.122). It is given by intramuscular injection for the
porphyria and is considered unsafe in porphyric patients. References. treatment of rheumatoid arthritis (p.11). The initial dose is 25 mg
1. Suarez-Almazor ME, et al. Auranofin versus placebo in rheuma- weekly, increased to 50 to 100 mg weekly, until a total dose of
toid arthritis. Available in The Cochrane Database of Systematic 1.2 to 1.5 g has been given. If improvement has occurred with no
Interactions Reviews; Issue 2. Chichester: John Wiley; 2000 (accessed signs of toxicity, this may be followed by a dose of 50 to 100 mg
As for Sodium Aurothiomalate, p.123. 09/05/05). intramuscularly every month.
Preparations Preparations
Pharmacokinetics Proprietary Preparations (details are given in Part 3)
Proprietary Preparations (details are given in Part 3)
Auranofin is incompletely absorbed from the gastroin- Belg.: Allochrysine†; Fr.: Allochrysine.
Austral.: Ridaura; Austria: Ridaura; Belg.: Ridaura; Braz.: Ridaura†; Ca-
testinal tract, only about 25% of the gold being ab- nad.: Ridaura†; Denm.: Ridaura†; Fin.: Ridaura; Fr.: Ridauran; Ger.: Ridau-
sorbed. Gold from auranofin is bound to plasma pro- ra; Gr.: Ridaura; Hong Kong: Ridaura; India: Goldar; Irl.: Ridaura; Israel:
Ridaura; Ital.: Ridaura; Neth.: Ridaura; Norw.: Ridaura; NZ: Ridaura;
teins as well as to red blood cells. After 2 to 3 months Port.: Ridaura; Rus.: Auropan (Ауропан); S.Afr.: Ridaura; Spain: Ridaura; Azapropazone (BAN, rINN)
of treatment the steady-state concentration of gold in Swed.: Ridaura†; Switz.: Ridaura; UK: Ridaura; USA: Ridaura. AHR-3018; Apazone (USAN); Atsapropatsoni; Azapropazon; Az-
the blood is reported to be about 0.7 micrograms/mL. apropazona; Azapropazonum; Mi85; NSC-102824. 5-Dimethyl-
The average terminal plasma half-life of gold at steady amino-9-methyl-2-propylpyrazolo[1,2-a][1,2,4]benzotriazine-
1,3(2H)-dione.
state is about 26 days while the biological half-life is 80 Aurothioglucose
Азапропазон
days. Tissue retention and total gold accumulation in 1-Aurothio-D-glucopyranose; Aurotioglucosa; (D-Glucosylthio)- C 16 H 20N 4 O 2 = 300.4.
the body are less than with intramuscular gold. Gold gold; Gold Thioglucose. (1-Thio-D-glucopyranosato)gold. C AS — 13539-59-8.
from auranofin penetrates into synovial fluid. ATC — M01AX04.
Ауротиоглюкоза
Most of a dose of auranofin appears in the faeces due ATC Vet — QM01AX04.
C 6 H 11AuO 5S = 392.2.
to its poor absorption. About 60% of the absorbed gold C AS — 12192-57-3.
from auranofin is excreted in the urine and the remain- ATC — M01CB04. CH3
der in the faeces. ATC Vet — QM01CB04. O
◊ Reviews.
1. Blocka KLN, et al. Clinical pharmacokinetics of oral and inject-
H 3C N O
able gold compounds. Clin Pharmacokinet 1986; 11: 133–43. O S N
2. Benn HP, et al. Pharmacokinetics of auranofin: a single dose HO Au
study in man. J Rheumatol 1990; 17: 466–8. CH3
HO OH N N
Uses and Administration
Auranofin is a gold compound with a gold content of OH CH3
about 29%; it has similar actions and uses to those of
Pharmacopoeias. In US. Pharmacopoeias. Br. includes the dihydrate.
sodium aurothiomalate (p.123). It is given orally in ac- BP 2008 (Azapropazone). The dihydrate is a white to pale yel-
USP 31 (Aurothioglucose). A yellow odourless or practically
tive progressive rheumatoid arthritis (below); such oral odourless powder. An aqueous solution is unstable on long low crystalline powder. Very slightly soluble in water and in
treatment is less toxic than intramuscular gold but is standing. It is stabilised by the addition of a small amount of so- chloroform; soluble in alcohol; dissolves in solutions of alkali
also much less effective. The usual initial dose of au- dium acetate. pH of a 1% solution in water is about 6.3. Freely hydroxides.
ranofin is 6 mg daily given in two divided doses at first, soluble in water; practically insoluble in alcohol, in acetone, in Profile
then, if tolerated, as a single dose. Treatment should be chloroform, and in ether. Store in airtight containers. Protect Azapropazone is an NSAID (see p.96), structurally related to
from light. phenylbutazone (p.117). It also has uricosuric properties. Be-
continued for at least 6 months to assess the response;
Adverse Effects, Treatment, and Precautions cause azapropazone appears to be associated with a higher inci-
the dose may be increased after 6 months, if the re- dence of adverse effects than with some other NSAIDs, its use
sponse is inadequate, to 3 mg three times daily. If the As for Sodium Aurothiomalate, p.122.
has been restricted to the treatment of rheumatoid arthritis, anky-
response is still inadequate after 3 months at this dos- Effects on the blood. Thrombocytopenia developed in 2 pa- losing spondylitis, and acute gout in patients for whom other
age, then treatment should be stopped. tients treated with intramuscular aurothioglucose.1 NSAIDs have been ineffective.
1. Levin M-D, et al. Two patients with acute thrombocytopenia fol- Azapropazone is used as the dihydrate and doses are expressed
Asthma. A systematic review1 found that oral or parenteral lowing gold administration and five-year follow-up. Neth J Med in terms of this hydrated form. For the treatment of rheumatoid
gold compounds reduced corticosteroid requirements in the 2003; 61: 223–5. arthritis or ankylosing spondylitis the usual oral dose was up to
management of asthma (p.1108); however, it was considered that 1.2 g daily in 2 divided doses. Patients over 60 years of age have
the effect was probably of limited clinical significance and, given Interactions been given 300 mg twice daily. Reduced doses were also recom-
the adverse effects and monitoring requirements of gold com- As for Sodium Aurothiomalate, p.123. mended in patients with renal impairment, see below.
pounds, their use in asthma could not be recommended.
Pharmacokinetics Administration in renal impairment. In the treatment of
1. Evans DJ, et al. Gold as an oral corticosteroid sparing agent in As for Sodium Aurothiomalate, p.123; absorption is slower and
stable asthma. Available in The Cochrane Database of Systemat- rheumatoid arthritis or ankylosing spondylitis in patients with re-
ic Reviews; Issue 4. Chichester: John Wiley; 2000 (accessed
more irregular. duced renal function the usual dose was reduced according to
25/10/06).
Uses and Administration creatinine clearance (CC) as follows:
Lupus. Since the introduction of less toxic drugs gold com- Aurothioglucose is a gold compound with a gold content of • CC 50 to 75 mL/minute: reduce usual dose (see above) by
pounds are now rarely used in the treatment of SLE, however, about 50%; it has similar actions and uses to those of sodium one-third to one-half
there have been anecdotal reports suggesting that auranofin may aurothiomalate (p.123). It is used in the treatment of active rheu- • CC less than 50 mL/minute: reduce usual dose by one-half to
still be of use in patients with discoid lupus erythematosus1 or matoid arthritis (p.11) and juvenile idiopathic arthritis (p.10). two-thirds
cutaneous lupus erythematosus2 refractory to conventional treat- Aurothioglucose is given intramuscularly as a suspension in oil Breast feeding. Small quantities of azapropazone are excreted
ment. in an initial weekly dose of 10 mg increasing gradually to up to into breast milk. 1 However, the American Academy of
1. Dalziel K, et al. Treatment of chronic discoid lupus erythemato- 50 mg weekly. Therapy is continued at weekly intervals until a Pediatrics2 states that there have been no reports of any clinical
sus with an oral gold compound (auranofin). Br J Dermatol total dose of 0.8 to 1 g has been given; if improvement has oc- effect on the infant associated with the use of azapropazone by
1986; 115: 211–16. curred with no signs of toxicity 50 mg may then be given at in- breast-feeding mothers, and that therefore it may be considered
2. Farrell AM, Bunker CB. Oral gold therapy in cutaneous lupus tervals of 3 to 4 weeks. Children aged 6 to 12 years have been to be usually compatible with breast feeding.
erythematosus (revisited). Br J Dermatol 1996; 135 (suppl 47): given one-quarter the adult dose, to a maximum of 25 mg per 1. Bald R, et al. Excretion of azapropazone in human breast milk.
41. dose. Eur J Clin Pharmacol 1990; 39: 271–3.
Pemphigus. A patient with long-standing pemphigus foliaceus 2. American Academy of Pediatrics. The transfer of drugs and oth-
◊ For comment on the relative efficacy and tolerability of au- er chemicals into human milk. Pediatrics 2001; 108: 776–89.
being treated with prednisolone and hydroxychloroquine had rothioglucose and aurothiomalate see Rheumatic Disorders, un- Correction. ibid.; 1029. Also available at:
healing of his lesions within 6 months of auranofin being substi- der Sodium Aurothiomalate, p.124. h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
tuted for the hydroxychloroquine.1 pediatrics%3b108/3/776 (accessed 01/11/07)
1. Bagheri MM, et al. Pemphigus foliaceus presenting as eruptive Preparations
Effects on the blood. Auto-immune haemolytic anaemia, oc-
seborrheic keratosis and responding to oral gold treatment. J USP 31: Aurothioglucose Injectable Suspension.
Drugs Dermatol 2002; 1:333–4. casionally fatal, often with pulmonary infiltration, allergic alve-
Proprietary Preparations (details are given in Part 3) olitis, pulmonary fibrosis, or fibrosing alveolitis, has been report-
Psoriasis. Although topical auranofin has been shown in a pla- Canad.: Solganal†; Israel: Solganal; Neth.: Auromyose†; USA: Solganal. ed in patients receiving azapropazone.1-3
cebo-controlled study1 to be effective in the treatment of plaque- 1. Chan-Lam D, et al. Red cell antibodies and autoimmune haemo-
type psoriasis (p.1583) the high incidence of adverse skin reac- lysis after treatment with azapropazone. BMJ 1986; 293: 1474.
 Aurothioglucose/Benzydamine Hydrochloride 27
2. Albazzaz MK, et al. Alveolitis and haemolytic anaemia induced Profile that have occurred with benoxaprofen include skin disorders,
by azapropazone. BMJ 1986; 293: 1537–8. Bendazac is an NSAID (p.96) structurally related to indometacin notably photosensitivity reactions but also erythema multiforme
3. Montgomery RD, Babb RG. Alveolitis and haemolytic anaemia (p.66). It has been used topically in preparations containing 1 or and the Stevens-Johnson syndrome, onycholysis and other nail
induced by azapropazone. BMJ 1987; 294: 375.
3% for the treatment of various inflammatory skin disorders. disorders, gastrointestinal disturbances including peptic ulcera-
Effects on the gastrointestinal tract. In a review1 of the rel- Bendazac lysine has been used in the management of cataract, tion and bleeding, blood disorders such as thrombocytopenia,
ative safety of 7 oral NSAIDs, the UK CSM commented that eye drops containing 0.5% being instilled three times daily. cholestatic jaundice and other liver or biliary disorders, and renal
azapropazone was associated with the highest risk of gastrointes- Hepatotoxicity has been reported. failure.
tinal reactions in both epidemiological studies and an analysis of
spontaneous reporting of adverse reactions. Although it appeared ◊ References.
that some patients over 60 years of age had received doses ex- 1. Balfour JA, Clissold SP. Bendazac lysine: a review of its phar-
ceeding those recommended for this age group, it was considered macological properties and therapeutic potential in the manage- Benzydamine Hydrochloride (BANM, USAN, rINNM)
that even when this was taken into account a marked difference ment of cataracts. Drugs 1990; 39: 575–96.
2. Prieto de Paula JM, et al. Hepatotoxicidad por bendazaco: análi- AF-864; Benzidamin Hidroklorür; Benzindamine Hydrochloride;
remained between gastrointestinal reactions for azapropazone sis de 16 casos. Rev Clin Esp 1995; 195: 387–9. Benzydamine, Chlorhydrate de; Benzydamini Hydrochloridum;
compared with other NSAIDs. Benzydaminy chlorowodorek; Hidrocloruro de bencidamina. 3-
Preparations
The CSM recommended that azapropazone should be restricted (1-Benzyl-1H-indazol-3-yloxy)-NN-dimethylpropylamine hydro-
to use in rheumatoid arthritis, ankylosing spondylitis, and acute Proprietary Preparations (details are given in Part 3)
Austria: Versus; Gr.: Versalba; Ital.: Bendalina; Versus; Philipp.: Bendalina; chloride.
gout and only when other NSAIDs have been ineffective. Its use Port.: Bendalina; Venez.: Bendalina.
in patients with a history of peptic ulceration was contra-indicat- Бензидамина Гидрохлорид
ed. It was also recommended that when used in patients over 60 C 19 H 23 N 3 O,HCl = 345.9.
years of age for rheumatoid arthritis or ankylosing spondylitis C AS — 642-72-8 (benzydamine); 132-69-4 (benzydam-
the dose should be restricted to a maximum of 600 mg daily. Benorilate (BAN, rINN) ine hydrochloride).
Azapropazone has been withdrawn in many countries including Benorilaatti; Benorilat; Bénorilate; Benorilato; Benorilatum; ATC — A01AD02; G02CC03; M01AX07; M02AA05.
the UK. Benorylate; FAW-76; Fenasprate; Win-11450. 4-Acetamidophe- ATC Vet — QA01AD02; QG02CC03; QM01AX07;
QM02AA05.
1. CSM/MCA. Relative safety of oral non-aspirin NSAIDs. Cur- nyl O-acetylsalicylate.
rent Problems 1994; 20: 9–11. Also available at: http://
w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ Бенорилат
FILE&dDocName=CON2015615&RevisionSelectionMethod= C 17 H 15 NO 5 = 313.3.
LatestReleased (accessed 01/11/07) C AS — 5003-48-5.
Effects on the skin. Of 917 reports of adverse reactions asso- ATC — N02BA10.
ATC Vet — QN02BA10. N
ciated with azapropazone forwarded to the WHO Collaborating
Centre for International Drug Monitoring1 before September N
1984, 190 (21%) were of photosensitivity. Of 154 reports of pho- CH3
tosensitivity evaluated a causal relationship to use of azapropa- O
H O N
zone was considered certain in 6, probable in 138, and possible N CH3
in 10. In May 1994 the UK CSM stated2 that since 1976 they had H3 C O O CH3
received 464 reports of photosensitivity reactions associated
with azapropazone and commented that, when corrected for pre- O (benzydamine)
scription volume, reporting of this reaction was 50 times greater O
than with other commonly prescribed NSAIDs. They recom- Pharmacopoeias. In Br. and Pol.
mended that patients should be advised to avoid direct exposure BP 2008 (Benzydamine Hydrochloride). A white crystalline
to sunlight or to use sunblock preparations. powder. Very soluble in water; freely soluble in alcohol and in
1. Olsson S, et al. Photosensitivity during treatment with azapropa- Pharmacopoeias. In Br. and Chin.
BP 2008 (Benorilate). A white or almost white, odourless or al- chloroform; practically insoluble in ether. A 10% solution in wa-
zone. BMJ 1985; 291: 939.
2. CSM/MCA. Photosensitivity associated with azapropazone most odourless, crystalline powder. Practically insoluble in wa- ter has a pH of 4.0 to 5.5.
(Rheumox). Current Problems 1994; 20: 6. Also available at: ter; sparingly soluble in alcohol and in methyl alcohol; soluble in Adverse Effects
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ acetone and in chloroform. After topical application to the skin local reactions such as ery-
FILE&dDocName=CON2015616&RevisionSelectionMethod=
LatestReleased (accessed 01/11/07) Profile thema or rash may occur and photosensitivity has been reported.
Benorilate is an aspirin-paracetamol ester with analgesic, anti- After use as mouth and throat preparations, numbness or stinging
Porphyria. Azapropazone is considered to be unsafe in patients sensations of the oral mucosa have been reported; hypersensitiv-
with porphyria because it has been shown to be porphyrinogenic inflammatory, and antipyretic properties. After absorption, it is
rapidly metabolised to salicylate and paracetamol. It has been ity reactions including urticaria, photosensitivity, and bronchos-
in animals. pasm may also occur rarely.
used orally in the treatment of mild to moderate pain (see Choice
Preparations of Analgesic, p.2) and fever (p.10). It has also been used in oste- Effects on the kidneys. A 57-year-old woman who had used
BP 2008: Azapropazone Capsules; Azapropazone Tablets. oarthritis, rheumatoid arthritis, and soft-tissue rheumatism. 400 g of a topical cream containing benzydamine hydrochloride
Proprietary Preparations (details are given in Part 3) When an overdose of benorilate is suspected, it has been suggest- 3% over a period of 4 months was found to have raised plasma
Arg.: Debelex†; Austria: Prolixan†; Gr.: Prolixan†; Hung.: Prolixan†; Irl.: ed that plasma concentrations of both salicylate and paracetamol concentrations of creatinine and urea consistent with a substan-
Rheumox†; Port.: Prolixan†; S.Afr.: Rheumox; Turk.: Prodisan; UK: Rheu- should be measured since a normal plasma-paracetamol concen- tial reduction in glomerular filtration rate.1
mox†. tration cannot necessarily be assumed from a normal plasma-sal- 1. O’Callaghan CA, et al. Renal disease and use of topical non-
icylate measurement. steroidal anti-inflammatory drugs. BMJ 1994; 308: 110–11.
◊ References. Effects on the skin. Photoallergic contact dermatitis devel-
Bendazac (BAN, USAN, rINN) 1. Aylward M. Toxicity of benorylate. BMJ 1973; 2: 118. oped on the hands of a 65-year-old woman after the use of a gen-
AF-983; Bendazaco; Bendazacum; Bindazac. (1-Benzyl-1H-inda- 2. Symon DNK, et al. Fatal paracetamol poisoning from benorylate ital wash containing benzydamine 0.1% for several years.1 The
zol-3-yloxy)acetic acid. therapy in child with cystic fibrosis. Lancet 1982; ii: 1153–4. lesions disappeared once the patient stopped using the solution.
Бендазак Preparations 1. Lasa Elgezua O, et al. Photoallergic hand eczema due to benzy-
damine. Eur J Dermatol 2004; 14: 69–70.
C 16 H 14N 2 O 3 = 282.3. BP 2008: Benorilate Oral Suspension; Benorilate Tablets.
C AS — 20187-55-7. Proprietary Preparations (details are given in Part 3) Overdose. A 6-year old girl had hallucinations1 after receiving
Belg.: Duvium†; Fr.: Salipran†; Irl.: Benoral†; Switz.: Duvium†; UK: Beno- 500 mg of benzydamine orally; it had been intended as a vaginal
ATC — M02AA11; S01BC07. ral†. douche for pruritus vulvae; recovery was spontaneous.
ATC Vet — QM02AA11; QS01BC07.
1. Gómez-López L, et al. Acute overdose due to benzydamine.
Hum Exp Toxicol 1999; 18: 471–3.

OH Benoxaprofen (BAN, USAN, rINN) Uses and Administration

O Benoksaprofeeni; Bénoxaprofène; Benoxaprofeno; Benoxapro- Benzydamine hydrochloride is an NSAID (p.99). It is used topi-
fenum; Compound 90459; LRCL-3794. 2-[2-(4-Chlorophe- cally on the skin in concentrations of 3 to 5% in painful muscu-
loskeletal and soft-tissue disorders. Benzydamine hydrochloride
O nyl)benzoxazol-5-yl]propionic acid.
is also used as a mouthwash or spray in concentrations of 0.15%
Беноксапрофен for the relief of inflammatory conditions of the mouth and throat.
C 16 H 12 ClNO 3 = 301.7. It has been given orally or rectally for the relief of painful and
N C AS — 51234-28-7. inflammatory conditions, and as a topical solution for vaginal ir-
N ATC — M01AE06. rigation.
ATC Vet — QM01AE06. Benzydamine salicylate (benzasal) has been used topically on
the skin as a 6% cream or spray.
O Mouth disorders. Results of a randomised placebo-controlled
study in patients undergoing radiotherapy for oropharyngeal can-
Cl
COOH cer indicated that benzydamine as an oral rinse was effective in
Bendazac Lysine (BANM, rINNM) N reducing the area and severity of mucositis.1 Benzydamine is
AF-1934; Bendazac lisina; Bendazacum Lysinum. L-Lysine-(1-ben- also used locally for the management of mouth ulcers (p.1700)
zyl-1H-indazol-3-yloxy)acetic acid. CH3 although an early study2 found it no more useful than placebo.
Бендазак Лизин 1. Epstein JB, et al. Benzydamine HCl for prophylaxis of radiation-
Profile induced oral mucositis: results from a multicenter, randomized,
C 22 H 28N 4 O 5 = 428.5. Benoxaprofen is an NSAID (p.96) structurally related to ibupro- double-blind, placebo-controlled clinical trial. Cancer 2001; 92:
C AS — 81919-14-4. fen (p.64). It was formerly given orally in rheumatoid arthritis 875–85.
ATC — S01BC07. 2. Matthews RW, et al. Clinical evaluation of benzydamine, chlo-
and osteoarthritis but because of reports of adverse reactions and rhexidine, and placebo mouthwashes in the management of re-
ATC Vet — QS01BC07. fatalities the manufacturers halted worldwide marketing of the current aphthous stomatitis. Oral Surg Oral Med Oral Pathol
Pharmacopoeias. In Chin. preparation known as Opren in the early 1980s. Adverse effects 1987; 63: 189–91.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
28 Analgesics Anti-inflammatory Drugs and Antipyretics
Preparations Bicifadine Hydrochloride (USAN, rINNM) fects have been reported with other ophthalmic NSAID prepara-
BP 2008: Benzydamine Cream; Benzydamine Mouthwash; Benzydamine Bicifadina, hidrocloruro de; Bicifadine, Hydrochloride de; Bicifadi- tions; for further details see under Adverse Effects of Diclofenac,
Oromucosal Spray. p.45.
ni Hydrochloridum; CL-220075. (±)-1-p-Tolyl-3-azabicyclo-
Proprietary Preparations (details are given in Part 3) 1. Asai T, et al. Three cases of corneal melting after instillation of
Arg.: Actifedrin; Bencifem; Ernex; Sandival Desleible; Austral.: Difflam; Dif- [3.1.0]hexane hydrochloride. a new nonsteroidal anti-inflammatory drug. Cornea 2006; 25:
flam Anti-inflammatory Throat Spray; Difflam Solution; Austria: Tantum; Бицифадина Гидрохлорид 224–7.
Tantumar; Braz.: Benflogin; Benzitrat; Ciflogex; Eridamin†; Flogin-Ped†; Fl- C 12 H 15N,HCl = 209.7.
ogo Rosa; Flogolab; Flogoral; Fonergoral; Neoflogin; Canad.: Sun-Benz†; Preparations
Tantum; Cz.: Rosalgin; Tantum; Denm.: Andolex; Fr.: Opalgyne; Ger.: Tan- C AS — 71195-57-8 (bicifadine); 66504-75-4 (bicifadine
tum Rosa; Tantum Verde; Gr.: Tantum; Hong Kong: Dantum; Difflam; Ve- hydrochloride). Proprietary Preparations (details are given in Part 3)
rax; Hung.: Tantum Verde; Indon.: Tanflex; Tantum; Irl.: Difflam; Israel: Jpn: Bronuck; USA: Xibrom.
Easy gel; Ital.: Afloben; Benzirin; Ginesal; Lagin†; Multum†; Saniflor Colluto-
rio; Tantum; Verax; Xentafid; Malaysia: Difflam Anti-inflammatory Lozeng-
es; Difflam Solution; Mex.: Artroben; Lonol; Vantal; Neth.: Tantum; NZ: HN
Difflam; Philipp.: Difflam; Pol.: Hascosept; Tantum; Port.: Flogoral;
Momen; Rosalgin; Tantum; Tantum Rosa; Tantum Verde; Rus.: Tantum Rose Bufexamac (BAN, rINN)
(Тантум Роза); Tantum Verde (Тантум Верде); S.Afr.: Andolex; Singa- Bufeksamaakki; Bufeksamakas; Bufexamaco; Bufexamacum;
pore: Difflam; Spain: Agilona; Fulgium; Rosalgin; Tantum; Tantum Verde;
Swed.: Andolex; Switz.: Bucco-Tantum; Thai.: Difflam; Turk.: Benzidan; Bufexamák; Bufexamak. 2-(4-Butoxyphenyl)acetohydroxamic ac-
Tanflex; Tantum; Ternex; UK: Difflam; Venez.: Azutan; Bevi Dam; Biozendi; id.
Flodont; Ginacol; Tantum; Tantum Verde; Zydan.
Буфексамак
Multi-ingredient: Arg.: Buchex; Dresan Biotic†; Dresan†; Ernex Duo;
Espectocural; Pentadent†; Austral.: Difflam Anti-inflammatory Lozenges C 12 H 17NO 3 = 223.3.
with Cough Suppressant; Difflam Lozenges; Difflam Mouth Gel; Difflam-C; C AS — 2438-72-4.
Logicin Rapid Relief; Braz.: Angino-Rub; Hong Kong: Difflam Anti-inflam- CH3
matory Lozenges; Difflam Mouth Gel; Difflam-C; Logicin Rapid Relief; ATC — M01AB17; M02AA09.
Hung.: Tantum Rosa; Ital.: Algolisina†; Gola Action; Linea F; Mediplus; (bicifadine) ATC Vet — QM01AB17; QM02AA09.
Malaysia: Difflam Anti-inflammatory Lozenges (with Antibacterial); Dif-
flam Anti-Inflammatory Lozenges (with cough suppressant); Difflam Mouth
Gel; Difflam-C; Mex.: Lonol Sport; NZ: Difflam Cough; Difflam Mouth Gel; Profile
Difflam-C; Port.: Benoral; Gartun; Tantum Verde; S.Afr.: Andolex-C; Sin- Bicifadine hydrochloride is a novel analgesic under investigation H
gapore: Difflam Anti-inflammatory Anti-Bacterial Lozenges; Difflam Mouth
for the treatment of painful conditions including postoperative N
Gel; Difflam-C; Spain: Bristaciclina Dental; Dolosarto†; Etermol Antitusivo; OH
Mentamida; Prosturol; Tantum; Vinciseptil Otico; Turk.: Kloroben; Venez.: dental pain.
Amicets; Gencivol Compuesto; Solunovar Compuesto. O
H 3C O
Bornyl Salicylate Pharmacopoeias. In Eur. (see p.vii) and Jpn.
Benzyl Nicotinate
Borneol Salicylate; Salicilato de bornilo. 2-Hydroxybenzoic acid Ph. Eur. 6.2 (Bufexamac). A white or almost white, crystalline
Bensylnikotinat; Bentsyylinikotinaatti; Benzil Nikotinat; Benzyli
1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester. powder. Practically insoluble in water; soluble in dimethylfor-
Nicotinas; Nicotinato de bencilo. Benzyl pyridine-3-carboxylate.
Борнилсалицилат mamide; slightly soluble in ethyl acetate and in methyl alcohol.
C 13 H 11 NO 2 = 213.2. Protect from light.
C AS — 94-44-0. C 17 H 22O 3 = 274.4.
C AS — 560-88-3. Profile
Bufexamac is an NSAID (p.96) that is applied topically in con-
N centrations of 5% in various skin disorders. Stinging and burning
CH3 may occur after application; hypersensitivity reactions have been
H3C HO reported.
O
H3 C O Preparations
O Proprietary Preparations (details are given in Part 3)
Arg.: Parfenac†; Austral.: Paraderm†; Austria: Bufex; Bufexan; Droxaryl;
Pharmacopoeias. In Ger. O Parfenac; Belg.: Bufexine†; Droxaryl†; Cz.: Droxaryl†; Fr.: Parfenac; Ger.:
Bufederm†; duradermal; Haemo-Exhirud Bufexamac; Jomax; Malipuran;
Profile Parfenac; Windol; Ital.: Fansamac; Viafen; Neth.: Droxaryl; Parfenac; Port.:
Benzyl nicotinate is used in topical preparations as a rubefacient.
Profile Parfenac; Switz.: Parfenac.
Bornyl salicylate is a salicylic acid derivative that has been used
Preparations Multi-ingredient: Austral.: Paraderm Plus; Resolve; Austria: Droxaryl;
topically in rubefacient preparations similarly to methyl sali- Cz.: Mastu S; Ger.: Faktu akut; Hamo-ratiopharm N; Hamoagil plus; Mastu
Proprietary Preparations (details are given in Part 3) cylate (p.85) for the relief of pain in musculoskeletal and joint S; Hong Kong: Fungo Soothing Balm; Mastu S; Hung.: Mastu S; NZ: Para-
Ger.: Leukona-Aktiv-Rheumabad†; Pernionin Thermo Teilbad; Pernionin disorders. derm Plus; Rus.: Proctosan (Проктозан); Thai.: Mastu S.
Thermo Vollbad; Pykaryl T; Rubriment; Rubriment-BN.
Multi-ingredient: Arg.: Butidiona†; Oxa Sport; Pergalen; Austria: Am- Preparations
benat; Derivon; Expectal-Balsam; Igitur-antirheumatische; Igitur-Rheumaflu- Proprietary Preparations (details are given in Part 3)
id; Menthoneurin; Mobilisin plus; Rheumex; Rubizon-Rheumagel; Rubri- Bumadizone Calcium (rINNM)
ment; Thermo-Rheumon; Thrombophob; Braz.: Etrat†; Trombofob; Multi-ingredient: Ger.: Forapin E†; Switz.: Forapin†; Hygiodermil.
Chile: Bayro-Therm†; Cz.: Dolo-Rubriment†; Rheuma-Salbe†; Rubriment- Bumadizona cálcica; Bumadizone Calcique; Calcii Bumadizonum.
N†; Thermo-Rheumon†; Fin.: Trombosol; Fr.: Lumbalgine; Ger.: ABC
Warme-Salbe†; Ambene N; Arthrodestal N†; Auroanalin Thermo; Cam- Calcium 2-(1,2-diphenylhydrazinocarbonyl)hexanoate hemihy-
phopin; Capsamol N†; Caye Rheuma-Balsam; Cor-Select†; DoloVisano Bromfenac Sodium (USAN, rINNM) drate.
Salbe†; Emasex-N†; Forapin E†; Hot Thermo; Lomazell for te N†;
Lumbinon Thermo†; mikanil†; Ostochont†; Pelvichthol N; Phardol Rheu- AHR-10282; AHR-10282B; Bromfénac Sodique; Bromfenaco Кальций Бумадизон
ma†; Phardol Warme-Balsam†; Phlogont-Thermal; Praecordin S†; Rheu- sódico; Natrii Bromfenacum. Sodium [2-amino-3-(p-bromoben- (C 19 H 21 N 2 O 3 ) 2 Ca, ⁄ H 2 O = 699.8.
balmin Thermo†; Rheuma-Salbe N; Rheuma-Salbe†; Rheumasalbe†; Rheu- zoyl)phenyl]acetate sesquihydrate.
masan N†; Rheumasit†; Rubriment; Rubriment-N†; Tachynerg Campher C AS — 3583-64-0 (bumadizone); 34461-73-9 (bumadi-
Herzsalbe; Thermo-Menthoneurin†; Thermo-Rheumon N†; Thermo- Натрий Бромфенак zone calcium).
Rheumon†; Thermosenex; Togal Mobil-Gel†; Warme-Gel†; zuk thermo†; C 15 H 11BrNNaO 3 ,1 ⁄ H 2 O = 383.2. ATC — M01AB07.
Gr.: Bayolin; Ehrlich; Striafissan†; Thermo-Roiplon; Hong Kong: Salome- C AS — 91714-94-2 (bromfenac); 91714-93-1 (brom-
thyl; Hung.: Bayolin†; Thermo-Rheumon†; India: Beparine; K5 Hair Tinc- ATC Vet — QM01AB07.
ture†; Thrombophob; Indon.: Stop X; Thrombophob; Zeropain; Ital.: Sa- fenac sodium); 120638-55-3 (bromfenac sodium).
lonpas; Sloan; Mex.: Bayro Termo; Pol.: Lumbolin; Thermo-Rheumon;
Port.: Adrinex†; Balsamo Analgesico; Medalginan; Rus.: Capsicam
(Капсикам); Heparin Ointment (Гепариновая Мазь); Switz.: Assan ther- Br
mo; Demotherm Pommade contre le rhumatisme†; Dolo Demotherm;
Forapin†; Histalgane; Marament-N; Thermocutan†; Turk.: Thermo-Doline; HO
Thermo-Rheumon; Thermoflex; UK: Salonair; Venez.: Ehrlich Balsamo.
NH2
O NH
N O
Beta-aminopropionitrile
Aminopropionitrile; β-Aminopropionitrile; β-Aminopropionitri-
O O OH
lo; BAPN. 3-Aminopropionitrile.
Бета-аминопропионитрил (bromfenac)
C 3 H 6 N 2 = 70.09. CH3
C AS — 151-18-8 (beta-aminopropionitrile); 1119-28-4 Profile
(beta-aminopropionitrile fumarate). Bromfenac sodium, a phenylacetic acid derivative related to di- (bumadizone)
ATC Vet — QM01AX91.
clofenac (p.44), is an NSAID (p.96). It is instilled twice daily as
0.1% eye drops for ocular pain and inflammation including post- Profile
operative inflammation in patients who have undergone cataract Bumadizone calcium is an NSAID (p.96) that is metabolised to
NH2 extraction. When used postoperatively, it may be started 24 hours phenylbutazone (p.117) and oxyphenbutazone (p.107). Use has
N after surgery and continued for the next 14 days. been limited by the risk of agranulocytosis and other haemato-
It was formerly given orally in the management of acute pain but logical adverse effects.
Profile was withdrawn from the market after reports of severe and some-
Beta-aminopropionitrile, a lysyl oxidase inhibitor, is an anti-in- times fatal hepatic failure. Preparations
flammatory used as the fumarate in veterinary medicine for the Proprietary Preparations (details are given in Part 3)
Effects on the eyes. Severe corneal melting (ulceration) was
treatment of tendinitis. Mex.: Desflam.
seen in 3 patients after topical use of bromfenac sodium.1 All
patients recovered after bromfenac was withdrawn. Similar ef-
 Benzyl Nicotinate/Buprenorphine 29
Buprenorphine (BAN, rINN) ⊗ phine are only partially reversed by naloxone (see Ef- ride is available in some countries for the treatment of opioid de-
pendence.
fects on the Respiratory System, below) but use of the
Buprenorfiini; Buprenorfin; Buprenorfina; Buprenorfinas; Bu- 1. Dahan A, et al. Comparison of the respiratory effects of intrave-
prénorphine; Buprenorphinum; RX-6029-M. (6R,7R,14S)-17-Cy-
latter is still recommended. nous buprenorphine and fentanyl in humans and rats. Br J
clopropylmethyl-7,8-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethyl- Incidence of adverse effects. Adverse effects reported after 1 Anaesth 2005; 94: 825–34.
2. Schmidt JF, et al. Postoperative pain relief with naloxone: severe
propyl]-6-O-methyl-6,14-ethano-17-normorphine; (2S)-2-[(−)- parenteral buprenorphine in 8187 patients were nausea (8.8%), respiratory depression and pain after high dose buprenorphine.
(5R,6R,7R,14S)-9a-Cyclopropylmethyl-4,5-epoxy-3-hydroxy-6- vomiting (7.4%), drowsiness (4.3%), sleeping (1.9%), dizziness Anaesthesia 1985; 40: 583–6.
methoxy-6,14-ethanomorphinan-7-yl]-3,3-dimethylbutan-2-ol. (1.2%), sweating (0.98%), headache (0.55%), confusion 3. Thörn S-E, et al. Prolonged respiratory depression caused by
(0.53%), lightheadedness (0.38%), blurred vision (0.28%), eu- sublingual buprenorphine. Lancet 1988; i: 179–80.
Бупренорфин phoria (0.27%), dry mouth (0.11%), depression (0.09%), and 4. Gal TJ. Naloxone reversal of buprenorphine-induced respiratory
C 29 H 41NO 4 = 467.6. hallucinations (0.09%). Some studies2,3 have reported nausea, depression. Clin Pharmacol Ther 1989; 45: 66–71.
5. Dahan A. Opioid-induced respiratory effects: new data on bu-
C AS — 52485-79-7. vomiting, and dizziness to be more troublesome with buprenor- prenorphine. Palliat Med 2006; 20 (Suppl 1): s3–s8.
ATC — N02AE01; N07BC01. phine than with morphine. 6. van Dorp E, et al. Naloxone reversal of buprenorphine-induced
ATC Vet — QN02AE01; QN07BC01. In a study4 of sublingual buprenorphine, 50 of 141 cancer pa- respiratory depression. Anesthesiology 2006; 105: 51–7.
tients withdrew because of adverse effects, especially dizziness, 7. Lehmann KA, et al. Influence of naloxone on the postoperative
analgesic and respiratory effects of buprenorphine. Eur J Clin
nausea, vomiting, and drowsiness; constipation was not reported. Pharmacol 1988; 34: 343–52.
HO A woman developed5 a painless ulcer on the upper surface of her
tongue after she had put sublingual buprenorphine tablets on Overdosage. A small case series reported1 acute buprenor-
rather than under her tongue. phine intoxication in 5 children, aged from 15 to 22 months, after
Shock occurred6 in 2 patients 2 hours after receiving epidural accidental ingestion of sublingual tablets; of these, 4 had ingest-
buprenorphine 300 micrograms; treatment with naloxone was ed a combined preparation containing naloxone (Suboxone;
O Reckitt Benckiser, USA). Symptoms included drowsiness and
unsuccessful but symptoms disappeared spontaneously after 2 to
N 3 hours. miosis; decreased respiratory rates were reported in 4. All 5 chil-
dren required hospital admission; 4 were treated with naloxone
In a multicentre study7 of transdermal buprenorphine, 252 of
and 1 needed mechanical ventilation. Accidental poisoning has
H3CO 1223 patients with moderate to severe cancer pain or non-cancer
pain withdrew due to adverse effects. The most commonly re- also been reported2 in a 9-month-old infant who ingested Subox-
H one; his symptoms were reversed by naloxone. A retrospective
ported were nausea (11%), vomiting (9.2%), constipation
HO CH3 (7.8%), dizziness (7.5%), drowsiness (4.0%), retching (3.7%), review3 of buprenorphine overdoses in children under 6 years of
C(CH3)3 generalised pruritus (2.0%), and headache (1.6%); local adverse age reported by US poison centres to a national surveillance sys-
effects included pruritus (1.4%), dermatitis (1.3%), and ery- tem from November 2002 to December 2005 concluded that
thema (1.3%). Another study8 reported oedema, headache, nau- overdosage is generally well tolerated. Out of 86 reports, 54 chil-
NOTE. The following terms have been used as ‘street names’ (see dren developed symptoms of toxicity. Such symptoms included:
p.vi) or slang names for various forms of buprenorphine: sea, palpitation, and difficulty concentrating as causes for thera-
drowsiness or lethargy (55%), vomiting (21%), miosis (21%),
TEM; Tems. py withdrawal in 4 out of 90 patients.
respiratory depression (7%), agitation or irritability (5%), pallor
Pharmacopoeias. In Eur. (see p.vii). 1. Harcus AW, et al. Methodology of monitored release of a new
preparation: buprenorphine. BMJ 1979; 2: 163–5. (3%), and coma (2%). There were no fatalities, and significant
Ph. Eur. 6.2 (Buprenorphine). A white or almost white crystal- 2. Sear JW, et al. Buprenorphine for postoperative analgesia. Br J CNS and respiratory depression occurred in 7%. Suboxone prep-
line powder. Very slightly soluble in water; freely soluble in Anaesth 1979; 51: 71. arations were the most commonly ingested products. The authors
acetone; slightly soluble in cyclohexane; soluble in methyl alco- 3. Kjaer M, et al. A comparative study of intramuscular buprenor- considered that any child who has ingested more than 2 mg and
hol. It dissolves in dilute solutions of acids. Protect from light. phine and morphine in the treatment of chronic pain of malignant any aged under 2 years who has had more than a lick or taste
origin. Br J Clin Pharmacol 1982; 13: 487–92.
4. Robbie DS. A trial of sublingual buprenorphine in cancer pain.
should be referred to the emergency department.
Buprenorphine Hydrochloride Br J Clin Pharmacol 1979; 7 (suppl 3): 315S–317S. During the years 1980 to 2002, buprenorphine was mentioned in
(BANM, USAN, rINNM) ⊗ 5. Lockhart SP, Baron JH. Tongue ulceration after lingual bu- 43 cases of adult fatalities in the UK.4 Of these, 27 deaths were
prenorphine. BMJ 1984; 288: 1346. confirmed to have involved buprenorphine including 7 cases
Buprenorfiinihydrokloridi; Buprenorfin-hidroklorid; Buprenorfin- 6. Christensen FR, Andersen LW. Adverse reaction to extradural where it was taken alone. In those deaths where multiple drugs
hydrochlorid; Buprenorfinhydroklorid; Buprenorfino hidrochlori- buprenorphine. Br J Anaesth 1982; 54: 476.
7. Muriel C, et al. Effectiveness and tolerability of the buprenor- were involved sedatives or benzodiazepines were detected in 23
das; Buprénorphine, chlorhydrate de; Buprenorphini hydrochlo- phine transdermal system in patients with moderate to severe cases and other opioids were found in 17 cases; alcohol had also
ridum; CL-112302; Hidrocloruro de buprenorfina; NIH-8805; chronic pain: a multicenter, open-label, uncontrolled, prospec- been taken in 10 cases. The authors also found an increase in
UM-952. tive, observational clinical study. Clin Ther 2005; 27: 451–62. buprenorphine-related fatalities since 1999 when the high-dose
8. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of formulation became available.
Бупренорфина Гидрохлорид chronic pain: results of a phase III, multicenter, randomized,
C 29 H 41NO 4 ,HCl = 504.1. 1. Geib A-J, et al. Adverse effects in children after unintentional
double-blind, placebo-controlled study. Clin Ther 2004; 26:
buprenorphine exposure. Pediatrics 2006; 118: 1746–51.
C AS — 53152-21-9. 1808–20.
2. Cho CS, et al. Exploratory buprenorphine ingestion in an infant.
Pharmacopoeias. In Chin., Eur. (see p.vii), and US. Effects on the heart. For a report of myocardial infarction as- Ann Emerg Med 2006; 48: 109.
Ph. Eur. 6.2 (Buprenorphine Hydrochloride). A white or almost sociated with abuse of buprenorphine, see Abuse under Precau- 3. Hayes BD, et al. Toxicity of buprenorphine overdoses in chil-
white crystalline powder. Sparingly soluble in water; soluble in tions, below. dren. Pediatrics 2008; 121: 807–8. Full version:
http://pediatrics.aappublications.org/cgi/reprint/121/4/e782 (ac-
alcohol; practically insoluble in cyclohexane; freely soluble in Effects on mental function. Psychotomimetic effects have cessed 22/07/08)
methyl alcohol. Protect from light. been relatively uncommon with buprenorphine. Hallucinations 4. Schifano F, et al. Buprenorphine mortality, seizures and pre-
USP 31 (Buprenorphine Hydrochloride). pH of a 1% solution in were reported1 in only 7 of 8147 patients (0.09%) given bu- scription data in the UK, 1980–2002. Hum Psychopharmacol
water is between 4.0 and 6.0. Store in airtight containers. Protect 2005; 20: 343–8.
prenorphine by injection. There have been reports of hallucina-
from light. tions after sublingual2 or epidural3 use.
1. Harcus AW, et al. Methodology of monitored release of a new
Precautions
Dependence and Withdrawal preparation: buprenorphine. BMJ 1979; 2: 163–5. As for Opioid Analgesics in general, p.103.
As for Opioid Analgesics, p.101. 2. Paraskevaides EC. Near fatal auditory hallucinations after bu-
prenorphine. BMJ 1988; 296: 214. Buprenorphine has opioid antagonist actions and may
Buprenorphine may have a lower potential for produc- 3. MacEvilly M, O’Carroll C. Hallucinations after epidural bu- precipitate withdrawal symptoms if given to patients
prenorphine. BMJ 1989; 298: 928–9. physically dependent on opioids.
ing dependence than pure agonists such as morphine.
However, it has been subject to abuse (see under Pre- Effects on the respiratory system. There have been varying Respiratory depression, if it occurs, is relatively slow
reports on the occurrence of respiratory depression with bu-
cautions, below). Abrupt withdrawal of buprenorphine prenorphine. It may be subject to a ‘ceiling effect’ in which res- in onset and of prolonged duration; it may be only par-
is said to produce only a mild abstinence syndrome, piratory depression does not increase further above doses of tially reversed by naloxone.
which may be delayed in onset. about 3 micrograms/kg.1 However, high doses of 30 or Licensed product information states that baseline liver
Buprenorphine is used for substitution therapy in the 40 micrograms/kg given as sole intravenous analgesic in bal- function levels should be established before starting
anced anaesthesia have been associated with severe respiratory
management of opioid dependence (see under Uses depression.2 buprenorphine therapy, and periodic monitoring of liv-
and Administration, below). Respiratory depression may be delayed in onset and more pro- er function should be performed throughout therapy in
longed than with morphine and is only partially reversed by patients being treated for opioid dependence. It should
Adverse Effects and Treatment naloxone, possibly because buprenorphine is very firmly bound be used with caution in all patients with pre-existing
As for Opioid Analgesics in general, p.102. to opioid receptors. A study of sublingual buprenorphine for hepatic impairment.
postoperative pain relief was abandoned when 3 of the first 16
Acute hepatotoxicity, including elevated liver enzyme patients showed signs of late-onset respiratory depression after Absorption of buprenorphine from transdermal patch-
values, hepatitis with jaundice, hepatic failure, necro- the second dose of buprenorphine; the respiratory depression did es may be increased as the temperature rises and pa-
sis, and encephalopathy, and hepatorenal syndrome, not respond to naloxone.3 Successful reversal has been shown in tients should therefore avoid exposing the patch to ex-
has been reported in opioid-dependent addicts; these healthy subjects with buprenorphine-induced respiratory depres- ternal heat; similarly, patients with fever may require
sion given large doses of naloxone 5 or 10 mg, but not with 1 mg;
reactions have also occurred after the misuse of bu- reversal was gradual in onset and decreased the duration of the monitoring because of increased absorption. It may
prenorphine, particularly after high doses or intrave- normally prolonged respiratory depression.4 Other studies found take up to 30 hours for plasma concentrations of bu-
nous use. that lower doses of naloxone 2 to 4 mg given over 30 minutes,5,6 prenorphine to decrease by 50% after removal of a
Local reactions such as rash, erythema, and itching or bolus doses of 2 to 3 mg followed by a continuous infusion of patch; patients who have had adverse effects should be
4 mg/hour,6 were effective in reversing buprenorphine-induced
have been reported with the transdermal patches. In respiratory depression. The authors of both these studies suggest-
monitored during this period.
isolated cases delayed local allergic reactions with ed that a longer duration of naloxone infusion may be needed for Abuse. A 22-year-old man had chest pains on each of two occa-
marked signs of inflammation have occurred; the reversal of respiratory depression caused by high doses of bu- sions after he had inhaled crushed buprenorphine tablets.1 An
patches should be withdrawn in such cases. prenorphine. The respiratory depressant and analgesic effects of ECG taken after the second episode suggested that the patient
buprenorphine were decreased by the concomitant use of had suffered a myocardial infarction. Intravenous injection of
Treatment of adverse effects is similar to that for other naloxone.7 It should be noted that a combined sublingual prepa- crushed sublingual tablets was associated with rhabdomyolysis
opioid analgesics (p.102). The effects of buprenor- ration of buprenorphine hydrochloride and naloxone hydrochlo- and sciatic neuropathy in 2 patients.2 A case series3 of 4 patients
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
30 Analgesics Anti-inflammatory Drugs and Antipyretics
reported severe limb and digit complications, such as ischaemia the dose of buprenorphine should be halved when start- concentrations after 400 or 800 micrograms given sublingual-
and gangrene, from parenteral abuse of sublingual buprenor- ing treatment with the potent CYP3A4 inhibitor, keto- ly peaked at about 200 minutes (range 90 to 360 minutes) and
phine tablets; intra-arterial injection in 2 cases resulted in ampu- buprenorphine was still detected in plasma at the end of the
tation of the affected digits or limb. The use of adulterants in il- conazole. study. Systemic availability was about 55% (range 16 to 94%)
licit preparations may also cause adverse effects: 4 patients on There have been reports of respiratory and cardiovas- and absorption was more or less complete 5 hours after a
substitution treatment developed candida endophthalmitis after cular collapse in patients given therapeutic doses of in- dose. However, the authors of a subsequent study2 considered
intravenously injecting sublingual buprenorphine diluted with that this was an overestimation, possibly due to methodolog-
lemon juice.4
travenous buprenorphine and diazepam. ical flaws. The later study results indicated that the bioavail-
Hepatotoxicity has been seen in opioid-dependent addicts after Use with other potentially hepatotoxic drugs may in- ability of sublingual buprenorphine is about 30% and that
buprenorphine abuse (see Adverse Effects and Treatment, crease the risk of liver damage. sublingual holding times between 3 and 5 minutes are
above). bioequivalent. Another single-dose study3 found that the bio-
Analgesics. There is a risk that, with opioid agonist-antagonists availability of sublingual buprenorphine was 50% less from a
1. Cracowski J-L, et al. Myocardial infarction associated with bu-
prenorphine. Ann Intern Med 1999; 130: 537.
such as buprenorphine, their antagonistic effects might impair tablet than from a liquid formulation. Later studies4,5 noted
2. Seet RCS, Lim ECH. Intravenous use of buprenorphine tablets more effective analgesic therapy. This appeared to happen in 2 that the bioavailability of buprenorphine from a sublingual
associated with rhabdomyolysis and compressive sciatic neurop- cancer patients both of whom were given sublingual buprenor- tablet relative to a sublingual liquid formulation was about
athy. Ann Emerg Med 2006; 47: 396–7. phine that was later substituted by morphine.1 Conventional dos- 70% after daily dosing for 7 days. One of these studies4 also
3. Loo HW, et al. Severe upper limb complications from parenteral es of morphine were inadequate and in one patient raising the found that the bioavailability of sublingual buprenorphine
abuse of Subutex. Ann Acad Med Singapore 2005; 34: 575–8. dose of morphine proved fatal. from a tablet formulation containing naloxone was higher
4. Cassoux N, et al. Presumed ocular candidiasis in drug misusers 1. Overweg-van Kints J, Stricker BHC. Falende pijnbestrijding ti- than from a single-ingredient tablet formulation and similar to
after intravenous use of oral high dose buprenorphine (Subutex). jdens sublinguaal gebruik van buprenorfine. Ned Tijdschr Ge-
Br J Ophthalmol 2002; 86: 940–1.
that seen with liquid formulations.
neeskd 1987; 131: 1973–4.
1. Bullingham RES, et al. Sublingual buprenorphine used postop-
Breast feeding. From a study1 of a breast-feeding mother who Antivirals. Various HIV-protease inhibitors and NNRTIs can eratively: ten hour plasma drug concentration analysis. Br J Clin
was receiving buprenorphine 4 mg daily, it was estimated that at inhibit or induce cytochrome P450 isoenzymes, and most are Pharmacol 1982; 13: 665–73.
the age of 4 weeks the total amount ingested by the infant during also substrates for CYP3A4; thus, they have the potential to in- 2. Mendelson J, et al. Bioavailability of sublingual buprenorphine.
a 24-hour period was 3.28 micrograms for buprenorphine and teract with buprenorphine. A pharmacokinetic study1 found that J Clin Pharmacol 1997; 37: 31–7.
0.33 micrograms for norbuprenorphine. Another study2 found usual doses of nelfinavir, ritonavir, and lopinavir-ritonavir given 3. Nath RP, et al. Buprenorphine pharmacokinetics: relative bioa-
that buprenorphine was present in the breast milk of a breast- to HIV-negative patients taking buprenorphine with naloxone for vailability of sublingual tablet and liquid formulations. J Clin
feeding mother with a maternal milk-to-plasma ratio of about opiate dependence did not produce any clinically significant in- Pharmacol 1999; 39: 619–23.
one. The authors of both studies considered the amount absorbed teractions: ritonavir increased the area under the concentration- 4. Strain EC, et al. Relative bioavailability of different buprenor-
through breast feeding to be low. time curve (AUC) of buprenorphine by about 57%, although no phine formulations under chronic dosing conditions. Drug Alco-
The BNF and some licensed product information states that bu- adverse effects were seen. Another pharmacokinetic study2 in a hol Depend 2004; 74: 37–43.
prenorphine should not be given to mothers who are breast feed- similar group of patients also found no clinically significant in- 5. Compton P, et al. Pharmacokinetics, bioavailability and opioid
ing. teractions between buprenorphine with naloxone and delavirdine effects of liquid versus tablet buprenorphine. Drug Alcohol De-
or efavirenz: delavirdine increased the AUC of buprenorphine pend 2006; 82: 25–31.
Studies in rats have shown that it may inhibit lactation.
1. Marquet P, et al. Buprenorphine withdrawal syndrome in a new- fourfold, and efavirenz decreased it by about 50%, but no ad- Children. The terminal elimination half-life of buprenorphine
born. Clin Pharmacol Ther 1997; 62: 569–71. verse effects were seen. However, a small case series3 of 3 opio- was only about 1 hour in small children aged 4 to 7 years given
2. Johnson RE, et al. Buprenorphine treatment of pregnant opioid- id-dependent patients reported symptoms of buprenorphine tox- 3 micrograms/kg intravenously as premedication, but could not
dependent women: maternal and neonatal outcomes. Drug Alco- icity, such as dizziness, daytime somnolence, and decreased be estimated reliably because of the rapid decline in plasma-
hol Depend 2001; 63: 97–103. mental functioning, with concomitant atazanavir and ritonavir buprenorphine concentrations.1 Clearance values did, however,
Pregnancy. An infant born to a mother who was being treated therapy. appear higher than in adults; steady-state volume of distribution
with buprenorphine 4 mg daily for diamorphine addiction suf- Buprenorphine does not appear to significantly affect the phar- was similar. Premature neonates (gestational age 27 to 32
fered a minor withdrawal syndrome 2 days after birth.1 The in- macokinetics of antiretrovirals.1,2 weeks) given a similar dose followed by an infusion of
fant rapidly recovered without any treatment. No further signs of 1. McCance-Katz EF, et al. Interactions between buprenorphine 0.72 micrograms/kg per hour had a considerably lower clearance
withdrawal occurred when breast feeding was abruptly stopped and antiretrovirals: I—The nonnucleoside reverse-transcriptase rate and had a mean elimination half-life of 20 hours.2 Although
at the age of 8 weeks. In another report2 of 15 opioid-dependent inhibitors efavirenz and delavirdine. Clin Infect Dis 2006; 43 this dosing regimen appeared to be safe, sedation was judged to
mothers who had received buprenorphine maintenance during (suppl 4): S224–S234.
be inadequate in 4 of the 12 neonates studied. It was suggested
their pregnancies, withdrawal symptoms were either absent or 2. McCance-Katz EF, et al. Interactions between buprenorphine
and antiretrovirals: II—The protease inhibitors nelfinavir, lopi- that as buprenorphine given by infusion might not produce con-
mild in 12 of the neonates. The remaining 3 neonates required navir/ritonavir, and ritonavir. Clin Infect Dis 2006; 43 (suppl 4): sistent sedation and analgesia in premature neonates, it could not
treatment with morphine. There appeared to be no correlation be- S235–S246. be recommended for use in neonatal care.
tween the buprenorphine dose and the degree of withdrawal 3. Bruce RD, Altice FL. Three case reports of a clinical pharmacok- 1. Olkkola KT, et al. Pharmacokinetics of intravenous buprenor-
symptoms. A literature review3 found that of about 309 infants inetic interaction with buprenorphine and atazanavir plus ritona- phine in children. Br J Clin Pharmacol 1989; 28: 202–4.
born to opioid-dependent mothers maintained on buprenorphine vir. AIDS 2006; 20: 783–4.
2. Barrett DA, et al. The pharmacokinetics and physiological effect
(sublingual dose range: 0.4 to 24 mg daily), 193 developed neo- of buprenorphine infusion in premature neonates. Br J Clin
natal abstinence syndrome; of these, 149 required treatment. Pharmacokinetics Pharmacol 1993; 36: 215–19.
More than 40% of treated cases were confounded by misuse of After intramuscular injection, buprenorphine rapidly
other drugs. Onset of symptoms occurred within the first 12 to 48 Renal impairment. Buprenorphine clearance appears to occur
hours and peaked within about 72 to 96 hours; duration of symp-
reaches peak plasma concentrations. Absorption also mainly by hepatic extraction and metabolism and would not be
toms was about 120 to 168 hours although in some infants, it was takes place through the buccal mucosa after sublingual expected to be related to renal function, whereas metabolites are
reported to last for 6 to 10 weeks. doses and peak plasma concentrations are achieved af- excreted in urine. In a study, buprenorphine kinetics were similar
The 67 pregnancies of 66 women using buprenorphine have ter 90 minutes. Transdermal application results in ab- in anaesthetised healthy patients to those in patients with renal
been followed in a prospective study.4 The incidences of prema- sorption through the skin; the minimum effective con- impairment, with a mean elimination half-life of 398 and 239
ture birth, caesarean section, and low Apgar scores in buprenor- minutes, respectively.1 Plasma concentrations of the metabolites
centration is reached in 12 to 24 hours and peak plasma norbuprenorphine and buprenorphine-3-glucuronide were in-
phine-exposed neonates were no greater than those seen in the
general population although the mean birth-weight of the ex- concentrations are achieved after about 60 hours. How- creased about 4 times and 15 times, respectively in patients with
posed neonates was significantly lower. In the exposed group, ever, there is a lack of correlation between plasma con- renal impairment,1 but significant pharmacological activity was
91% of neonates needed intensive care treatment: 76% had neo- centrations and analgesic activity. Buprenorphine is unlikely since norbuprenorphine has little analgesic activity
natal abstinence syndrome and 57% needed opioid replacement about 96% bound to plasma proteins. compared with the parent compound and buprenorphine-3-glu-
therapy. There were also 2 cases of sudden infant deaths in the curonide has none.
exposed group, which was considered to be higher than that gen- Elimination of buprenorphine is bi- or triphasic; 1. Hand CW, et al. Buprenorphine disposition in patients with renal
erally expected. metabolism takes place in the liver by oxidation via the impairment: single and continuous dosing, with special refer-
1. Marquet P, et al. Buprenorphine withdrawal syndrome in a new- cytochrome P450 isoenzyme CYP3A4 to the pharma- ence to metabolites. Br J Anaesth 1990; 64: 276–82.
born. Clin Pharmacol Ther 1997; 62: 569–71. cologically active metabolite N-dealkylbuprenorphine
2. Fischer G, et al. Treatment of opioid-dependent pregnant women Uses and Administration
with buprenorphine. Addiction 2000; 95: 239–44. (norbuprenorphine), and by conjugation to glucuro-
3. Johnson RE, et al. Use of buprenorphine in pregnancy: patient nide metabolites. Buprenorphine is subject to consider- Buprenorphine is an opioid analgesic (p.104) classified
management and effects on the neonate. Drug Alcohol Depend able first-pass metabolism after oral doses. However, as an opioid agonist and antagonist. It is used for the
2003; 70 (suppl 2): S87–S101.
4. Kahila H, et al. A prospective study on buprenorphine use during when given by the usual routes buprenorphine is ex- relief of moderate to severe pain and as an adjunct to
pregnancy: effects on maternal and neonatal outcome. Acta Ob- creted mainly unchanged in the faeces; there is some anaesthesia. Buprenorphine is also used in the treat-
stet Gynecol Scand 2007; 86: 185–90. ment of opioid dependence.
evidence for enterohepatic recirculation. Plasma elim-
ination half-lives have ranged from 1.2 to 7.2 hours af- Buprenorphine has a relatively slow onset but pro-
Interactions
ter intravenous injection; elimination half-lives after longed duration of action. On intramuscular injection
For interactions associated with opioid analgesics, see
sublingual or transdermal use are longer and may range analgesia is apparent within 15 minutes and lasts up to
p.103.
from 20 to 36 hours or more. Metabolites are excreted 6 hours. A slower, more prolonged response is
Buprenorphine is metabolised by the cytochrome P450 in the urine, but very little unchanged drug is excreted
isoenzyme CYP3A4; consequently, use with other achieved after sublingual doses. The analgesic effects
in this way. Buprenorphine crosses the placenta and of buprenorphine after transdermal application may
drugs that induce or inhibit this isoenzyme may result small amounts are distributed into breast milk.
in changes in plasma concentrations of buprenorphine not be seen for at least 12 to 24 hours or up to 72 hours
and, possibly adverse effects. Some manufacturers ◊ References. in the case of the once-weekly patch.
1. Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics
state that dosage adjustment of buprenorphine may be in the treatment of opioid dependence. Clin Pharmacokinet Buprenorphine is usually given by intramuscular or in-
necessary when used with such drugs. The UK li- 2005; 44: 661–80. travenous injection or sublingually as the hydrochlo-
censed product information for one sublingual formu- Administration. BUCCAL ROUTE. Absorption of sublingual ride or as transdermal patches as the base. For all routes
lation (Subutex; Schering-Plough) recommends that buprenorphine is relatively slow. In a 10-hour study1 plasma doses are expressed in terms of the base. Buprenor-
 Buprenorphine/Butibufen Sodium 31
phine hydrochloride 107.8 micrograms is equivalent to affinity for the μ and δ receptors and lesser affinity for the κ re- investigation for the management of postoperative pain.1
about 100 micrograms of buprenorphine. ceptor.1 Buprenorphine, like fentanyl, has high lipid solubility, Patient-controlled analgesia with intravenous 3 and
but has a lower intrinsic activity than fentanyl. Differences be- intramuscular4 buprenorphine has been effective although its
Buprenorphine is given by all the above routes for opi- tween buprenorphine and pure μ opioid agonists such as fenta- long half-life may limit such use.
nyl, including relatively slow onset of action, prolonged duration Buprenorphine had no adverse cardiovascular effects when giv-
oid analgesia in moderate to severe pain. of action, resistance to antagonism by naloxone, and lack of cor- en intravenously after open-heart surgery,5 suggesting that it was
relation between plasma concentrations and analgesic effects, a suitable analgesic for patients with unstable circulation. Epi-
• The dose by intramuscular or slow intravenous in- have been explained by differences in the way buprenorphine
jection is 300 to 600 micrograms repeated every 6 to dural analgesia with buprenorphine has also been used after car-
binds to opioid receptors. In a study in vitro buprenorphine had diac surgery.6 Buprenorphine was also considered suitable for
8 hours as required slow rates of association and dissociation from the opioid recep- the relief of pain in myocardial infarction.7
tor when compared with fentanyl.2
• By the sublingual route, doses of 200 to 1. Miwa Y, et al. Epidural administered buprenorphine in the peri-
1. Bovill JG. Which potent opioid? Important criteria for selection. operative period. Can J Anaesth 1996; 43: 907–13.
400 micrograms may be repeated every 6 to 8 hours Drugs 1987; 33: 520–30. 2. Kawamata T, et al. Pain management after lumbar spinal fusion
as required 2. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenor- surgery using continuous subcutaneous infusion of buprenor-
phine: the significance of receptor binding. Br J Anaesth 1985; phine. J Anesth 2005; 19: 199–203.
• For opioid treatment of chronic pain in patients aged 57: 192–6. 3. Dingus DJ, et al. Buprenorphine versus morphine for patient-
controlled analgesia after cholecystectomy. Surg Gynecol Obstet
18 years and over transdermal patches delivering Administration in children. Buprenorphine is used for the 1993; 177: 1–6.
varying amounts of buprenorphine are available. relief of moderate to severe pain in children. In the UK, those 4. Harmer M, et al. Intramuscular on demand analgesia: double
Doses should be individually titrated for each patient aged from 6 months to 12 years may be given 3 to blind controlled trial of pethidine, buprenorphine, morphine, and
6 micrograms/kg by intramuscular or slow intravenous injection meptazinol. BMJ 1983; 286: 680–2.
according to previous opioid usage. During transfer every 6 to 8 hours; up to 9 micrograms/kg may be given if re- 5. Rosenfeldt FL, et al. Haemodynamic effects of buprenorphine
to treatment with buprenorphine patches previous quired in refractory cases. In the USA, parenteral buprenorphine after heart surgery. BMJ 1978; 2: 1602–3.
opioid analgesic therapy should be phased out grad- is licensed in children aged 2 years and over; usual doses of 2 to 6. Mehta Y, et al. Lumbar versus thoracic epidural buprenorphine
ually in order to allow for the gradual increase in 6 micrograms/kg may be given intramuscularly or intravenously for postoperative analgesia following coronary artery bypass
every 4 to 6 hours to those up to 12 years old. The sublingual graft surgery. Acta Anaesthesiol Scand 1999; 43: 388–93.
plasma-buprenorphine concentrations. Depending 7. Hayes MJ, et al. Randomised trial comparing buprenorphine and
route is licensed in the UK in children aged from 6 to 12 years
on dose required up to 2 patches may be applied, and the following doses are given every 6 to 8 hours according to diamorphine for chest pain in suspected myocardial infarction.
however, this should be done at the same time to BMJ 1979; 2: 300–2.
body-weight: 16 to 25 kg, 100 micrograms; 25 to 37.5 kg, 100 to
avoid confusion. Buprenorphine patches are not ap- 200 micrograms; 37.5 to 50 kg, 200 to 300 micrograms. Older CHRONIC PAIN. Transdermal buprenorphine is used for chronic
propriate for acute pain. In the UK, transdermal bu- children requiring pain relief may be given the usual adult dose intractable cancer pain.1-4 It has also been used successfully
(see above) for all the above routes. in chronic non-cancer pain including neuropathic pain;1,2,4-6
prenorphine patches are available as follows: however, licensed product information states that this route is
Buprenorphine is also used in the treatment of opioid depend-
Transtec (Napp, UK) delivering buprenorphine in a ence; adolescents aged 16 years and over may be given the usual not suitable for the treatment of acute pain.
adult dose (see above). 1. Böhme K. Buprenorphine in a transdermal therapeutic system—
range of 35 to 70 micrograms/hour. Initial dosages a new option. Clin Rheumatol 2002; 21 (suppl 1): S13–S16.
should not exceed 35 micrograms/hour in opioid- Opioid dependence. Buprenorphine is used in the treatment 2. Evans HC, Easthope SE. Transdermal buprenorphine. Drugs
naive patients. For patients who have been receiving of opioid dependence (p.101). Its agonist-antagonist properties 2003; 63: 1999–2010.
a strong opioid analgesic the initial dose should be may mean that it has a lower potential for dependence and a low- 3. Sittl R. Transdermal buprenorphine in cancer pain and palliative
er risk of respiratory depression in overdose than pure agonists care. Palliat Med 2006; 20 (suppl 1): S25–S30.
based on the previous 24-hour opioid requirement. 4. Sittl R. Transdermal buprenorphine in the treatment of chronic
such as methadone. Buprenorphine can be used as substitution
Use of a patch providing 35 micrograms/hour of bu- therapy in patients with moderate opioid dependence for acute pain. Expert Rev Neurother 2005; 5: 315–23.
prenorphine is roughly equivalent to 30 to 60 mg management of withdrawal and in maintenance treatment as an 5. Bálint G. Buprenorphine treatment of patients with non-malig-
nant musculoskeletal diseases. Clin Rheumatol 2002; 21 (suppl
daily of oral morphine sulfate. Patches should be re- alternative to or together with methadone. However, in patients 1): S17–S18.
placed every 96 hours at the latest with the new patch dependent on high doses of opioids buprenorphine may precipi-
6. Hans G. Buprenorphine—a review of its role in neuropathic pain.
tate withdrawal due to its partial antagonist properties; the daily
being applied to a different site; use of the same area opioid dose should be reduced gradually in such patients before
J Opioid Manag 2007; 3: 195–206.
of the skin should be avoided for at least the next 2 beginning buprenorphine. Abuse of the preparation, as with oth- Preparations
applications. er substitution therapies, may be a problem. A combined sublin- Proprietary Preparations (details are given in Part 3)
gual preparation of buprenorphine hydrochloride and naloxone Arg.: Magnogen†; Temgesic†; Austral.: Norspan; Subutex; Temgesic; Aus-
BuTrans (Napp, UK) delivering buprenorphine in a hydrochloride is available in some countries as a deterrent to tria: Subutex; Temgesic; Transtec; Tridol; Belg.: Subutex; Temgesic; Tran-
range of 5 to 20 micrograms/hour. Initial dosages abuse. stec; Braz.: Temgesic; Chile: Transtec; Cz.: Norspan; Suboxone; Subutex;
Temgesic; Transtec; Denm.: Anorfin; Norspan; Subutex; Temgesic; Tran-
should not exceed 5 micrograms/hour in all patients. References. stec; Fin.: Subutex; Temgesic; Fr.: Suboxone; Subutex; Temgesic; Ger.: Sub-
Patches should be replaced every 7 days with the 1. Kakko J, et al. 1-year retention and social function after bu- utex; Temgesic; Transtec; Gr.: Subutex; Hong Kong: Subutex; Temgesic;
Hung.: Bupren; Transtec; India: Norphin; Pentorel; Tidigesic†; Indon.:
new patch being applied to a different site; use of the prenorphine-assisted relapse prevention treatment for heroin de-
Subutex; Irl.: BuTrans; Temgesic; Transtec; Israel: Nopan; Subutex; Ital.:
pendence in Sweden: a randomised, placebo-controlled trial.
same area of the skin should be avoided for the next Lancet 2003; 361: 662–8. Subutex; Temgesic; Transtec; Malaysia: Suboxone; Subutex†; Temgesic†;
Mex.: Brospina; Temgesic; Transtec; Neth.: Temgesic; Norw.: Subutex;
3 to 4 weeks. 2. Fudala PJ, et al. Office-based treatment of opiate addiction with Temgesic; NZ: Suboxone; Temgesic; Pol.: Bunondol; Transtec; Port.: Bu-
a sublingual-tablet formulation of buprenorphine and naloxone. prex; Norspan; Suboxone; Subutex; Transtec; Rus.: Nopan (Нопан)†;
When used in balanced anaesthesia 300 micrograms N Engl J Med 2003; 349: 949–58. Transtec (Транстек); S.Afr.: Subutex; Temgesic; Singapore: Subutex†;
3. Montoya ID, et al. Randomized trial of buprenorphine for treat- Temgesic†; Spain: Buprex; Prefin†; Subutex; Transtec; Swed.: Norspan;
may be given intramuscularly or 400 micrograms sub- ment of concurrent opiate and cocaine dependence. Clin Phar- Subutex; Temgesic; Switz.: Subutex; Temgesic; Transtec; Thai.: Buprine;
lingually for premedication; 300 to 450 micrograms macol Ther 2004; 75: 34–48. Temgesic†; UK: BuTrans; Suboxone; Subutex; Temgesic; Transtec; USA: Bu-
prenex; Suboxone; Subutex.
may be given intravenously as a perioperative analge- 4. Fiellin DA, et al. Consensus statement on office-based treat-
ment of opioid dependence using buprenorphine. J Subst Abuse
sic supplement. Treat 2004; 27: 153–9.
5. Donaher PA, Welsh C. Managing opioid addiction with bu-
For the treatment of opioid dependence in patients prenorphine. Am Fam Physician 2006; 73: 1573–8. Butibufen Sodium (rINNM)
aged 16 years and over, the initial dose is 0.8 to 4 mg 6. Sung S, Conry JM. Role of buprenorphine in the management Butibufén sódico; Butibufène Sodique; FF-106 (butibufen); Natrii
sublingually once daily. The dose may be increased as of heroin addiction. Ann Pharmacother 2006; 40: 501–5.
Butibufenum. Sodium 2-(4-isobutylphenyl)butyrate.
necessary but maintenance doses should not exceed 7. Robinson SE. Buprenorphine-containing treatments: place in
the management of opioid addiction. CNS Drugs 2006; 20: Натрий Бутибуфен
32 mg daily. Once the patient has been stabilised, the 697–712.
C 14 H 19 NaO 2 = 242.3.
dosage should be reduced gradually to a lower mainte- 8. Gowing L, et al. Buprenorphine for the management of opioid
C AS — 55837-18-8 (butibufen); 60682-24-8 (butibufen
nance dose; treatment may eventually be stopped if ap- withdrawal. Available in The Cochrane Database of Systematic
Reviews; Issue 2. Chichester: John Wiley; 2006 (accessed sodium).
propriate. For addicts who have not undergone opioid 26/06/08).
withdrawal before starting buprenorphine, the first 9. NICE. Methadone and buprenorphine for the management of
opioid dependence: Technology Appraisal Guidance 114 (is- H 3C
dose of buprenorphine should not be given until the sued January 2007). Available at: http://www.nice.org.uk/
first signs of craving appear or until at least 4 (USA) or nicemedia/pdf/TA114Niceguidance.pdf (accessed 26/06/08)
6 (UK) hours after the last opioid use. In those already 10. Boothby LA, Doering PL. Buprenorphine for the treatment of
opioid dependence. Am J Health-Syst Pharm 2007; 64: 266–72.
receiving methadone replacement, the dose of metha-
11. Mattick RP, et al. Buprenorphine maintenance versus placebo or H 3C OH
done should be reduced to a maximum of 30 mg daily methadone maintenance for opioid dependence. Available in
before starting buprenorphine therapy. As a deterrent The Cochrane Database of Systematic Reviews; Issue 2. Chich- CH3 O
ester: John Wiley; 2008 (accessed 26/06/08).
to abuse, a combined sublingual preparation of bu- 12. Sullivan LE, Fiellin DA. Narrative review: buprenorphine for (butibufen)
prenorphine hydrochloride and naloxone hydrochlo- opioid-dependent patients in office practice. Ann Intern Med
ride is available in some countries for the treatment of 2008; 148: 662–70.
opioid dependence. Profile
Pain. ACUTE PAIN. The BNF considers that buprenorphine may Butibufen sodium is an NSAID (p.96) that has been used orally
antagonise the analgesic effect of other opioids and is gener- in inflammatory and rheumatic disorders.
For details of doses in children, see below. ally not recommended for the management of postoperative
pain. Nonetheless, it can be given intramuscularly, intrave- Preparations
Action. Buprenorphine is generally described as a mixed agon- nously, or sublingually for this purpose, although the intrave- Proprietary Preparations (details are given in Part 3)
ist-antagonist acting mainly as a partial agonist at μ opioid recep- nous route may be preferred for acute pain relief. The epidural
Spain: Mijal†.
tors, with some antagonist activity at κ receptors. It has also been route1 and continuous subcutaneous infusion2 have also been
shown to bind at μ, δ, and κ opioid binding sites and to have high used; an intranasal formulation of buprenorphine is under
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
32 Analgesics Anti-inflammatory Drugs and Antipyretics
Butorphanol Tartrate (BANM, USAN, rINNM) 2. Wagner JM, Cohen S. Fibrous myopathy from butorphanol in- In obstetric analgesia 1 to 2 mg may be given by intramuscular
jections. J Rheumatol 1991; 18: 1934–5. or intravenous injection during early labour in women at term.
levo-BC-2627 (butorphanol); Butorfanolitartraatti; Butorfanoltar- 3. Loder E. Post-marketing experience with an opioid nasal spray This dose may be repeated after 4 hours if necessary but an alter-
trat; Butorphanol, Tartrate de; Butorphanoli Tartras; Tartrato de for migraine: lessons for the future. Cephalalgia 2006; 26: native analgesic should be used if delivery is expected within 4
butorfanol. (−)-17-(Cyclobutylmethyl)morphinan-3,14-diol hy- 89–97.
hours.
drogen tartrate. Breast feeding. No adverse effects have been seen in breast- In anaesthesia, 2 mg may be given intramuscularly for premed-
Буторфанола Тартрат fed infants whose mothers were given butorphanol, and the ication 60 to 90 minutes before surgery. For use in balanced
American Academy of Pediatrics considers1 that it is therefore anaesthesia, a usual dose is 2 mg given intravenously shortly be-
C 21 H 29 NO 2,C 4 H 6 O 6 = 477.5.
usually compatible with breast feeding. fore induction and/or 0.5 to 1 mg given intravenously in incre-
C AS — 42408-82-2 (butorphanol); 58786-99-5 (butorph-
anol tartrate). In a study2 of 12 women, butorphanol was detected in breast milk ments during anaesthesia. The total dose needed varies but most
after both intramuscular and oral doses. However, the milk-to- patients require 4 to 12.5 mg.
ATC — N02AF01.
plasma ratio after a 2-mg intramuscular dose (0.7) was signifi- Dosage adjustment may be needed in the elderly. When given
ATC Vet — QN02AF01.
cantly less than that after an 8-mg oral dose (1.9). Although the by injection the initial dose of butorphanol for pain should be half
mothers were not breast feeding at the time of the study, the au- the usual initial adult dose. Subsequent doses should be deter-
thors concluded that the potential for any adverse effects on nurs- mined by the patient’s response; a dosage interval of at least 6
HO ing infants after maternal butorphanol use would be minimal. hours has been recommended. For nasal use the initial dose
1. American Academy of Pediatrics The transfer of drugs and other should be limited to 1 mg followed by 1 mg after 90 to 120 min-
chemicals into human milk. Pediatrics 2001; 108: 776–89. Cor- utes if necessary; subsequent doses if required should generally
rection. ibid.; 1029. Also available at: be given at intervals of not less than 6 hours. Similar recommen-
OH h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l / dations have also been made for patients with hepatic or renal
pediatrics%3b108/3/776 (accessed 26/06/08)
impairment, see below.
N 2. Pittman KA, et al. Human perinatal distribution of butorphanol.
Am J Obstet Gynecol 1980; 138: 797–800. ◊ References.
1. Atkinson BD, et al. Double-blind comparison of intravenous bu-
Pregnancy. Two instances of sinusoidal fetal heart rate pattern torphanol (Stadol) and fentanyl (Sublimaze) for analgesia during
were noted out of 188 consecutive cases of butorphanol use in labor. Am J Obstet Gynecol 1994; 171: 993–8.
(butorphanol) active-phase labour.1 Visual hallucinations and paranoid delu- 2. Gillis JC, et al. Transnasal butorphanol: a review of its pharma-
sions developed in a woman on receiving a 1-mg intravenous codynamic and pharmacokinetic properties, and therapeutic po-
Pharmacopoeias. In US. injection of butorphanol early in labour; the psychosis had re- tential in acute pain management. Drugs 1995; 50: 157–75.
USP 31 (Butorphanol Tartrate). A white powder. Its solutions solved 40 hours after the injection and was not noted on follow- 3. Commiskey S, et al. Butorphanol: effects of a prototypical ago-
nist-antagonist analgesic on κ-opioid receptors. J Pharmacol Sci
are slightly acidic. Sparingly soluble in water; insoluble in alco- up 2 weeks later.2 2005; 98: 109–16.
hol, in chloroform, in ether, in ethyl acetate, and in hexane; 1. Welt SI. Sinusoidal fetal heart rate and butorphanol administra-
slightly soluble in methyl alcohol; soluble in dilute acids. Store tion. Am J Obstet Gynecol 1985; 152: 362–3. Administration in hepatic or renal impairment. The dos-
in airtight containers at a temperature of 25°, excursions permit- 2. Davis A, et al. Acute psychosis associated with butorphanol. J age of butorphanol may need to be adjusted in patients with he-
ted between 15° and 30°. Neuropsychiatr Clin Neurosci 1998; 10: 236–7. patic or renal impairment. When given by injection the initial
dose for pain should be half the usual initial adult dose (see
Dependence and Withdrawal Interactions above). Subsequent doses should be determined by the patient’s
As for Opioid Analgesics, p.101. For interactions associated with opioid analgesics, see p.103. response; a dosage interval of at least 6 hours has been recom-
Butorphanol may have a lower potential for producing depend- Antimigraine drugs. No pharmacokinetic interactions were mended. For nasal use the initial dose should be limited to 1 mg
ence than pure agonists such as morphine. However, it has been reported when butorphanol nasal spray and subcutaneous su- followed by 1 mg after 90 to 120 minutes if necessary; subse-
subject to abuse (see under Precautions, below). Abruptly stop- matriptan were used together within a minute of each other in quent doses if required should generally be given at intervals of
ping chronic butorphanol has produced a less severe withdrawal healthy subjects.1 However, another study2 in healthy subjects not less than 6 hours.
syndrome than with morphine. found that the AUC and maximum plasma concentration of in- Headache. Butorphanol has been advocated for use as a nasal
tranasal butorphanol were reduced by about 29% and 38%, re- spray in the treatment of migraine, but there have been problems
Adverse Effects and Treatment
spectively when given 1 minute after intranasal sumatriptan. No with abuse and dependence (see above) and its place in therapy,
As for Opioid Analgesics in general, p.102, and for Pentazocine,
such effect was noted when administration was separated by 30 if any, still remains to be established. See also Antimigraine
p.112.
minutes. It was suggested that sumatriptan may reduce butorph- Drugs, under Interactions, above.
Headache, and feelings of floating may also occur. Hallucina- anol absorption by inducing transient nasal vasoconstriction. References.
tions and other psychotomimetic effects are rare and have been 1. Srinivas NR, et al. Lack of pharmacokinetic interaction between 1. Freitag FG. The acute treatment of migraine with transnasal bu-
reported less frequently than with pentazocine. In addition in- butorphanol tartrate nasal spray and sumatriptan succinate. J torphanol (TNB). Headache Q 1993; 4 (suppl 3): 22–8.
somnia and nasal congestion may occur frequently when butor- Clin Pharmacol 1995; 35: 432–7. 2. Hoffert MJ, et al. Transnasal butorphanol in the treatment of
phanol is given intranasally. 2. Vachharajani NN, et al. A pharmacokinetic interaction study be- acute migraine. Headache 1995; 35: 65–9.
Because butorphanol has opioid agonist and antagonist activity, tween butorphanol and sumatriptan nasal sprays in healthy sub- 3. Melanson SW, et al. Transnasal butorphanol in the emergency
jects: importance of the timing of butorphanol administration. department management of migraine headache. Am J Emerg Med
naloxone is the recommended antagonist for the treatment of Cephalalgia 2002; 22: 282–7. 1997; 15: 57–61.
overdosage.
Pharmacokinetics Pruritus. Results from a small study1 of 6 patients with severe
Effects on the respiratory system. Butorphanol 2 mg pro- Butorphanol is absorbed from the gastrointestinal tract but it un- opioid-induced pruritus unresponsive to diphenhydramine, and
duces a similar degree of respiratory depression to morphine dergoes extensive first-pass metabolism. Peak plasma concentra- from a case series of 5 patients with intractable pruritus from oth-
10 mg, but a ceiling effect is apparent with higher doses of butor- tions occur 0.5 to 1 hour after intramuscular and intranasal doses er causes,2 suggest that intranasal butorphanol may be an effec-
phanol.1 It has been reported to be a less potent respiratory de- and 1 to 1.5 hours after oral doses. Butorphanol has a plasma tive treatment. Doses have ranged from 1 mg every other day to
pressant than fentanyl,2 but more potent than nalbuphine.3 elimination half-life of about 4.5 hours. About 80% is bound to 2 mg every 4 to 6 hours.
1. Nagashima H, et al. Respiratory and circulatory effects of intra- plasma proteins. 1. Dunteman E, et al. Transnasal butorphanol for the treatment of
venous butorphanol and morphine. Clin Pharmacol Ther 1976; opioid-induced pruritus unresponsive to antihistamines. J Pain
19: 738–45. Butorphanol is extensively metabolised in the liver through hy- Symptom Manage 1996; 12: 255–60.
2. Dryden GE. Voluntary respiratory effects of butorphanol and droxylation, N-dealkylation, and conjugation, only 5% being ex- 2. Dawn AG, Yosipovitch G. Butorphanol for treatment of intracta-
fentanyl following barbiturate induction: a double-blind study. J creted unchanged. Excretion is mainly in the urine; about 15% of ble pruritus. J Am Acad Dermatol 2006; 54: 527–31.
Clin Pharmacol 1986; 26: 203–7. a parenteral dose is excreted in the bile. It crosses the placenta Preparations
3. Zucker JR, et al. Respiratory effects of nalbuphine and butorph- and is distributed into breast milk. USP 31: Butorphanol Tartrate Injection; Butorphanol Tartrate Nasal Solu-
anol in anesthetized patients. Anesth Analg 1987; 66: 879–81. tion.
Administration. INTRANASAL ROUTE. References.
Precautions 1. Davis GA, et al. Pharmacokinetics of butorphanol tartrate ad-
Proprietary Preparations (details are given in Part 3)
As for Opioid Analgesics in general, p.103. Canad.: Stadol†; Chile: Stadol†; Cz.: Beforal†; Moradol†; India: Butrum;
ministered from single-dose intranasal sprayer. Am J Health-Syst Mex.: Stadol; Philipp.: Stadol; Rus.: Stadol (Стадол); USA: Stadol.
Although cardiovascular effects may be less than with pentazoc- Pharm 2004; 61: 261–6.
ine, butorphanol should generally be avoided after myocardial 2. Davis GA, et al. Bioavailability of intranasal butorphanol ad-
infarction. ministered from a single-dose sprayer. Am J Health-Syst Pharm
2005; 62: 48–53. Capsaicin
Butorphanol may precipitate withdrawal symptoms if given to 3. Wermeling DP, et al. Pharmacokinetics, bioequivalence, and
patients physically dependent on opioids. The dosage regimen of spray weight reproducibility of intranasal butorphanol after ad- Capsaicina; Capsaicinum; Kapsaicin; Kapsaicyna; Kapsaisiini. (E)-8-
butorphanol may need to be adjusted in the elderly and in pa- ministration with 2 different nasal spray pumps. J Clin Pharma- Methyl-N-vanillylnon-6-enamide.
tients with hepatic or renal impairment. col 2005; 45: 969–73. C 18 H 27NO 3 = 305.4.
Uses and Administration C AS — 404-86-4.
Abuse. A WHO expert committee considered in 2006 that the ATC — N01BX04.
likelihood of butorphanol abuse was low and was not great Butorphanol tartrate, a phenanthrene derivative, is an opioid
analgesic (p.104) with opioid agonist and antagonist properties; ATC Vet — QN01BX04.
enough to warrant international control.1 Abuse had been report-
ed infrequently and only in a few countries. The committee also it is pharmacologically similar to pentazocine (p.113). Butorph-
commented that, pharmacologically, intranasal preparations of anol is used for the relief of moderate to severe pain, including
H3 C
butorphanol do not appear to differ in their abuse potential from the pain of labour, and as an adjunct to anaesthesia. Onset of an-
parenteral preparations; however, other factors such as availabil- algesia occurs within 15 minutes of intramuscular injection or an CH3 O
ity and usage patterns may affect the likelihood of abuse. Indeed, intranasal dose and may last for 3 to 4 hours after parenteral dos- H 3C
US licensed product information states that there have been more es or for 4 to 5 hours after intranasal doses.
O OH
reports of abuse with intranasal preparations than with injectable For the relief of moderate to severe pain, butorphanol tartrate is
given in doses of 1 to 4 mg (usually 2 mg) by intramuscular in- NH
ones.
Cases of butorphanol abuse have been published2,3 including a jection or in doses of 0.5 to 2 mg (usually 1 mg) by intravenous
report of fibrous myopathy associated with chronic intramuscu- injection every 3 to 4 hours. It may also be given as a nasal spray,
in usual doses of 1 mg (1 spray in 1 nostril), repeated after 60 to NOTE. Do not confuse capsaicin with capsicin, which is capsicum
lar abuse. oleoresin (see Capsicum, p.2276).
90 minutes, if necessary. This sequence may be repeated after 3
1. WHO. WHO expert committee on drug dependence: thirty-
fourth report. WHO Tech Rep Ser 942 2006. Also available at: to 4 hours as needed. An initial dose of 2 mg (1 spray in each Pharmacopoeias. In US.
http://libdoc.who.int/trs/WHO_TRS_942_eng.pdf (accessed nostril) may be given for severe pain, but should not be repeated USP 31 (Capsaicin). An off-white powder. M.p. 57° to 66°.
26/06/08) until 3 to 4 hours later. Practically insoluble in cold water; soluble in alcohol, in chloro-
 Butorphanol Tartrate/Carbasalate Calcium 33
form, and in benzene; slightly soluble in carbon disulfide. Store rological bladder disorders. Instillation into the ureter has also Rheumatic disorders. Topical capsaicin is used for the tem-
in a cool place in airtight containers. Protect from light. been tried in the management of the loin pain/haematuria syn- porary relief of the pain of arthritis. From the results of a meta-
Adverse Effects drome.10 analysis1 of randomised, double-blind, placebo-controlled stud-
A warm, stinging, or burning sensation may occur at the site of 1. Lazzeri M, et al. Intravesical capsaicin for treatment of severe ies and later studies2,3 it appears that capsaicin is effective in eas-
bladder pain: a randomized placebo controlled study. J Urol ing the pain of osteoarthritis (p.11) but its role, if any, is unclear;
application; this usually disappears after a few days of use but (Baltimore) 1996; 156: 947–52.
may persist longer if applications are less frequent than recom- published evidence4 for efficacy in rheumatoid arthritis (p.11)
2. de Sèze M, et al. Capsaicin and neurogenic detrusor hyper-
mended (see Uses and Administration, below). Coughing, sneez- reflexia: a double-blind placebo-controlled study in 20 patients appears to be limited. A review of use in both neuropathic and
ing, or other signs of respiratory irritation may occur if dried res- with spinal cord lesions. Neurourol Urodyn 1998; 17: 513–23. musculoskeletal chronic pain concluded that its benefits were at
idue from topical preparations is inhaled. 3. Petersen T, et al. Intravesical capsaicin in patients with detrusor best moderate, but noted that in a minority of patients unrespon-
hyper-reflexia: a placebo-controlled cross-over study. Scand J sive to, or intolerant of, other treatments it might be useful.5 Cap-
Precautions Urol Nephrol 1999; 33: 104–10. saicin may be a useful therapy for pain associated with primary
4. de Sèze M, et al. Intravesical instillation of capsaicin in urology:
Capsaicin should be handled with care. Particles should not be a review of the literature. Eur Urol 1999; 36: 267–77. fibromyalgia6 (see under Soft Tissue Rheumatism, p.13), which
inhaled nor come into contact with any part of the body. 5. de Sèze M, et al. Capsaïcine intravésicale et hyperréflexie du responds poorly to conventional treatment.
For topical application, contact with eyes and broken or irritated détrusor: expérience de 100 instillations sur une période de cinq 1. Zhang WY, Li Wan Po A. The effectiveness of topically applied
skin should be avoided. The hands should be washed after appli- ans. Ann Readapt Med Phys 2001; 44: 514–24. capsaicin. Eur J Clin Pharmacol 1994; 46: 517–22.
6. Szallasi A, Fowler CJ. After a decade of intravesical vanilloid 2. Altman RD, et al. Capsaicin cream 0.025% as monotherapy for
cation of the cream, unless the hands are the treated areas, in therapy: still more questions than answers. Lancet Neurol 2002;
which case, they should be washed 30 minutes after application. osteoarthritis: a double-blind study. Semin Arthritis Rheum
1: 167–72. 1994; 23 (suppl 3): 25–33.
If bandages are used to cover treated areas they should not be 7. de Sèze M, et al. Intravesical capsaicin versus resiniferatoxin 3. McCleane G. The analgesic efficacy of topical capsaicin is en-
wound too tightly. Heating pads should not be used with capsai- for the treatment of detrusor hyperreflexia in spinal cord injured hanced by glyceryl trinitrate in painful osteoarthritis: a rand-
cin, and patients should avoid taking a hot bath or shower imme- patients: a double-blind, randomized, controlled study. J Urol
(Baltimore) 2004; 171: 251–5. omized, double blind, placebo controlled study. Eur J Pain 2000;
diately before or after application, as the burning sensation may 8. Lazzeri M, et al. Intravesical vanilloids and neurogenic inconti- 4: 355–60.
be exacerbated. Thick applications of the cream should be avoid- nence: ten years experience. Urol Int 2004; 72: 145–9. 4. Deal CL, et al. Treatment of arthritis with topical capsaicin: a
ed. 9. El-Mahrouky AS, et al. The effect of intravesical capsaicin and double-blind trial. Clin Ther 1991; 13: 383–95.
resiniferatoxin in neurogenic bladder dysfunction. Adv Exp Med 5. Mason L, et al. Systematic review of topical capsaicin for the
Uses and Administration Biol 2003; 539: 359–79. treatment of chronic pain. BMJ 2004; 328: 991–4.
Capsaicin is the active principle of the dried ripe fruits of Capsi- 10. Bultitude MI. Capsaicin in treatment of loin pain/haematuria 6. McCarty DJ, et al. Treatment of pain due to fibromyalgia with
cum spp. It is used as a topical analgesic (p.5) in painful condi- syndrome. Lancet 1995; 345: 921–2. topical capsaicin: a pilot study. Semin Arthritis Rheum 1994; 23
(suppl 3): 41–7.
tions such as postherpetic neuralgia after the lesions have healed, Neuropathic pain. Capsaicin has been tried topically in vari-
diabetic neuropathy, osteoarthritis, and rheumatoid arthritis. ous types of pain including neuropathic pain, which does not Preparations
Capsaicin is usually applied sparingly 3 or 4 times daily (and not generally respond to conventional systemic analgesics. Topical Proprietary Preparations (details are given in Part 3)
more often than every 4 hours) as a 0.025% or 0.075% cream; in capsaicin is used in the management of diabetic neuropathy (p.6) Austral.: Zostrix; Belg.: Hansamedic Warmtepleister; Braz.: Moment;
the UK these creams are not licensed for use in children, but in and postherpetic neuralgia (p.9), but while a meta-analysis1 of Canad.: Antiphlogistine Rub A-535 Capsaicin; Arthricare for Women Ex-
tra Moisturizing†; Zostrix; Chile: Presyc; Gr.: Gelcen; Zacin; Indon.: Cap-
the USA they may be used in children over 2 years of age. A randomised, double-blind, placebo-controlled studies and later zacin; Irl.: Axsain; Zacin; Israel: Zostrix; Mex.: Capsidol; Norw.: Capsina;
more concentrated cream containing 0.25% capsaicin is availa- studies2 suggested that it is effective in painful diabetic neuropa- NZ: Zostrix; Port.: Hansaplast Emplastro Termico; Hansaterm; Spain:
ble in some countries. thy the evidence for efficacy in postherpetic neuralgia was Capsicin; Capsicum Farmaya; Capsidol; Gelcen; Hansaterm; Katrum; Swed.:
Capsaicin cream should be rubbed well into the skin until little or considered1 to be less convincing. Another meta-analysis3 and a Capsina; Switz.: Emplatre antirhumatismal Isola Capsicum N; Emplatre
Etoile†; UK: Axsain; Zacin; USA: Axsain; Capsin; Capzasin-HP; Capzasin-P;
no residue is left on the surface. Therapeutic response may not be systematic review4 have suggested that capsaicin was of benefit Dolorac; Doublecap; No Pain-HP; R-Gel; Rid-a-Pain HP; Theragen; Zostrix.
evident for 1 to 2 weeks for arthritic disorders, or 2 to 4 weeks for in neuropathic pain, although this effect may be modest.4 The Multi-ingredient: Arg.: Atomo Desinflamante C; Rati Salil Crema; Rati
neuralgias (or even longer if the head or neck are involved). For difficulty of blinding in placebo-controlled trials of capsaicin has Salil Flex; Austria: Rubizon-Rheumagel; Canad.: Arthricare for Women
the management of painful diabetic neuropathy, licensed UK also been noted, because of the burning sensation it produces. Multi-Action†; Heet; Menthacin; Midalgan†; Cz.: Capsicolle; Dr Theiss
product information recommends that capsaicin should only be Other types of pain syndrome for which capsaicin has been tried Rheuma Creme†; Fr.: Capsic; Cliptol Sport†; Ger.: Capsamol N†; Gr.: Pon-
used under specialist supervision and that treatment should be include reflex sympathetic dystrophy (see Complex Regional ostop; Hong Kong: Salomethyl; Hung.: Nicoflex; India: Nimulid Nugel;
Irl.: Algipan; Radian-B†; Ital.: Disalgil†; Pol.: Capsigel N; Neo-Capsiderm;
reviewed after the first 8 weeks and regularly re-evaluated there- Pain Syndrome, p.6), postmastectomy neuroma, amputation Switz.: Emplatre antirhumatismal Isola Capsicum N a l’huile essentielle de
after. stump pain, chronic neck pain, and the pain of oral mucositis.5 Gaultherie; Emplatre Etoile salicyle†; UK: NatraFlex; USA: Arthricare Odor
Although not a counter-irritant itself, capsaicin has been included See also Rheumatic Disorders, below for use in musculoskeletal Free; Heet; Menthacin; Pain Doctor; Ziks.
in rubefacient preparations for the relief of muscular and rheu- pain.
matic pain. 1. Zhang WY, Li Wan Po A. The effectiveness of topically applied
capsaicin. Eur J Clin Pharmacol 1994; 46: 517–22.
Action. The action of capsaicin and related compounds (vanil- 2. Biesbroeck R, et al. A double-blind comparison of topical cap-
Carbasalate Calcium (BAN, rINN)
loids) are complex and still being investigated. Capsaicin has saicin and oral amitriptyline in painful diabetic neuropathy. Adv Calcium Acetylsalicylate Carbamide; Calcium Carbaspirin; Car-
been found to produce burning pain1,2 by activating specific va- Therapy 1995; 12: 111–20. basalate calcique; Carbasalato cálcico; Carbasalatum calcicum;
nilloid receptors such as TRPV1 (transient receptor potential 3. Kingery WS. A critical review of controlled clinical trials for
peripheral neuropathic pain and complex regional pain syn- Carbasalatum Calcium; Carbaspirin Calcium (USAN); Karbasalaat-
channel, vanilloid subfamily member 1) which are also stimulat- tikalsium; Karbasalát vápenatá sůl; Karbasalatkalcium; Karbasalato
dromes. Pain 1997; 73: 123–39.
ed by heat and acids. TRPV1 is expressed by nerves and other 4. Mason L, et al. Systematic review of topical capsaicin for the kalcio druska; Karbaszalát-kálcium. Calcium bis[2-(acetoxy)ben-
tissues such as the keratinocytes of the epidermis, bladder treatment of chronic pain. BMJ 2004; 328: 991–4.
urothelium and smooth muscle, and liver. zoate]—urea.
5. Hautkappe M, et al. Review of the effectiveness of capsaicin for
The analgesic effect of capsaicin has been suggested to be due to painful cutaneous disorders and neural dysfunction. Clin J Pain Карбасалат Кальций
both depletion of substance P from local sensory C-type nerve 1998; 14: 97–106. C 19 H 18 CaN 2O 9 = 458.4.
fibres3-7 and to the desensitisation of vanilloid receptors.1,2,8 Pruritus. Substance P is a possible mediator of itch sensations C AS — 5749-67-7.
Since the effect of capsaicin does not rely on vasodilatation in the and since capsaicin acts as a depletor of substance P it has been ATC — B01AC08; N02BA15.
skin it is therefore not considered to be a traditional counter-irri- tried in the relief of pruritus (p.1582) associated with various dis- ATC Vet — QB01AC08; QN02BA15.
tant. eases and haemodialysis.1-7 It has also been used to provide relief
1. Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and from pruritus induced by hetastarch8 and for the itch and pain
mechanisms. Pharmacol Rev 1999; 51: 159–211. associated with PUVA therapy.9,10 O O
2. Cortright DN, Szallasi A. Biochemical pharmacology of the va- 1. Breneman DL, et al. Topical capsaicin for treatment of hemodi-
nilloid receptor TRPV1: an update. Eur J Biochem 2004; 271: alysis-related pruritus. J Am Acad Dermatol 1992; 26: 91–4.
Ca
1814–19. O O O
2. Leibsohn E. Treatment of notalgia paresthetica with capsaicin.
3. Rumsfield JA, West DP. Topical capsaicin in dermatologic and Cutis 1992; 49: 335–6.
peripheral pain disorders. DICP Ann Pharmacother 1991; 25: 3. Fölster-Holst R, Brasch J. Effect of topically applied capsaicin O O H 2N NH2
381–7. on pruritus in patients with atopic dermatitis. J Dermatol Treat
4. Cordell GA, Araujo OE. Capsaicin: identification, nomencla- 1996; 7: 13–15.
ture, and pharmacotherapy. Ann Pharmacother 1993; 27: 330–6. 4. Hautmann G, et al. Aquagenic pruritus, PUVA and capsaicin O CH3 O CH3
5. Winter J, et al. Capsaicin and pain mechanisms. Br J Anaesth treatments. Br J Dermatol 1994; 131: 920–1.
1995; 75: 157–68. 5. Ständer S, et al. Treatment of prurigo nodularis with topical cap-
6. Del Bianco E, et al. The effects of repeated dermal application of saicin. J Am Acad Dermatol 2001; 44: 471–8. Pharmacopoeias. In Eur. (see p.vii).
capsaicin to the human skin on pain and vasodilatation induced 6. Lysy J, et al. Topical capsaicin— a novel and effective treatment Ph. Eur. 6.2 (Carbasalate Calcium). A white or almost white,
by intradermal injection of acid and hypertonic solutions. Br J for idiopathic intractable pruritus ani: a randomised, placebo crystalline powder. It contains not less than 99.0% and not more
Clin Pharmacol 1996; 41: 1–6. controlled, crossover study. Gut 2003; 52: 1323–6.
7. Hautkappe M, et al. Review of the effectiveness of capsaicin for
than the equivalent of 101.0% of an equimolecular compound of
7. Fusco BM, Giacovazzo M. Peppers and pain: the promise of cap-
saicin. Drugs 1997; 53: 909–14. painful cutaneous disorders and neural dysfunction. Clin J Pain calcium di[2-(acetyloxy)benzoate] and urea, calculated with ref-
8. Tominaga M, Julius D. Capsaicin receptor in the pain pathway. 1998; 14: 97–106. erence to the anhydrous substance. Freely soluble in water and in
Jpn J Pharmacol 2000; 83: 20–4. 8. Szeimies R-M, et al. Successful treatment of hydroxyethyl dimethylformamide; practically insoluble in acetone and in
starch-induced pruritus with topical capsaicin. Br J Dermatol anhydrous methyl alcohol. Store in airtight containers.
Headache. Prevention of attacks of cluster headache (p.616) 1994; 131: 380–2.
by repeated application of capsaicin to the nasal mucosa has been 9. Burrows NP, Norris PG. Treatment of PUVA-induced skin pain Adverse Effects, Treatment, and Precautions
reported.1 The Z-isomer (zucapsaicin; civamide) has also been with capsaicin. Br J Dermatol 1994; 131: 584–5. As for Aspirin, p.20.
10. Kirby B, Rogers S. Treatment of PUVA itch with capsaicin. Br
found to be modestly effective.2 J Dermatol 1997; 137: 152. Carbasalate calcium, like aspirin, should not generally be given
Repeated nasal application of capsaicin has also been found to be to children because of the risk of Reye’s syndrome.
effective in chronic migraine.3 Psoriasis. Since substance P has been implicated in the patho-
physiology of several inflammatory dermatological processes, Effects on hearing. As of June 2006 the Netherlands Pharma-
1. Fusco BM, et al. Preventative effect of repeated nasal applica-
tions of capsaicin in cluster headache. Pain 1994; 59: 321–5. capsaicin, a substance P depletor, has been tried with some ben- covigilance Centre1 database contained 8 reports of tinnitus and
2. Saper JR, et al. Intranasal civamide for the treatment of episodic efit in a number of skin disorders including psoriasis.1-3 1 of ototoxicity associated with use of low oral doses of carba-
cluster headaches. Arch Neurol 2002; 59: 990–4. The usual management of psoriasis is discussed on p.1583. salate calcium (38 or 100 mg usually once daily). The associa-
3. Fusco BM, et al. Repeated intranasal capsaicin applications to 1. Bernstein JE, et al. Effects of topically applied capsaicin on tion between low-dose carbasalate calcium and tinnitus was con-
treat chronic migraine. Br J Anaesth 2003; 90: 812. moderate and severe psoriasis vulgaris. J Am Acad Dermatol sidered to be disproportional.
Micturition disorders. Intravesical capsaicin has been tried 1986; 15: 504–7. 1. Nederlands Bijwerkingen Centrum. Low dosage carbasalate cal-
for painful bladder disorders and to treat bladder detrusor hyper- 2. Ellis CN, et al. A double-blind evaluation of topical capsaicin in cium and tinnitus. Available at: http://www.lareb.nl/documents/
pruritic psoriasis. J Am Acad Dermatol 1993; 29: 438–42. kwb_2006_3_carbas.pdf (accessed 12/04/07)
reflexia.1-9 Results have been variable, and the characteristic sen- 3. Hautkappe M, et al. Review of the effectiveness of capsaicin for
sory effects of capsaicin make blinding of studies difficult, but painful cutaneous disorders and neural dysfunction. Clin J Pain Interactions
some patients have reported benefit particularly those with neu- 1998; 14: 97–106. For interactions associated with aspirin, see p.23.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
34 Analgesics Anti-inflammatory Drugs and Antipyretics
Uses and Administration Celecoxib (BAN, USAN, rINN) nal dose. Similar values have also been estimated from a study of
Carbasalate calcium is a 1:1 complex of calcium acetylsalicylate blood and milk concentrations of celecoxib in 6 women.2
and urea. It is metabolised to aspirin after absorption and thus has Célécoxib; Celecoxibum; Celekoxib; SC-58635; Selekoksib; Sele- 1. Hale TW, et al. Transfer of celecoxib into human milk. J Hum
the actions of aspirin (p.23). Carbasalate calcium is given in oral koksibi; YM-177. p-[5-p-Tolyl-3-(trifluoromethyl)pyrazol-1- Lact 2004; 20: 397–403.
doses equivalent to about 400 to 800 mg of aspirin every 4 to 8 2. Gardiner SJ, et al. Quantification of infant exposure to celecoxib
yl]benzenesulfonamide. through breast milk. Br J Clin Pharmacol 2006; 61: 101–4.
hours up to a maximum of about 3 g daily for pain or fever. Car-
basalate calcium has also been used in the management of throm- Целекоксиб Effects on the blood. Severe methaemoglobinaemia has been
boembolic disorders. C 17 H 14F 3 N 3 O 2 S = 381.4. reported in an elderly patient after taking celecoxib for 1 month.1
C AS — 169590-42-5. 1. Kaushik P, et al. Celecoxib-induced methemoglobinemia. Ann
Preparations Pharmacother 2004; 38: 1635–8.
ATC — L01XX33; M01AH01.
Proprietary Preparations (details are given in Part 3) Effects on the cardiovascular system. Prelicensing studies
Austria: Iromin; Vascal; Neth.: Ascal; Port.: Ascal; Spain: Ascal; Switz.: ATC Vet — QL01XX33; QM01AH01.
did not report any increased risk of serious cardiovascular effects
Alcacyl. in patients given celecoxib.1,2 Nonetheless, by February 2001 the
Multi-ingredient: Austria: Irocopar c C; Irocophan; Iromin-Chinin-C; UK CSM had received a small number of reports3 of myocardial
Cz.: Cephalgan†; Fr.: Cephalgan†; Switz.: Alca-C. O O infarction or ischaemia associated with the selective cyclo-oxy-
S genase-2 (COX-2) inhibitors. There have also been 3 cases of
H 2N torsade de pointes associated with celecoxib use.4 Subsequently,
in September 2004, the COX-2 inhibitor rofecoxib was generally
Carfentanil Citrate (USAN, rINNM) ⊗ N withdrawn worldwide by the manufacturer after further reports
Carfentanil, Citrate de; Carfentanili Citras; Citrato de carfentani- N CF3 of cardiovascular adverse effects (see p.121) and this has
lo; R-33799. Methyl 1-phenethyl-4-(N-phenylpropionamido)iso- prompted re-evaluation of the safety of other selective COX-2
nipecotate citrate. inhibitors.
In December 2004 a large study of celecoxib for prevention of
Карфентанила Цитрат colon polyps (the APC study) was halted because of an increased
C 24 H 30 N 2 O 3 ,C 6H 8 O 7 = 586.6. risk of cardiovascular events (including death from cardiovascu-
C AS — 59708-52-0 (carfentanil); 61380-27-6 (carfen- H 3C lar causes, myocardial infarction, stroke, and heart failure) in pa-
tanil citrate). tients receiving the drug compared with those receiving place-
bo.5 The results of this long-term study suggested that there was
Adverse Effects, Treatment, and Precau- a 2.8-fold increase in the risk of such events in patients taking
tions either celecoxib 400 or 800 mg daily and that the increase was
O As for NSAIDs in general, p.96. dose-related. The possibility of a dose-adverse effect relationship
H 3C was supported by some at-the-time unpublished studies, the Pre-
O
Serious skin reactions such as exfoliative dermatitis, SAP and ADAPT studies, that showed no increase in the risk of
N
Stevens-Johnson syndrome, and toxic epidermal cardiovascular effects with celecoxib 400 mg daily when com-
CH3 necrolysis have been reported with celecoxib. Other pared with placebo.6 These studies7,8 have since been published
N and their finished reports were less reassuring than initially
hypersensitivity reactions, including anaphylaxis and thought. The risk of serious cardiovascular events was found to
O angioedema, have also occurred. Celecoxib should be be increased in the celecoxib group when compared with the pla-
stopped at the first signs of hypersensitivity. Some of cebo group although the difference was not significant. In addi-
these reactions have been seen in patients with a histo- tion, an update9 of the original APC study confirmed that the risk
(carfentanil) ry of allergic reactions to sulfonamides and the use of of adverse cardiovascular events was significantly increased for
both high-dose (800 mg daily) and low-dose (400 mg daily)
celecoxib is contra-indicated in such patients. celecoxib when compared with placebo treatment; however,
Profile
Carfentanil citrate is an opioid analgesic related to fentanyl Celecoxib should not be used after coronary artery by- high-dose treatment was associated with the greatest risk. In-
(p.55). It is used in veterinary medicine. pass surgery as there may be an increased risk of ad- creases in blood pressure were also more likely with both
celecoxib groups than with placebo. An analysis10 using pooled
verse effects such as myocardial infarction and stroke. data from the APC and PreSAP studies provides further evidence
It should be used with caution, if at all, in patients with of an increased cardiovascular risk with celecoxib.
Carprofen (BAN, USAN, rINN) a history of ischaemic heart disease, peripheral arterial Based on the findings of the above studies, EU regulatory
disease, or cerebrovascular disease; it should also be authorities11-13 recommend that:
C-5720; Carprofène; Carprofeno; Carprofenum; Karprofeeni; used with caution in patients with significant risk fac- • selective COX-2 inhibitors should not be used in patients with
Karprofen; Ro-20-5720/000. (±)-2-(6-Chlorocarbazol-2-yl)pro- established ischaemic heart disease or cerebrovascular dis-
pionic acid.
tors for cardiovascular disease such as hypertension,
ease; they are also contra-indicated in those with peripheral
hyperlipidaemia, and diabetes mellitus. For further de- arterial disease
Карпрофен tails see Effects on the Cardiovascular System, below. • patients with risk factors for heart disease such as hyperten-
C 15 H 12 ClNO 2 = 273.7.
Therapy is contra-indicated in patients with moderate sion, hyperlipidaemia, diabetes, and smoking should be care-
C AS — 53716-49-7. fully monitored if given selective COX-2 inhibitors
ATC Vet — QM01AE91. to severe heart failure (NYHA class II to IV), inflam-
matory bowel disease, and renal impairment associated • all patients should be assessed individually on the risks and
benefits of selective COX-2 inhibitor treatment, particularly
with a creatinine clearance of less than 30 mL/minute. cardiovascular and gastrointestinal risk factors, and alterna-
H 3C Celecoxib should also not be used in patients with se- tive treatments considered
Cl
vere hepatic impairment (Child-Pugh category C). Similar advice has also been issued by the FDA;14 however, the
Caution is recommended when using celecoxib in only absolute contra-indication is in the immediate postoperative
HO period after coronary artery bypass surgery. (In the USA celecox-
dehydrated patients; rehydration may be advisable be-
O N ib is currently the only available selective COX-2 inhibitor.)
H fore giving celecoxib. COX-2 inhibitors such as celecoxib do not possess the intrinsic
Celecoxib treatment may need to be stopped if signs or antiplatelet activity associated with aspirin and possibly other
Pharmacopoeias. In Eur. (see p.vii) and US for veterinary use symptoms of organ toxicity develop. non-selective NSAIDs and consequently do not provide protec-
only. tion against ischaemic cardiac events.3,15
Ph. Eur. 6.2 (Carprofen for Veterinary Use). A white or almost Incidence of adverse effects. A prescription-event monitor- 1. Silverstein FE, et al. Gastrointestinal toxicity with celecoxib vs
white, crystalline powder. Practically insoluble in water; freely ing study1 conducted after the introduction of celecoxib in Eng- nonsteroidal anti-inflammatory drugs for osteoarthritis and
soluble in acetone; soluble in methyl alcohol; slightly soluble in land in May 2000 found that the most common adverse events rheumatoid arthritis. The CLASS study: a randomized control-
reported were gastrointestinal effects including dyspepsia (4.7% led trial. JAMA 2000; 284: 1247–55.
isopropyl alcohol. It exhibits polymorphism. Protect from light. 2. White WB, et al. Comparison of thromboembolic events in pa-
USP 31 (Carprofen). A white crystalline powder. Practically of all events), abdominal pain (1.8%), nausea or vomiting tients treated with celecoxib, a cyclooxygenase-2 specific inhib-
insoluble in water; freely soluble in acetone, in ether, in ethyl (1.6%), and diarrhoea (1.4%). Rash (1.2%) was also common. itor, versus ibuprofen or diclofenac. Am J Cardiol 2002; 89:
acetate, and in solutions of sodium carbonate and of sodium Uncommon events included anaemia, cough, anxiety, hyperten- 425–30.
sion, visual disturbances, and insomnia. Blood dyscrasias, gas- 3. CSM/MCA. COX-2 selective NSAIDs lack antiplatelet activity.
hydroxide. Store in airtight containers at a temperature of 25°, Current Problems 2001; 27: 7. Also available at: http://
excursions permitted between 15° and 30°. Protect from light. trointestinal bleeds, myocardial infarction, heart failure, abnor- w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _
mal liver function tests, nephritis, confusion, hallucinations, FILE&dDocName=CON007458&RevisionSelectionMethod=
Profile serious skin disorders, anaphylaxis, and bronchospasm were LatestReleased (accessed 01/11/07)
Carprofen, a propionic acid derivative, is an NSAID (p.96) used rare. 4. Pathak A, et al. Celecoxib-associated torsade de pointes. Ann
in veterinary medicine. Pharmacother 2002; 36: 1290–1.
1. Layton D, et al. Safety profile of celecoxib as used in general 5. Solomon SD, et al. Adenoma Prevention with Celecoxib (APC)
practice in England: results of a prescription-event monitoring Study Investigators. Cardiovascular risk associated with
Adverse effects. A pruritic, erythematous, eczematous erup- study. Eur J Clin Pharmacol 2004; 60: 489–501. celecoxib in a clinical trial for colorectal adenoma prevention.
tion developed in a 27-year-old woman after occupational expo- N Engl J Med 2005; 352: 1071–80.
sure to carprofen.1 Patch testing showed a strong positive photo- Breast feeding. Licensed product information recommends 6. FDA. Celecoxib (marketed as Celebrex) (issued 7th April
allergic reaction to carprofen. that celecoxib should not be used in breast-feeding women be- 2005). Available at: http://www.fda.gov/cder/drug/infopage/
1. Walker SL, et al. Occupational photoallergic contact dermatitis cause of the potential for serious adverse effects in nursing in- celebrex/celebrex-hcp.pdf (accessed 01/11/07)
fants. 7. Arber N, et al. Celecoxib for the prevention of colorectal adeno-
in a pharmaceutical worker manufacturing carprofen, a canine matous polyps. N Engl J Med 2006; 355: 885–95.
nonsteroidal anti-inflammatory drug. Br J Dermatol 2006; 154: No adverse effects were noted in 2 older infants (aged 17 and 22 8. ADAPT Research Group. Cardiovascular and cerebrovascular
569–70. months) whose mothers took celecoxib while breast feeding.1 events in the randomized, controlled Alzheimer’s disease anti-
Preparations The authors of this report also measured celecoxib plasma con- inflammatory prevention trial (ADAPT). Available at: http://
clinicaltrials.plosjournals.org/archive/1555-5887/1/7/pdf/
centrations in 2 other women; from these values, the average 10.1371_journal.pctr.0010033-L.pdf (accessed 01/11/07)
USP 31: Carprofen Tablets.
milk-to-plasma ratio was calculated to be 0.23 and infant expo- 9. Bertagnolli MM, et al. Celecoxib for the prevention of sporadic
sure was estimated at about 0.3% of the weight-adjusted mater- colorectal adenomas. N Engl J Med 2006; 355: 873–84.
 Carfentanil Citrate/Celecoxib 35
10. Solomon SD, et al. Effect of celecoxib on cardiovascular events 2. Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a Pharmacokinetics
and blood pressure in two trials for the prevention of colorectal pattern of nephrotoxicity similar to traditional nonsteroidal anti-
adenomas. Circulation 2006; 114: 1028–35. inflammatory drugs. Am J Med 2001; 111: 64–7. Celecoxib is absorbed from the gastrointestinal tract,
11. MHRA. Updated advice on the safety of selective COX-2 inhib- 3. Graham MG. Acute renal failure related to high-dose celecoxib. peak plasma concentrations being achieved after about
itors. Message from Professor G Duff, Chairman of CSM (is- Ann Intern Med 2001; 135: 69–70.
sued 17th February, 2005). Available at: 4. Alkhuja S, et al. Celecoxib-induced nonoliguric acute renal fail- 3 hours. Protein binding is about 97%. Celecoxib is
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ ure. Ann Pharmacother 2002; 36: 52–4. metabolised in the liver mainly by the cytochrome
FILE&dDocName=CON019458&RevisionSelectionMethod= 5. Ahmad SR, et al. Renal failure associated with the use of
LatestReleased (accessed 01/11/07) celecoxib and rofecoxib. Drug Safety 2002; 25: 537–44. P450 isoenzyme CYP2C9; the three identified metab-
12. EMEA. European Medicines Agency announces regulatory ac- 6. Alper AB, et al. Nephrotic syndrome and interstitial nephritis olites are inactive as inhibitors of COX-1 or COX-2
tion on COX-2 inhibitors (issued 17th February, 2005). Availa- associated with celecoxib. Am J Kidney Dis 2002; 40: 1086–90.
ble at: http://www.emea.europa.eu/pdfs/human/press/pr/ 7. Akhund L, et al. Celecoxib-related renal papillary necrosis. enzymes. It is eliminated mainly as metabolites in the
6275705en.pdf (accessed 29/08/08) Arch Intern Med 2003; 163: 114–15. faeces and urine; less than 3% is recovered as
13. EMEA. European Medicines Agency concludes action on 8. Markowitz GS, et al. Membranous glomerulopathy and acute
COX-2 inhibitors (issued 27th June, 2005). Available at: http:// interstitial nephritis following treatment with celecoxib. Clin unchanged drug. The effective terminal half-life is
www.emea.europa.eu/pdfs/human/press/pr/20776605en.pdf Nephrol 2003; 59: 137–42. about 11 hours. Celecoxib is distributed into breast
(accessed 01/11/07) 9. Brewster UC, Perazella MA. Acute tubulointerstitial nephritis
associated with celecoxib. Nephrol Dial Transplant 2004; 19: milk. The pharmacokinetics of celecoxib may vary in
14. FDA. FDA issues public health advisory recommending limited
use of cox-2 inhibitors: agency requires evaluation of preven- 1017–18. different ethnic groups; it has been stated that the area
tion studies involving cox-2 selective agents. (issued 23rd De- 10. Clifford TM, et al. Celecoxib-induced nephrotoxicity in a renal
transplant recipient. Pharmacotherapy 2005; 25: 773–7. under the curve is elevated in patients of Afro-Carib-
cember, 2004). Available at: http://www.fda.gov/bbs/topics/
ANSWERS/2004/ANS01336.html (accessed 01/11/07) Effects on the liver. Cholestatic hepatitis developed in a 54- bean origin, although any clinical significance is
15. Bing RJ, Lomnicka M. Why do cyclo-oxygenase-2 inhibitors year-old woman taking celecoxib;1 her liver function tests im- unclear.
cause cardiovascular events? J Am Coll Cardiol 2002; 39:
521–2. proved and her symptoms resolved after drug withdrawal. De- ◊ References.
spite the temporal relationship between celecoxib use and the on- 1. Davies NM, et al. Clinical pharmacokinetics and pharmacody-
Effects on the gastrointestinal tract. It is generally accept- set of hepatotoxicity, the manufacturers have stated that current namics of celecoxib: a selective cyclo-oxygenase-2 inhibitor.
ed that the inhibition of cyclo-oxygenase-1 (COX-1) plays a role evidence does not support such a relationship.2 Other cases3,4 Clin Pharmacokinet 2000; 38: 225–42.
in the adverse gastrointestinal effects of the NSAIDs, and that the have since been reported. 2. Stempak D, et al. Single-dose and steady-state pharmacokinetics
selective inhibition of the other isoform, COX-2, by NSAIDs For a case of acute hepatitis with pancreatitis, see Pancreatitis, of celecoxib in children. Clin Pharmacol Ther 2002; 72: 490–7.
such as celecoxib may cause less gastrotoxicity than the non-se- below. Correction. ibid. 2006; 80: 667.
lective inhibition of the traditional NSAIDs. 3. Kirchheiner J, et al. Influence of CYP2C9 genetic polymor-
1. O’Beirne JP, Cairns SR. Cholestatic hepatitis in association with phisms on pharmacokinetics of celecoxib and its metabolites.
Results from controlled studies suggested that NSAIDs selective celecoxib. BMJ 2001; 323: 23. Pharmacogenetics 2003; 13: 473–80.
for COX-2 were associated with a lower incidence of serious 2. Arellano FM, et al. Case of cholestatic hepatitis with celecoxib 4. Lundblad MS, et al. Accumulation of celecoxib with a 7-fold
gastrointestinal effects. In a placebo-controlled study1 the inci- did not fulfil international criteria. BMJ 2002; 324: 789–90. higher drug exposure in individuals homozygous for
dence of endoscopically determined gastroduodenal ulcers in pa- 3. Grieco A, et al. Acute cholestatic hepatitis associated with CYP2C9*3. Clin Pharmacol Ther 2006; 79: 287–8.
celecoxib. Ann Pharmacother 2002; 36: 1887–9.
tients taking celecoxib for rheumatoid arthritis (dose range 200 4. Chamouard P, et al. Prolonged cholestasis associated with short-
to 800 mg daily) was not significantly different to that seen with term use of celecoxib. Gastroenterol Clin Biol 2005; 29: 1286–8. Uses and Administration
the placebo group. Another study2 in patients taking celecoxib at Celecoxib is an NSAID (p.99) reported to be a selec-
Effects on the lungs. Report of a case of pulmonary oedema
supratherapeutic doses (800 mg daily) concluded that there was tive inhibitor of cyclo-oxygenase-2 (COX-2). It is used
and possible pneumonitis in a patient taking celecoxib.1
a lower combined incidence of symptomatic gastrointestinal ul-
cers and ulcer complications (bleeding, perforation, and obstruc- 1. Olin JL, et al. Pulmonary edema and possible pneumonitis asso- in the treatment of rheumatoid arthritis including juve-
ciated with celecoxib. Ann Pharmacother 2004; 38: 1086.
tion) after 6 months of treatment when compared with non-selec- nile idiopathic arthritis, osteoarthritis, and ankylosing
tive NSAIDS (ibuprofen 2.4 g daily or diclofenac 150 mg daily). Effects on the nervous system. Acute neuropsychiatric re- spondylitis, and in the adjunctive treatment of adenom-
However, the incidence of ulcer complications alone was not sig- actions such as confusion, somnolence, and insomnia, have oc-
curred after celecoxib use.1 There has also been a case report of atous colorectal polyps. Celecoxib is also used in the
nificantly different to that seen with other NSAIDs. A re-analysis
of the study by the FDA, including both the 6-month and full- aseptic meningitis.2 management of acute pain and dysmenorrhoea.
term data, also found that there was no significant reduction in 1. Adverse Drug Reations Advisory Committee (ADRAC). Acute For osteoarthritis the recommended oral dose is
neuropsychiatric events with celecoxib and rofecoxib. Aust Ad-
the rate of ulcer complications with celecoxib compared with the
verse Drug React Bull 2003; 22: 3. Also available at: http:// 200 mg daily given as a single dose or in 2 divided dos-
non-selective NSAIDs although, in subjects not taking aspirin, www.tga.health.gov.au/adr/aadrb/aadr0302.pdf (accessed es. If necessary a dose of 200 mg twice daily may be
there was a strong trend in favour of celecoxib compared to ibu- 01/11/07)
profen.3 The risk of ulcer complications was also significantly 2. Papaioannides DH, et al. Aseptic meningitis possibly associated
used. For rheumatoid arthritis the dose is 100 to
increased in celecoxib users taking concomitant low-dose aspi- with celecoxib. Ann Pharmacother 2004; 38: 172. 200 mg given twice daily. Celecoxib is also used for
rin.2 A later systematic review4 of studies of patients receiving Hypersensitivity. A 52-year-old man suffered an allergic vas- ankylosing spondylitis in an initial dose of 200 mg
celecoxib or NSAIDs for at least 12 weeks claimed to show im- culitis after 8 days of treatment with celecoxib.1 Despite inten- daily, as a single dose or in 2 divided doses. In the
proved gastrointestinal safety and tolerability in those receiving sive treatment the patient died from multiple organ failure and USA, the dose may be increased to 400 mg daily after
celecoxib (including in patients also taking low-dose aspirin) but diffuse cutaneous necrolysis. The authors noted that potentially
this has been criticised on grounds of data selection.5,6 6 weeks, although if no response is seen at this dose
fatal skin reactions have occurred with other sulfa-containing
It has been noted that the use of aspirin appears to nullify any drugs, although there is some evidence suggesting that the poten- after a further 6 weeks, alternative treatments should be
potential protective effect of COX-2 selectivity by celecoxib.7,8 tial for cross-reactivity in patients sensitive to sulfonamides is considered. A similar increase is also permitted in UK
There have been individual case reports of gastrotoxicity with relatively low;2 nonetheless, licensed product information con- licensed product information; however, it is recom-
celecoxib.9-11 tra-indicates the use of celecoxib in such patients. mended that if ineffective, the higher dose should only
1. Schneider F, et al. Fatal allergic vasculitis associated with
1. Simon LS, et al. Anti-inflammatory and upper gastrointestinal
celecoxib. Lancet 2002; 359: 852–3. be continued for 2 weeks before considering alterna-
effects of celecoxib in rheumatoid arthritis: a randomized con-
trolled trial. JAMA 1999; 282: 1921–8. 2. Shapiro LE, et al. Safety of celecoxib in individuals allergic to tive treatments. In elderly patients treatment should be
2. Silverstein FE, et al. Gastrointestinal toxicity with celecoxib vs sulfonamide: a pilot study. Drug Safety 2003; 26: 187–95. begun at the lowest recommended dose.
nonsteroidal anti-inflammatory drugs for osteoarthritis and Pancreatitis. Acute hepatitis and pancreatitis developed in an
rheumatoid arthritis. The CLASS study: a randomized control- For doses in children with juvenile idiopathic arthri-
led trial. JAMA 2000; 284: 1247–55. elderly patient with a reported history of hypersensitivity to sul-
fonamides who was given celecoxib.1 Symptoms resolved on tis, see below.
3. FDA. Celebrex capsules (celecoxib) NDA 20-998/S009—Med-
ical Officer Review. 2000. Available at: http://www.fda.gov/ stopping the drug. Pancreatitis has also been reported in a patient In the treatment of pain and dysmenorrhoea, an initial
ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf (accessed known to be tolerant of sulfonamides.2 dose of 400 mg followed by an additional dose of
01/11/07)
Celecoxib was one of the more commonly implicated drugs cited 200 mg, if necessary, is recommended on the first day;
4. Deeks JJ, et al. Efficacy, tolerability, and upper gastrointestinal
in case reports of drug-induced pancreatitis received by the Ad-
safety of celecoxib for treatment of osteoarthritis and rheuma-
verse Drug Reactions Advisory Committee in Australia.3
thereafter the dose is 200 mg twice daily.
toid arthritis: systematic review of randomised controlled trials.
BMJ 2002; 325: 619–23. 1. Carrillo-Jimenez R, Nurnberger M. Celecoxib-induced acute Celecoxib is also used as an adjunct to standard therapy
5. Jüni P, et al. Systematic review of celecoxib for osteoarthritis pancreatitis and hepatitis: a case report. Arch Intern Med 2000; to reduce the number of adenomatous colorectal pol-
and rheumatoid arthritis: problems compromise review’s valid- 160: 553–4.
ity. BMJ 2003; 326: 334. 2. Baciewicz AM, et al. Acute pancreatitis associated with celecox- yps in patients with familial adenomatous polyposis.
6. Metcalfe S, et al. Systematic review of celecoxib for osteoar- ib. Ann Intern Med 2000; 132: 680. For this purpose it may be given in doses of 400 mg
thritis and rheumatoid arthritis: celecoxib’s relative gastrointes- 3. Australian Adverse Drug Reactions Advisory Committee
tinal safety is overstated. BMJ 2003; 326: 334–5. (ADRAC). Drug induced pancreatitis. Aust Adverse Drug React twice daily with food.
7. Lichtenstein DR, Wolfe MM. COX-2-selective NSAIDs: new Bull 2006; 25: 22. Also available at: http://www.tga.gov.au/adr/ Reduced doses are recommended in patients with he-
and improved? JAMA 2000; 284: 1297–9. aadrb/aadr0612.pdf (accessed 01/11/07)
8. Bates DE, Lemaire JB. Possible celecoxib-induced gastroduo- patic impairment (see below).
denal ulceration. Ann Pharmacother 2001; 35: 782–3.
9. Mohammed S, Croom DW. Gastropathy due to celecoxib, a cy- Interactions ◊ Reviews.
clooxygenase-2 inhibitor. N Engl J Med 1999; 340: 2005–6. The metabolism of celecoxib is mediated mainly by 1. Clemett D, Goa KL. Celecoxib: a review of its use in osteoarthri-
10. Adverse Drug Reactions Advisory Committee (ADRAC). tis, rheumatoid arthritis and acute pain. Drugs 2000; 59: 957–80.
Celecoxib: early Australian reporting experience. Aust Adverse
the cytochrome P450 isoenzyme CYP2C9. Use with 2. Frampton JE, Keating GM. Celecoxib: a review of its use in the
Drug React Bull 2000; 19: 6–7. Also available at: http:// other drugs that inhibit or induce or are metabolised by management of arthritis and acute pain. Drugs 2007; 67:
www.tga.gov.au/adr/aadrb/aadr0006.pdf (accessed 29/08/08) 2433–72.
this isoenzyme may result in changes in plasma con-
11. Adverse Drug Reactions Advisory Committee (ADRAC). Seri- Administration in children. In the USA, celecoxib is li-
ous gastrointestinal effects with celecoxib and rofecoxib. Aust centration of celecoxib; fluconazole has increased
Adverse Drug React Bull 2003; 22: 15. Also available at: http:// censed for the treatment of juvenile idiopathic arthritis in chil-
plasma concentrations of celecoxib and licensed prod- dren aged 2 years and over. The recommended oral doses, based
www.tga.health.gov.au/adr/aadrb/aadr0308.htm (accessed
01/11/07) uct information recommends that the dose of celecoxib on body-weight, are:
Effects on the kidneys. Increasing evidence suggests that se- should be halved when given with fluconazole. • 10 kg to 25 kg: 50 mg twice daily
lective cyclo-oxygenase-2 (COX-2) inhibitors such as celecoxib Celecoxib is an inhibitor of the isoenzyme CYP2D6 • over 25 kg: 100 mg twice daily
appear to have adverse effects on renal function similar to those and the potential therefore exists for an effect on drugs Licensed product information recommends that the contents of a
of the non-selective NSAIDs (see p.98). metabolised by this enzyme. celecoxib capsule may be sprinkled onto apple sauce if a patient
Some references to the adverse renal effects of celecoxib. has difficulty swallowing the capsules. The sprinkled capsule
1. Boyd IW, et al. COX-2 inhibitors and renal failure: the triple
For interactions associated with NSAIDs in general, should be taken immediately; however, it remains stable at a
whammy revisited. Med J Aust 2000; 173: 274. see p.99. temperature between 2° to 8° for up to 6 hours.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
36 Analgesics Anti-inflammatory Drugs and Antipyretics
Administration in hepatic impairment. Licensed product 5. Stengaard-Pedersen K, et al. Celecoxib 200 mg qd is efficacious Choline Salicylate (BAN, USAN, rINN)
information recommends that doses of celecoxib should be re- in the management of osteoarthritis of the knee or hip regardless
duced by 50% in patients with moderate hepatic impairment of the time of dosing. Rheumatology (Oxford) 2004; 43: 592–5. Choline, Salicylate de; Cholini Salicylas; Koliinisalisylaatti; Kolinsal-
(Child-Pugh category B); its use is contra-indicated in those with 6. Schnitzer TJ, et al. VACT-1 and VACT-2 (Protocols 106 and icylat; Salicilato de colina. (2-Hydroxyethyl)trimethylammonium
severe impairment (Child-Pugh category C or a score of 10 or 150) Study Groups. Efficacy of rofecoxib, celecoxib, and aceta- salicylate.
minophen in patients with osteoarthritis of the knee: a combined
more). analysis of the VACT studies. J Rheumatol 2005; 32: Холина Салицилат
1093–1105.
Familial adenomatous polyposis. Celecoxib is used in the C 12 H 19NO 4 = 241.3.
7. Singh G, et al. Celecoxib versus naproxen and diclofenac in os-
treatment of familial adenomatous polyposis, an inherited syn- teoarthritis patients: SUCCESS-I Study. Am J Med 2006; 119:
drome known to predispose sufferers to the development of co- 255–66.
C AS — 2016-36-6.
lonic cancer (see p.666). A randomised study1,2 found that treat- 8. Barkhuizen A, et al. Celecoxib is efficacious and well tolerated ATC — N02BA03.
ment with celecoxib reduced the number of colonic polyps; the in treating signs and symptoms of ankylosing spondylitis. J
authors considered celecoxib to be a useful adjunct to the stand- Rheumatol 2006; 33: 1805–12.
ATC Vet — QN02BA03.
ard therapy of colectomy. 9. Luyten FP, et al. A prospective randomised multicentre study
1. Steinbach G, et al. The effect of celecoxib, a cyclooxygenase-2 comparing continuous and intermittent treatment with celecoxib
inhibitor, in familial adenomatous polyposis. N Engl J Med in patients with osteoarthritis of the knee or hip. Ann Rheum Dis O
2000; 342: 1946–52. 2007; 66: 99–106.
H 3C CH3
2. Phillips RKS, et al. A randomised, double blind, placebo con- Palmar-plantar erythrodysesthesia syndrome. Celecoxib
trolled study of celecoxib, a selective cyclooxygenase 2 inhibi- N O
has been investigated in the treatment of capecitabine-induced HO CH3
tor, on duodenal polyposis in familial adenomatous polyposis.
Gut 2002; 50: 857–60.
hand-foot (palmar-plantar erythrodysesthesia) syndrome; for ref-
erences, see under Adverse Effects and Precautions of Capecit- HO
Malignant neoplasms. Celecoxib is under investigation as ad- abine, p.692.
juvant therapy in the treatment of cancer;1-9 preliminary results Pharmacopoeias. Br. includes a solution.
have been variable. It has also been investigated for chemopre- Preparations BP 2008 (Choline Salicylate Solution). An aqueous solution con-
vention of malignancy10-13 (see also Familial Adenomatous Proprietary Preparations (details are given in Part 3) taining 47.5 to 52.5% of choline salicylate. It is a clear colourless
Polyposis, above), but a large study for the prevention of colon Arg.: Algybrex; Celebrex; Celemax†; Cloxib†; Coxel†; Coxtenk; Niflam†; liquid. It may contain a suitable antimicrobial preservative.
cancer was terminated early because of increased cardiovascular Radicacine; Tisorek†; Austral.: Celebrex; Austria: Celebrex; Solexa; Belg.:
risk.11,12 Celebrex; Braz.: Celebra; Canad.: Celebrex; Chile: Celebra; Cz.: Cele- Profile
brex; Onsenal; Denm.: Celebra; Fin.: Celebra; Fr.: Celebrex; Onsenal; Choline salicylate is a salicylic acid derivative (see Aspirin, p.20)
1. Dang CT, et al. Phase II study of celecoxib and trastuzumab in Ger.: Celebrex; Gr.: Aclarex; Celebrex; Hong Kong: Celebrex; Hung.:
metastatic breast cancer patients who have progressed after pri- Celebrex; India: Celedol; Celib; Cobix; Orthocel; Ultracele†; Zycel; In- used in the treatment of pain and fever, and in the management
or trastuzumab-based treatments. Clin Cancer Res 2004; 10: don.: Celebrex; Irl.: Celebrex; Israel: Celcox; Celebra; Ital.: Artilog†; of rheumatic disorders. In terms of salicylate content, choline sal-
4062–7. Celebrex; Solexa†; Malaysia: Celebrex; Mex.: Celebrex; Neth.: Cele- icylate 435 mg is equivalent to about 325 mg of aspirin. Choline
2. Reardon DA, et al. Phase II trial of irinotecan plus celecoxib in brex; Onsenal; Solexa; Norw.: Celebra; Onsenal; NZ: Celebrex; Philipp.: salicylate is given orally in doses of 435 to 870 mg every four
adults with recurrent malignant glioma. Cancer 2005; 103: Celebrex; Flamar; Pol.: Celebrex; Port.: Celebrex; Onsenal; Solexa; Rus.: hours as necessary for pain and fever, and in doses of 4.8 to 7.2 g
329–38. Celebrex (Целебрекс); S.Afr.: Celebrex; Singapore: Celebrex; Spain:
Celebrex; Onsenal; Swed.: Celebra; Onsenal; Switz.: Celebrex; Thai.: daily in divided doses for rheumatic disorders.
3. Nugent FW, et al. Docetaxel and cyclooxygenase-2 inhibition
with celecoxib for advanced non-small cell lung cancer pro- Celebrex; UK: Celebrex; USA: Celebrex; Venez.: Celebrex†; Cexb.
Choline salicylate is also used as a local analgesic. Solutions con-
gressing after platinum-based chemotherapy: a multicenter taining up to about 20% choline salicylate are used in ear disor-
phase II trial. Lung Cancer 2005; 48: 267–73.
ders such as the relief of pain in otitis media and externa but are
4. Gasparini G, et al. The combination of the selective cyclooxy- considered to be of doubtful value; they are also used to soften
genase-2 inhibitor celecoxib with weekly paclitaxel is a safe and Choline Magnesium Trisalicylate ear wax as an aid to removal (see p.1725). An 8.7% gel is used
active second-line therapy for non-small cell lung cancer: a
phase II study with biological correlates. Cancer J 2005; 11: Trisalicilato de colina y magnesio. for lesions of the mouth (p.1700). Choline salicylate has also
209–16. been applied topically in a rubefacient preparation for the relief
5. Prince HM, et al. A multicenter phase II trial of thalidomide and
Холин Магнезиум Трисалицилаты of muscular and rheumatic pain.
celecoxib for patients with relapsed and refractory multiple my- C 26 H 29O 10 NMg = 539.8.
eloma. Clin Cancer Res 2005; 11: 5504–14. Choline salicylate is also given in the form of choline magnesi-
C AS — 64425-90-7. um trisalicylate (see above).
6. Pan CX, et al. A phase II trial of irinotecan, 5-fluorouracil and
leucovorin combined with celecoxib and glutamine as first-line
therapy for advanced colorectal cancer. Oncology 2005; 69: Adverse effects. A 21-month-old boy developed salicylate
63–70. poisoning after his mother had rubbed the contents of 3 tubes of
O O- O OH Mg2+
7. Ferrari V, et al. Gemcitabine plus celecoxib (GECO) in ad- CH3 OH Bonjela teething ointment (containing a total of 2.61 g of choline
vanced pancreatic cancer: a phase II trial. Cancer Chemother
OH H3C N+ OH
salicylate) on his gums over 48 hours.1
Pharmacol 2006; 57: 185–90.
8. Csiki I, et al. Targeting cyclooxygenase-2 in recurrent non- CH3 In another case, an 8-year-old boy with G6PD deficiency devel-
small cell lung cancer: a phase II trial of celecoxib and docetax- oped an oral mucosal burn a few hours after application of about
el. Clin Cancer Res 2005; 11: 6634–40. half a tube of Teejel oral gel.2 He developed mouth ulcers and
9. Chow LWC, et al. Serum lipid profiles in patients receiving en- displayed signs of apathy, lethargy, and nasal congestion 3 days
docrine treatment for breast cancer—the results from the Adverse Effects, Treatment, and Precautions after exposure. His condition improved after a week. The authors
Celecoxib Anti-Aromatase Neoadjuvant (CAAN) Trial. Biomed As for Aspirin, p.20. felt that G6PD deficiency may have been a contributing factor in
Pharmacother 2005; 59 (suppl 2): S302–S305.
The use of aspirin and other acetylated salicylates is generally the occurrence of adverse effects.
10. Limburg PJ, et al. Randomized, placebo-controlled, esophageal
squamous cell cancer chemoprevention trial of selenomethio- not recommended for children unless specifically indicated, be- 1. Paynter AS, Alexander FW. Salicylate intoxication caused by
nine and celecoxib. Gastroenterology 2005; 129: 863–73. cause of the risk of Reye’s syndrome. US licensing information teething ointment. Lancet 1979; ii: 1132.
11. Solomon SD, et al. Adenoma Prevention with Celecoxib (APC) extends this precaution to choline magnesium trisalicylate. 2. Sapir S, Bimstein E. Cholinsalicylate gel induced oral lesion: re-
Study Investigators. Cardiovascular risk associated with port of case. J Clin Pediatr Dent 2000; 24: 103–6.
celecoxib in a clinical trial for colorectal adenoma prevention. Effects on the liver. References.
N Engl J Med 2005; 352: 1071–80. 1. Cersosimo RJ, Matthews SJ. Hepatotoxicity associated with REYE’S SYNDROME. The link between aspirin use in children
12. Bertagnolli MM, et al. Celecoxib for the prevention of sporadic choline magnesium trisalicylate: case report and review of sali- and the development of Reye’s syndrome is established al-
colorectal adenomas. N Engl J Med 2006; 355: 873–84. cylate-induced hepatotoxicity. Drug Intell Clin Pharm 1987; 21: though the evidence for other salicylates could not be ade-
13. Arber N, et al. Celecoxib for the prevention of colorectal adeno- 621–5.
quately evaluated (see p.22). However, a 20-month-old boy
matous polyps. N Engl J Med 2006; 355: 885–95. 2. Nadkarni MM, et al. Eosinophilic hepatitis after ingestion of who had received a teething gel containing choline salicylate
choline magnesium trisalicylate. Am J Gastroenterol 1992; 87:
Musculoskeletal and joint disorders. Celecoxib is used in 151–3.
(applied in doses of 1.31 g daily, equivalent to acetylsali-
the treatment of osteoarthritis (p.11) and rheumatoid arthritis cylate 100 mg/kg daily, which exceeds the recommended
(p.11) including juvenile idiopathic arthritis (p.10). However, in Interactions dose) developed Reye’s syndrome following a viral illness.1
the UK it is recommended that the use of celecoxib and other For interactions associated with salicylates, see Aspirin, p.23. The authors noted that the MHRA in the UK were aware of
selective cyclo-oxygenase-2 (COX-2) inhibitors be limited to two earlier reports suggesting an association between choline
Uses and Administration salicylate and Reye’s syndrome.
those patients considered to be at high risk of developing serious
Choline magnesium trisalicylate is a combination of the salicylic
gastrointestinal problems if given a non-selective NSAID and 1. Oman TK, et al. Topical choline salicylates implicated in Reye’s
acid derivatives choline salicylate (p.36) and magnesium sali-
who do not have pre-existing cardiovascular risk factors (see Ad- syndrome. BMJ 2008; 336: 1376.
cylate (p.79). It has analgesic, anti-inflammatory, and antipyretic
verse Effects, above).
actions similar to those of aspirin (p.23). After oral administra- Preparations
Celecoxib is also used in the treatment of ankylosing spondylitis tion, choline magnesium trisalicylate dissociates and the sali-
(see Spondyloarthropathies, p.13). cylate moiety is rapidly absorbed. Each unit dose of 500 mg of BP 2008: Choline Salicylate Ear Drops; Choline Salicylate Oromucosal Gel.
salicylate is provided by about 293 mg of choline salicylate with
References. Proprietary Preparations (details are given in Part 3)
362 mg of magnesium salicylate (anhydrous). Choline magnesi-
1. Bensen WG, et al. Treatment of osteoarthritis with celecoxib, a um trisalicylate has been used in osteoarthritis, rheumatoid ar- Arg.: Dercolina; Austral.: Applicaine; Herron Baby Teething Gel; Ora-Sed
cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Jel; Belg.: Teejel; Ger.: Audax†; Hong Kong: Ora-Sed; India: Gelora;
thritis, and other arthritides in oral doses equivalent to 1 or 1.5 g Zytee; Irl.: Audax; Teejel; Israel: Teejel; NZ: Ora-Sed; Pol.: Cholinex; Oti-
Clin Proc 1999; 74: 1095–1105.
of salicylate twice daily; doses may also be given as a single dai- num; Port.: Bucagel; Rus.: Otinum (Отинум); Singapore: Ora-Sed; UK:
2. Simon LS, et al. Anti-inflammatory and upper gastrointestinal ly dose if required. A dose of 750 mg given three times daily may Audax†; Dinnefords Teejel†; USA: Arthropan†.
effects of celecoxib in rheumatoid arthritis: a randomized con- be more suitable for elderly patients. Choline magnesium trisali-
trolled trial. JAMA 1999; 282: 1921–28. Multi-ingredient: Arg.: Pansoral; Austral.: Bonjela; Seda-Gel; Austria:
cylate is also used in similar doses in the general management of Mundisal; Belg.: Givalex; Cz.: Mundisal; Fr.: Givalex; Pansoral; Ger.:
3. Emery P, et al. Celecoxib versus diclofenac in long-term man- other forms of pain and for fever.
agement of rheumatoid arthritis: randomised double-blind com- Givalex†; Mundisal†; Gr.: Mundisal; Hong Kong: Bonjela; Dermojela;
Hung.: Mundisal; Irl.: Bonjela; Israel: Baby Gum; Bonjela; Malaysia: Bon-
parison. Lancet 1999; 354: 2106–11. Preparations jela; Orregel; NZ: Bonjela; Pol.: Sachol zel Stomatologiczny; Rus.: Cholisal
4. Dougados M, et al. Efficacy of celecoxib, a cyclooxygenase 2- (Холисал); Pansoral (Пансорал); S.Afr.: Bonjela; Singapore: Bonjela; Sor-
specific inhibitor, in the treatment of ankylosing spondylitis: a Proprietary Preparations (details are given in Part 3) agel; Spain: Aldo Otico†; Switz.: Mundisal; Pansoral; Tenderdol; Thai.:
six-week controlled study with comparison against placebo and Canad.: Trilisate†; USA: Trilisate†. Bonjela; UK: Bonjela; Earex Plus.
against a conventional nonsteroidal antiinflammatory drug. Ar-
thritis Rheum 2001; 44: 180–5.
 Choline Magnesium Trisalicylate/Codeine 37
Clofexamide (rINN) Codeine (BAN) USP 31 (Codeine Phosphate). The hemihydrate occurs as fine,
white, needle-shaped crystals or white crystalline powder;
ANP-246; Clofexamida; Clofexamidum. 2-(4-Chlorophenoxy)- Codeína; Codéine; Codeinum; Codeinum Monohydricum; Ko- odourless. Soluble 1 in 2.5 of water, 1 in 0.5 of water at 80°, 1 in
N-(2-diethylaminoethyl)acetamide. deiini; Kodein; Kodein monohydrát; Kodeina; Kodeinas; Methyl- 325 of alcohol, and 1 in 125 of boiling alcohol. Its solutions are
Клофексамид morphine; Metilmorfina; Morphine Methyl Ether. 7,8-Didehydro- acid to litmus. Store in airtight containers at a temperature up to
4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol monohydrate. 40° as permitted by the manufacturer. Protect from light.
C 14 H 21ClN 2 O 2 = 284.8.
C AS — 1223-36-5. Кодеин Incompatibility. Acetylation of codeine phosphate by aspirin
C 18 H 21 NO 3 ,H 2 O = 317.4. has occurred in solid dosage forms containing the two drugs,
C AS — 76-57-3 (anhydrous codeine); 6059-47-8 (codeine even at a low moisture level.1 Animal work suggested that the
analgesic activity of codeine was not affected by acetylation.2
H 3C monohydrate).
O 1. Galante RN, et al. Solid-state acetylation of codeine phosphate
ATC — R05DA04. by aspirin. J Pharm Sci 1979; 68: 1494–8.
N O ATC Vet — QR05DA04. 2. Buckett WR, et al. The analgesic properties of some 14-substi-
N tuted derivatives of codeine and codeinone. J Pharm Pharmacol
H 1964; 16: 174–82.
CH3 H3CO
Cl Codeine Sulfate
Codeína, sulfato de; Codeine Sulphate (BANM).
Profile
Clofexamide has been used topically as the hydrochloride in Кодеина Сульфат
O H
preparations for musculoskeletal, joint, and soft-tissue disorders. (C 18 H 21 NO 3 ) 2 ,H 2 SO 4 ,3H 2 O = 750.9.
NCH3 C AS — 1420-53-7 (anhydrous codeine sulfate); 6854-40-
6 (codeine sulfate trihydrate).
HO Pharmacopoeias. In US.
Clofezone (rINN) USP 31 (Codeine Sulfate). White crystals, usually needle-like,
ANP-3260; Clofezona; Clofézone; Clofezonum. An equimolar or white crystalline powder. Soluble 1 in 30 of water, 1 in 6.5 of
NOTE. The following terms have been used as ‘street names’ (see
p.vi) or slang names for various forms of codeine: water at 80°, and 1 in 1300 of alcohol; insoluble in chloroform
combination of clofexamide and phenylbutazone.
AC/DC; Barr; Captain Cody; Cody; Coties; Cough Syrup; and in ether. Store in airtight containers. Protect from light.
Клофезон Down; Karo; Lean; Nods; School boy; Schoolboy; T3. Stability. Codeine sulfate solutions appear to be intrinsically
C 14 H 21ClN 2 O 2 ,C 19 H 20N 2 O 2 ,2H 2 O = 629.2. Pharmacopoeias. In Eur. (see p.vii), Int., US, and Viet. more stable than codeine phosphate solutions.1
C AS — 60104-29-2. Ph. Eur. 6.2 (Codeine). White or almost white, crystalline pow- 1. Powell MF. Enhanced stability of codeine sulfate: effect of pH,
ATC — M01AA05; M02AA03. der or colourless crystals. Soluble in boiling water; freely soluble buffer, and temperature on the degradation of codeine in aqueous
in alcohol. Protect from light. solution. J Pharm Sci 1986; 75: 901–3.
ATC Vet — QM01AA05; QM02AA03.
USP 31 (Codeine). Colourless or white crystals or white crys-
Profile talline powder. It effloresces slowly in dry air. Soluble 1 in 120 Dependence and Withdrawal
Clofezone, a combination molecule containing clofexamide of water, 1 in 2 of alcohol, 1 in 0.5 of chloroform, and 1 in 50 of As for Opioid Analgesics, p.101.
(above) and phenylbutazone (p.117), has been given orally and ether. Its saturated solution in water is alkaline to litmus. Store in
by rectal suppository and applied topically in preparations for airtight containers. Protect from light. Codeine is subject to abuse (see under Precautions, be-
musculoskeletal, joint, and soft-tissue disorders. low), but produces less euphoria and sedation than
Codeine Hydrochloride (BANM) morphine.
Codeína, hidrocloruro de; Codéine (chlorhydrate de) dihydraté; Neonatal abstinence syndrome. Some of the symptoms
Clonixin (USAN, rINN) Codeini hydrochloridum dihydricum; Kodeiinihydroklorididihy- characteristic of the neonatal abstinence syndrome were seen in
draatti; Kodein-hidroklorid-dihidrát; Kodein-hydrochlorid dihy- a neonate whose mother had taken about 90 mg of codeine daily
CBA-93626; Clonixine; Clonixino; Clonixinum; Sch-10304. 2-(3- drát; Kodeinhydrokloriddihydrat; Kodeino hidrochloridas dihidratas. during the last 2 months of pregnancy.1
Chloro-o-toluidino)nicotinic acid. 1. Khan K, Chang J. Neonatal abstinence syndrome due to codeine.
Кодеина Гидрохлорид Arch Dis Child 1997; 76: F59–F60.
Клониксин C 18 H 21 NO 3 ,HCl,2H 2 O = 371.9.
C 13 H 11ClN 2 O 2 = 262.7. C AS — 1422-07-7 (anhydrous codeine hydrochloride). Adverse Effects and Treatment
C AS — 17737-65-4. Pharmacopoeias. In Eur. (see p.vii). As for Opioid Analgesics in general, p.102.
Ph. Eur. 6.2 (Codeine Hydrochloride Dihydrate; Codeine Hydro-
chloride BP 2008). Small colourless crystals or a white or almost In therapeutic doses codeine is much less liable than
CH3 white, crystalline powder. Soluble in water; slightly soluble in al- morphine to produce adverse effects, although consti-
H cohol; practically insoluble in cyclohexane. Protect from light.
N N Cl pation may be troublesome with long-term use. After
large doses of codeine, excitement and convulsions
Codeine Phosphate (BANM) may occur.
COOH Codeína, fosfato de; Codéine, phosphate de; Codeine Phos- Codeine, like morphine, has a dose-related histamine-
phate Hemihydrate; Codeini phosphas; Codeini Phosphas Hemi-
hydricus; Codeinii Phosphas; Kodeiinifosfaatti; Kodein-fosfát
releasing effect. Anaphylactic reactions after intrave-
hemihydrát; Kodeinfosfathemi; Kodein-foszfát-hemihidrát; Kodei- nous use have been reported rarely.
Clonixin Lysine (rINNM)
no fosfatas hemihidratas; Kodeiny fosforan; Kodeiny fosforan Effects on mental function. Central effects of codeine phos-
Clonixin Lysinate; Clonixine Lysine; Clonixino lisina; Clonixinum półwodny; Methylmorphine Phosphate. phate appeared to be limited, but dose-related, in subjects given
Lysinum; L-104; Lysine Clonixinate; R-173. 30, 60, or 90 mg; visuo-motor coordination was altered with dos-
Кодеина Фосфат
Клониксина Лизин C 18 H 21 NO 3 ,H 3 PO 4 , ⁄ H 2 O = 406.4. es of 60 and 90 mg and dynamic visual acuity with 90 mg.1
Drowsiness reported by subjects given 90 mg of codeine phos-
C 13 H 11ClN 2 O 2 , C 6 H 14 N 2 O 2 = 408.9. C AS — 52-28-8 (anhydrous codeine phosphate); 41444-
62-6 (codeine phosphate hemihydrate); 5913-76-8 (co- phate could not be linked with impaired performance whereas
C AS — 55837-30-4. nausea could.
deine phosphate sesquihydrate).
Profile 1. Bradley CM, Nicholson AN. Effects of a μ-opioid receptor ago-
NOTE. Compounded preparations of codeine phosphate may be nist (codeine phosphate) on visuo-motor coordination and dy-
Clonixin is an NSAID (p.96). It has been used as the lysine salt represented by the following names: namic visual acuity in man. Br J Clin Pharmacol 1986; 22:
in oral doses of up to 250 mg four times daily for the relief of 507–12.
pain. Clonixin lysine has also been given by intramuscular or in- • Co-codamol x/y (BAN)—where x and y are the strengths in
travenous injection and as a rectal suppository. milligrams of codeine phosphate and paracetamol respective- Effects on the pancreas. A 26-year-old woman developed
ly acute pancreatitis on 2 separate occasions a few hours after tak-
◊ References. ing a single, 40-mg dose of codeine.1 There was no history of
• Co-codAPAP (PEN)—codeine phosphate and paracetamol
1. Eberhardt R, et al. Analgesic efficacy and tolerability of lysine- alcohol consumption and her recovery was uneventful. Other
clonixinate versus ibuprofen in patients with gonarthrosis. Curr • Co-codaprin (BAN)—codeine phosphate 1 part and aspirin 50 cases have been reported.2-5
Ther Res 1995; 56: 573–80. parts (w/w) 1. Hastier P, et al. Pancreatitis induced by codeine: a case report
Preparations • Co-codaprin (PEN)—codeine phosphate and aspirin. with positive rechallenge. Gut 1997; 41: 705–6.
2. Locher C, et al. Pancréatite aiguë après la prise d’une association
Proprietary Preparations (details are given in Part 3) Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and paracétamol-codéine. Gastroenterol Clin Biol 2003; 27: 124–5.
Arg.: Clonixil; Diclen; Dolex; Dolnot†; Dorixina; Braz.: Dolamin; Chile: Viet. 3. Kohlen K, et al. Codein-induzierte Pankreatitis. Dtsch Med Wo-
Blonax; Celex; Clonalgin; Colmax; Dentagesic; Diminon; Dolalgial†; Lafige- Pharmacopoeias may specify the hemihydrate, sesquihydrate, or chenschr 2005; 130: 878–9.
sic; Medigesic; Nefersil; Traumicid; Mex.: Disinal; Donodol; Dorixina; Firac; both, either under one monograph or as separate monographs. 4. Moreno Escobosa MC, et al. Pancreatitis due to codeine. Aller-
Lonixer; Prestodol; Sedepron; Port.: Algimate; Clonix; Spain: Dolalgial; Ph. Eur. 6.2 (Codeine Phosphate Hemihydrate; Codeine Phos- gol Immunopathol (Madr) 2005; 33: 175–7.
Venez.: Dorixina. 5. Belhassen García M, et al. Pancreatitis secundaria a paraceta-
phate BP 2008). A white or almost white, crystalline powder or
Multi-ingredient: Arg.: Amplibenzatin Bronquial; Aseptobron Ampicili- small, colourless crystals. Freely soluble in water; slightly solu- mol-codeína. An Med Interna 2006; 23: 400–401.
na†; Dorixina B1 B6 B12; Dorixina Forte; Dorixina Relax; Espasmo Dolex; ble or very slightly soluble in alcohol. A 4% solution in water has
Migra Dorixina; Mikesan; Nova Paratropina Compositum; Propalgin; Sertal Effects on the skin. Pruritus and burning erythemato-vesicular
Compuesto; Braz.: Dolamin Flex; Chile: Clonalgin Compuesto; Ergonef; a pH of 4.0 to 5.0. Protect from light. plaques that developed in a patient in response to oral codeine
Migra-Nefersil; Nefersil B; Neurocam; Mex.: Donodol Compuesto; Espacil Ph. Eur. 6.2 (Codeine Phosphate Sesquihydrate; Codeini Phos- were attributed to a fixed drug eruption.1 A similar reaction oc-
Compuesto; Firac Plus; Klonaza; Optium; Plidan Compuesto; Prestodol phas Sesquihydricus). A white or almost white, crystalline pow- curred in another patient after taking various analgesics includ-
Compuesto; Yuredol; Venez.: Dologinex; Dorixina Flex; Migradorixina; Pli- der or small, colourless crystals. Freely soluble in water; slightly ing a combined preparation of paracetamol and codeine;2 patch
dan Compuesto.
soluble in alcohol. A 4% solution in water has a pH of 4.0 to 5.0. testing showed a positive response for codeine only. Maculopa-
Protect from light. pular rash has been seen as part of a hypersensitivity syndrome
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
38 Analgesics Anti-inflammatory Drugs and Antipyretics
associated with oral codeine phosphate;3 fever, splenomegaly, Children. See Overdosage, above, and under Uses and Admin- with detectable plasma morphine concentrations.5 A study6 in-
and lymphadenopathy also occurred. istration, below. volving infants aged 6 to 10 months has indicated that children
1. Gonzalo-Garijo MA, Revenga-Arranz F. Fixed drug eruption Driving. Codeine phosphate 50 mg alone and with alcohol had were capable of demethylating codeine to morphine at the age of
due to codeine. Br J Dermatol 1996; 135: 498–9. 6 months although glucuronidation of the morphine appeared to
2. Gastaminza G, et al. Erythrodermia caused by allergy to codeine. a deleterious effect on driving skills in a simulated driving test.1
be impaired when compared with older children.
Contact Dermatitis 2005; 52: 227–8. 1. Linnoila M, Häkkinen S. Effects of diazepam and codeine, alone
3. Enomoto M, et al. Codeine phosphate-induced hypersensitivity and in combination with alcohol, on simulated driving. Clin For a report of severe toxicity thought to be due to altered metab-
syndrome. Ann Pharmacother 2004; 38: 799–802. Pharmacol Ther 1974; 15: 368–73. olism of codeine see Genetic Polymorphism, above.
Hypersensitivity. See Effects on the Skin, above. Genetic polymorphism. Life-threatening toxicity in a patient 1. Desmeules J, et al. Impact of environmental and genetic factors
given moderate doses of codeine was thought to be due to a gen- on codeine analgesia. Eur J Clin Pharmacol 1991; 41: 23–6.
Overdosage. Acute codeine intoxication in 430 children, due otype predisposing him to ultrarapid metabolism of the drug into 2. Chen ZR, et al. Disposition and metabolism of codeine after sin-
to accidental ingestion of antitussive preparations, was re- gle and chronic doses in one poor and seven extensive metabo-
morphine by the cytochrome P450 isoenzyme CYP2D6, cou- lisers. Br J Clin Pharmacol 1991; 31: 381–90.
viewed.1 The children were nearly all between 1 and 6 years old. pled with drug-induced inhibition of the usual major metabolic 3. Sindrup SH, et al. Codeine increases pain thresholds to copper
Symptoms in decreasing order of frequency included somno- pathway mediated by CYP3A4, and transient reduction in renal vapor laser stimuli in extensive but not poor metabolizers of
lence, rash, miosis, vomiting, itching, ataxia, and swelling of the function.1 For a report of the effect of this genotype in a breast- sparteine. Clin Pharmacol Ther 1991; 49: 686–93.
skin. Respiratory failure occurred in 8 children and 2 died; all 8 feeding mother, see Breast Feeding, above. 4. Williams DG, et al. Pharmacogenetics of codeine metabolism in
had taken 5 mg/kg or more. Infants are at special risk and there 1. Gasche Y, et al. Codeine intoxication associated with ultrarapid
an urban population of children and its implications for analgesic
have been fatalities2,3 and severe adverse effects4,5 after inappro- CYP2D6 metabolism. N Engl J Med 2004; 351: 2827–31. Cor-
reliability. Br J Anaesth 2002; 89: 839–45.
priate treatment in infants given mixtures containing codeine. rection. ibid. 2005; 352: 638. 5. Quiding H, et al. Analgesic effect and plasma concentrations of
codeine and morphine after two dose levels of codeine following
Opioid toxicity, in addition to severe salicylate toxicity, has oc- Pregnancy. See Neonatal Abstinence Syndrome under De- oral surgery. Eur J Clin Pharmacol 1993; 44: 319–23.
curred in adults after overdoses of aspirin and codeine tablets.6 pendence and Withdrawal, above. 6. Quiding H, et al. Infants and young children metabolise codeine
1. von Mühlendahl KE, et al. Codeine intoxication in childhood. to morphine: a study after single and repeated rectal administra-
Lancet 1976; ii: 303–5. Renal impairment. The renal clearance of codeine and its tion. Br J Clin Pharmacol 1992; 33: 45–9.
2. Ivey HH, Kattwinkel J. Danger of Actifed-C. Pediatrics 1976; metabolites is significantly reduced in patients with end-stage re-
57: 164–5. nal disease on regular haemodialysis therapy. One such elderly
3. Magnani B, Evans R. Codeine intoxication in the neonate. Ab- Uses and Administration
patient developed tonic-clonic seizures 7 days after starting oral
stract: Pediatrics 1999; 104: 1379. Full version:
codeine phosphate 30 mg 4 times daily; no further seizures oc- Codeine, a phenanthrene derivative, is an opioid
http://pediatrics.aappublications.org/cgi/content/full/104/6/e75 analgesic (p.104) obtained from opium or made by
(accessed 26/06/08) curred after codeine was stopped and naloxone started.1 The dos-
4. Wilkes TCR, et al. Apnoea in a 3-month-old baby prescribed age of codeine should be reduced according to renal function in methylating morphine. It is much less potent as an
compound linctus containing codeine. Lancet 1981; i: 1166–7. patients with renal impairment but no specific recommendations analgesic than morphine and has relatively mild seda-
5. Lee AC, et al. A case of probable codeine poisoning in a young appear to be given in the literature.
infant after the use of a proprietary cough and cold medicine. tive effects.
1. Kuo S-C, et al. Probable codeine phosphate-induced seizures.
Hong Kong Med J 2004; 10: 285–7. Ann Pharmacother 2004; 38: 1848–51. Codeine or its salts, especially the phosphate, are given
6. Leslie PJ, et al. Opiate toxicity after self poisoning with aspirin
and codeine. BMJ 1986; 292: 96. orally in the form of linctuses for the relief of cough,
Interactions and as tablets for the relief of mild to moderate pain,
Precautions For interactions associated with opioid analgesics, see often with a non-opioid analgesic such as aspirin, ibu-
As for Opioid Analgesics in general, p.103. p.103. profen, or paracetamol. The phosphate is also given by
Abuse. Although the risk of dependence on codeine is low with Quinidine. For reference to a suggestion that quinidine can in- intramuscular or subcutaneous injection, in doses sim-
normal use,1 it is the subject of deliberate abuse. In France2 and hibit the analgesic effect of codeine, see Metabolism under Phar- ilar to those used orally, for the relief of pain; the intra-
in the UK linctuses containing codeine have been particularly li- macokinetics, below. venous and rectal routes have also been used.
able to abuse. Reports in the literature include the use in New
Zealand of codeine-containing preparations to produce demeth- Pharmacokinetics For the relief of pain codeine phosphate may be given
ylated products known as "Homebake" containing variable Codeine and its salts are absorbed from the gastrointes- in doses of 30 to 60 mg every 4 hours to a usual maxi-
amounts of morphine3 and abuse of co-codaprin tablets for their mum of 240 mg daily.
codeine content.4-6
tinal tract. Rectal absorption of codeine phosphate has
1. Rowden AM, Lopez JR. Codeine addiction. DICP Ann Pharma- been reported. Ingestion of codeine phosphate produc- To allay non-productive cough codeine phosphate may
cother 1989; 23: 475–7. es peak plasma-codeine concentrations in about one be given in doses of 15 to 30 mg three or four times
2. Armand C, et al 10 ans de détournement d’usage du Néocodion hour. Codeine is metabolised by O- and N-demethyla- daily.
entre 1992 et 2002: Neocodion misuse: evolution between 1992
and 2002. Therapie 2004; 59: 547–53. tion in the liver to morphine, norcodeine, and other Codeine phosphate is also used as tablets or in mixtures
3. Shaw JP. Drug misuse in New Zealand. Pharm J 1987; 238: 607. metabolites including normorphine and hydrocodone. for the symptomatic relief of acute diarrhoea in doses
4. Sakol MS, Stark CR. Codeine abuse. Lancet 1989; ii: 1282.
5. Paterson JR, et al. Codeine abuse from co-codaprin. Lancet Metabolism to morphine is mediated by the cyto- of 15 to 60 mg given 3 or 4 times daily.
1990; 335: 224. chrome P450 isoenzyme CYP2D6, which shows ge- For details of doses in children, see below.
6. Sakol MS, Stark CR. Codeine abuse from co-codaprin. Lancet
netic polymorphism. Codeine and its metabolites are
1990; 335: 224. Other codeine salts used include the hydrochloride,
excreted almost entirely by the kidney, mainly as con-
Breast feeding. Breast-fed infants of mothers taking codeine sulfate, camsilate, and hydrobromide. Codeine
may be at an increased risk of toxicity from its metabolite, jugates with glucuronic acid.
polistirex (a codeine and sulfonated diethenylbenzene-
morphine, if the mother is an ultrarapid metaboliser of codeine. The plasma half-life has been reported to be between 3 ethenylbenzene copolymer complex) is used in modi-
In a recent report,1 a 13-day-old infant died from opioid toxicity and 4 hours after an oral or intramuscular dose.
after being exposed to morphine in his mother’s breast milk; the fied-release preparations.
mother had been taking oral codeine 30 mg twice daily as part Codeine crosses the placenta and is distributed into
Administration in children. Licensed product information
of a combination preparation with paracetamol for about 2 breast milk. for codeine in the treatment of pain often restricts its use to those
weeks. Assayed morphine concentrations in the breast milk ◊ References. over 1 year of age, but some authorities consider codeine to be an
were found to be 87 nanograms/mL; the usual range is 1.9 to 1. Guay DR, et al. Pharmacokinetics of codeine after single- and effective analgesic in neonates and children.1 In the UK, the
20.5 nanograms/mL after repeated doses of codeine 60 mg four multiple-oral-dose administration to normal volunteers. J Clin BNFC suggests that neonates and children aged up to 12 years
times daily. Subsequent investigations found that the mother’s Pharmacol 1987; 27: 983–7. may be given codeine phosphate 0.5 to 1 mg/kg every 4 to 6
genotype for the cytochrome P450 isoenzyme CYP2D6 (the en- 2. Persson K, et al. The postoperative pharmacokinetics of codeine. hours for mild to moderate pain up to the usual adult maximum
zyme involved in the conversion of codeine to morphine) classi- Eur J Clin Pharmacol 1992; 42: 663–6.
3. Lafolie P, et al. Urine and plasma pharmacokinetics of codeine
dose of 240 mg daily; these doses can be given orally, rectally, or
fied her as an ultrarapid metaboliser of codeine. by the subcutaneous or intramuscular routes. Guidelines2 for
in healthy volunteers: implications for drugs-of-abuse testing. J
Based on this case, the FDA has advised2 that nursing mothers Anal Toxicol 1996; 20: 541–6. analgesia in children in Accident and Emergency departments in
taking codeine should be informed of the potential risk of mor- 4. Kim I, et al. Plasma and oral fluid pharmacokinetics and phar- the UK recommend the use of oral codeine as an alternative, or
phine overdose and the need to monitor breast-fed infants for macodynamics after oral codeine administration. Clin Chem in addition, to diclofenac, for moderate pain such as that associ-
signs of toxicity such as increased sleepiness, difficulty feeding 2002; 48: 1486–96. ated with small burns or scalds, finger tip injuries, or appendici-
or breathing, or limpness. Nursing mothers, themselves, may Administration. In a comparative study1 codeine had an tis. With a single dose of codeine phosphate 1 mg/kg given orally
also experience overdose symptoms including extreme sleepi- oral/intramuscular analgesic relative potency ratio of 6:10. This or by intramuscular injection there was a relatively small risk of
ness, confusion, shallow breathing, and severe constipation. was high compared with that of morphine and was attributed to respiratory depression in neonates, but significant respiratory de-
Similar advice has also been issued by the MHRA in the UK.3 protection from rapid first-pass metabolism rather than more ef- pression has occurred with multiple doses and patients should be
Nonetheless, codeine appears to have been used safely for many ficient absorption after oral doses. In a comparative study in observed closely.1 Case reports of adverse reactions such as va-
years in breast-feeding mothers and several authorities including children2 the absorption rate of codeine from a suppository was sodilatation, severe hypotension, and apnoea in infants and chil-
the American Academy of Pediatrics4 and the BNF consider that found to be similar to that from an intramuscular injection; how- dren after intravenous doses of codeine have precluded its use by
it is usually compatible with breast feeding. ever, peak plasma concentrations were not as high when given this route in children of all ages.3
1. Koren G, et al. Pharmacogenetics of morphine poisoning in a rectally. Antimotility drugs such as codeine should not be used in infants
breastfed neonate of a codeine-prescribed mother. Lancet 2006; 1. Beaver WT, et al. Analgesic studies of codeine and oxycodone and young children with acute diarrhoea.4,5
368: 704. in patients with cancer I: comparisons of oral with intramuscular
2. FDA. Information for healthcare professional: use of codeine codeine and of oral with intramuscular oxycodone. J Pharmacol The BNFC advises that cough suppressants containing pholcod-
products in nursing mothers (issued 17th August, 2007). Availa- Exp Ther 1978; 207: 92–100. ine or similar opioids (such as codeine) are generally not recom-
ble at: http://www.fda.gov/cder/drug/InfoSheets/HCP/ 2. McEwan A, et al. A comparison of rectal and intramuscular co- mended for children and should be avoided in those under 2
codeineHCP.htm (accessed 26/06/08) deine phosphate in children following neurosurgery. Paediatr years of age. However, codeine phosphate is licensed to allay
3. MHRA/CHM. Codeine: very rare risk of side-effects in breastfed Anaesth 2000; 10: 189–93.
babies. Drug Safety Update 2007; 1 (4): 3. Available at: http:// non-productive cough and children aged 1 to 5 years may be giv-
w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ Metabolism. The analgesic effect of codeine may be partly due en 3 mg three or four times daily; and those aged 5 to 12 years,
FILE&dDocName=CON2032917&RevisionSelectionMethod= to its metabolite morphine and it has been suggested that its effi- 7.5 to 15 mg three or four times daily.
LatestReleased (accessed 26/06/08) cacy may be impaired in patients who are poor metabolisers of Children and adolescents aged 12 years and over may be given
4. American Academy of Pediatrics. The transfer of drugs and oth- codeine1-4 or in those who are also receiving drugs, such as qui-
er chemicals into human milk. Pediatrics 2001; 108: 776–89.
the usual adult doses of codeine phosphate for all these indica-
Correction. ibid.; 1029. Also available at: nidine, that impair its metabolism.1 However, patients unable to tions (see above).
http://aappolicy.aappublications .org/cgi/ content/full/ demethylate codeine to produce detectable plasma concentra- 1. Lloyd-Thomas AR. Pain management in paediatric patients. Br
pediatrics%3b108/3/776 (accessed 26/06/08) tions of morphine obtained a similar analgesic effect to patients J Anaesth 1990; 64: 85–104.
 Codeine/Dextromoramide 39
2. British Association for Emergency Medicine. Clinical Effective- 2. Mayrhofer F. Efficacy and long-term safety of dexibuprofen
ness Committee guideline for the management of pain in chil- [S(+)-ibuprofen]: a short-term efficacy study in patients with os-
dren (2004). Available at: http://www.emergencymed.org.uk/ HO teoarthritis of the hip and a 1-year tolerability study in patients
BAEM/CEC/assets/cec_pain_in_children.pdf (accessed with rheumatic disorders. Clin Rheumatol 2001; 20 (suppl 1):
26/06/08) S22–S29.
3. Marsh DF, et al. Opioid systems and the newborn. Br J Anaesth HO 3. Hawel R, et al. Comparison of the efficacy and tolerability of
1997; 79: 787–95. O dexibuprofen and celecoxib in the treatment of osteoarthritis of
4. Anonymous. Drugs in the management of acute diarrhoea in in- the hip. Int J Clin Pharmacol Ther 2003; 41: 153–64.
fants and young children. Bull WHO 1989; 67: 94–6. Administration in children. Although dexibuprofen is not li-
5. Cimolai N, Carter JE. Antimotility agents for paediatric use. HO O CH3 O censed for use in children under 18 years of age in the UK, some
Lancet 1990; 336: 874. H H
HO O countries permit such use. For example, in Switzerland, dexibu-
Administration in renal impairment. See under Precau- O profen has been given to children aged 6 years and over; usual
tions, above. oral doses are 10 to 15 mg/kg daily in 2 to 4 divided doses. Li-
censed product information for one preparation recommends a
Cough. A systematic review1 of over-the-counter preparations maximum dose of 300 mg daily for those weighing less than
for acute cough concluded that codeine appeared no more effec- OH OH
30 kg.
tive than placebo in reducing cough symptoms in adults or chil-
dren, although the number of patients in the studies considered (harpagoside) Administration in hepatic and renal impairment. UK li-
was small. censed product information specifies that the initial dose of dex-
See also Administration in Children, above. ibuprofen should be reduced in patients with mild to moderate
Pharmacopoeias. In Eur. (see p.vii), which also includes the hepatic or renal impairment; it should not be used in those with
1. Smith SM, et al. Over-the-counter medications for acute cough dry extract. severe impairment.
in children and adults in ambulatory settings. Available in The Ph. Eur. 6.2 (Devil’s Claw Root; Devil’s Claw BP 2008). The cut
Cochrane Database of Systematic Reviews; Issue 1. Chichester: and dried tuberous, secondary roots of Harpagophytum pro- Pharmacokinetics. For mention of the metabolism of dexibu-
John Wiley; 2008 (accessed 26/06/08). profen, see p.65.
cumbens and/or H. zeyheri. Greyish-brown to dark brown with
1,2 a bitter taste. Contains not less than 1.2% harpagoside Further references.
Pain. Systematic reviews comparing paracetamol-codeine
combinations versus paracetamol alone concluded that in single- (C24H30O11 = 494.5), calculated with reference to the dried drug. 1. Eller N, et al. Pharmacokinetics of dexibuprofen administered as
dose studies addition of codeine to paracetamol produced a com- Protect from light. 200 mg and 400 mg film-coated tablets in healthy volunteers. Int
paratively small but statistically significant increase in analgesic J Clin Pharmacol Ther 1998; 36: 414–17.
Profile
effect; however, there was an increased incidence of adverse ef- Devil’s claw root is used in herbal remedies for musculoskeletal Preparations
fects with the combination. and joint disorders. Its activity is attributed in part to the plant’s Proprietary Preparations (details are given in Part 3)
1. de Craen AJM, et al. Analgesic efficacy and safety of paraceta- content of iridoid glycosides, notably harpagoside. Arg.: Dextropirac†; Dolomin†; Austria: Actifen; Eu-Med Neu; Monactil;
mol-codeine combinations versus paracetamol alone: a system- Movone; Seractil; Chile: Dexelle; Cz.: Seractil; Denm.: Seractiv; Fin.: Dex-
atic review. BMJ 1996; 313: 321–5. Pain. Preparations containing devil’s claw root have been tried it; Ger.: Deltaran; Gr.: Seractil; Hung.: Seractil; India: Sibet; Ital.: Seractil;
2. Moore A, et al. Single dose paracetamol (acetaminophen), with with some success in the treatment of musculoskeletal disorders Neth.: Seractil; Norw.: Seractiv; Pol.: Dexprofen; Seractil; Port.: Seractil;
and without codeine, for postoperative pain. Available in The such as low back pain and osteoarthritis. There is some evidence Spain: Atriscal; Seractil; Swed.: Tradil; Switz.: DexOptifen; Seractil; UK:
Cochrane Database of Systematic Reviews; Issue 4. Chichester: of efficacy for daily doses standardised to 50 to 100 mg harpago- Seractil.
John Wiley; 1998 (accessed 26/06/08). side but the quality of reporting in trials is generally poor and
Preparations further studies are needed to establish its place in therapy.1,2
BP 2008: Co-codamol Capsules; Co-codamol Tablets; Co-codaprin Tab-
1. Gagnier JJ, et al. Harpgophytum [sic] procumbens for osteoar- Dextromoramide (BAN, pINN) ⊗
thritis and low back pain: a systematic review. BMC Complement
lets; Codeine Linctus; Codeine Phosphate Injection; Codeine Phosphate Altern Med 2004; 4: 13. Dekstromoramidi; Dextrodiphenopyrine; Dextromoramid;
Oral Solution; Codeine Phosphate Tablets; Dispersible Co-codaprin Tab- 2. Gagnier JJ, et al. Herbal medicine for low back pain. Available Dextromoramida; Dextromoramidum; d-Moramid; Pyrrolami-
lets; Effervescent Co-codamol Tablets; Paediatric Codeine Linctus; in The Cochrane Database of Systematic Reviews; Issue 2.
USP 31: Acetaminophen and Codeine Phosphate Capsules; Acetami- dol. (+)-1-(3-Methyl-4-morpholino-2,2-diphenylbutyryl)pyrroli-
Chichester: John Wiley; 2006 (accessed 05/10/06).
nophen and Codeine Phosphate Oral Solution; Acetaminophen and Co- dine.
deine Phosphate Oral Suspension; Acetaminophen and Codeine Phos- Preparations
p h a t e Ta bl e t s ; A s p i r i n a n d C o d e i n e P h o s p h a t e Ta bl e t s ; Декстроморамид
Bromodiphenhydramine Hydrochloride and Codeine Phosphate Oral So- Proprietary Preparations (details are given in Part 3)
Arg.: Herbaccion Flex†; Braz.: Tenitrat; Fr.: Elusanes Harpagesic; Harpadol; C 25 H 32 N 2 O 2 = 392.5.
lution; Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules; Cari- C AS — 357-56-2.
soprodol, Aspirin, and Codeine Phosphate Tablets; Codeine Phosphate In- Harpagocid; Ger.: Ajuta; Allya; Arthrosetten H; Arthrotabs; Bomarthros;
jection; Codeine Phosphate Tablets; Codeine Sulfate Tablets; Guaifenesin Cefatec; Dolo-Arthrodynat†; Dolo-Arthrosetten H; Doloteffin; flexi-loges; ATC — N02AC01.
and Codeine Phosphate Syrup; Terpin Hydrate and Codeine Elixir. Harpagoforte; HarpagoMega†; Harpagosan†; Herbadon†; Jucurba; Matai†; ATC Vet — QN02AC01.
Pargo†; Rheuferm Phyto; Rheuma-Sern; Rivoltan; Sogoon; Teltonal; Teufel-
Proprietary Preparations (details are given in Part 3) skralle; Pol.: Reumaphyt; Spain: Fitokey Harpagophytum; Harpagofito Or-
Austral.: Actacode; Austria: Codipertussin; Codipront Mono; Coditard; to; UK: Atrosan; Flexiherb.
Makatussin-Hustentropfen; Tricodein; Belg.: Bromophar; Bronchodine; Multi-ingredient: Austral.: Arthriforte; Arthritic Pain Herbal Formula 1; O
Bronchosedal; Eulyptan†; Gloceda†; Glottyl; Toularynx; Canad.: Codeine Bioglan Arthri Plus; Boswellia Compound; Devils Claw Plus; Extralife Arthri- N
Contin; Fr.: Codedrill; Codenfan; Neo-Codion; Paderyl; Ger.: Antitussivum Care; Guaiacum Complex†; Herbal Arthritis Formula†; Lifesystem Herbal
Burger; Bronchicum Mono Codein; codi OPT; Codicaps mono; Codicaps Formula 1 Arthritic Aid†; Prost-1†; Belg.: Algi-Cool; Cz.: Antirevmaticky
N†; Codicaps Neo; Codicompren; Codipertussin; Codipront Mono†; Caj; Fr.: Arkophytum†; Ger.: Dr Wiemanns Rheumatonikum; Ital.: Body-
Makatussin Codein; Melrosum Codein Hustensirup†; Neo-Codion NN†; guard; Cartago; Flodolor; Nevril; Pik Gel; Reumafort; Malaysia: Celery N
Optipect Kodein; Tryasol; Tussoret; Gr.: Codipront N†; Hong Kong: Plus†; Mex.: Rodan; Pol.: Reumaherb; Spain: Dolosul†; Natusor Harpa-
Codipront N†; India: Codifos; Irl.: Codant; Codinex; Israel: Codical; Re- gosinol†. CH3 O
kod; Malaysia: Setlinctus†; Neth.: Bronchicum Extra Sterk; Port.: Toseina;
Rus.: Neo-Codion (Нео-Кодион); Spain: Bisoltus; Codeisan; Codulin;
Fludan Codeina; Histaverin; Notusin; Perduretas Codeina; Toseina; Switz.:
Makatussin nouvelle formule; Tricodein†; UK: Bepro; Galcodine; Venez.: Dexibuprofen (BAN, USAN, rINN) NOTE. The following terms have been used as ‘street names’ (see
Codipront Mono.
Deksibuprofeeni; Dexibuprofène; Dexibuprofeno; Dexibuprofe- p.vi) or slang names for various forms of dextromoramide:
Multi-ingredient: numerous preparations are listed in Part 3. Palf.
num; S-(+)-Ibuprofen.
Дексибупрофен
C AS — 51146-56-6. Dextromoramide Tartrate (BANM, pINNM) ⊗
Croton Oil ATC — M01AE14. Bitartrate de Dextromoramide; Dekstromoramiditartraatti;
Aceite de crotón; Oleum Crotonis; Oleum Tiglii. ATC Vet — QM01AE14. Dekstromoramido tartratas; Dextromoramide Acid Tartrate;
C AS — 8001-28-3. Dextromoramide Hydrogen Tartrate; Dextromoramide, tar-
trate de; Dextromoramidi tartras; Dextromoramid-tartarát;
Pharmacopoeias. Chin. includes fruits of Croton tiglium. CH3 Dextromoramidtartrat; Tartrato de dextromoramida.
Profile OH Декстроморамида Тартрат
Croton oil is an oil expressed from the seeds of Croton tiglium CH3 C 25 H 32 N 2 O 2 ,C 4 H 6 O 6 = 542.6.
(Euphorbiaceae). Externally, it is a powerful counter-irritant and C AS — 2922-44-3.
vesicant. Croton oil is also used with phenol in cosmetic chemi- O
cal peeling of the skin. H 3C Pharmacopoeias. In Eur. (see p.vii).
Ph. Eur. 6.2 (Dextromoramide Tartrate). A white or almost
Croton oil has such a violent purgative action that it should not white, crystalline or amorphous powder. Soluble in water; spar-
be used as a laxative. Croton oil contains phorbol esters, which Profile
Dexibuprofen is the S(+)-enantiomer of ibuprofen (p.64) and is ingly soluble in alcohol. A 1% solution in water has a pH of 3.0
are carcinogenic. to 4.0.
used similarly in the management of mild to moderate pain and
Homoeopathy. Croton has been used in homoeopathic medi- inflammation in conditions such as dysmenorrhoea, headache,
cines under the following names: Croton tiglium; Crot. tig.
Profile
postoperative pain, dental pain, sprains, and soft-tissue rheuma- Dextromoramide is an opioid analgesic (p.104) structurally relat-
Preparations tism. It is also used in musculoskeletal and joint disorders such ed to methadone (p.82). It has been used in the treatment of se-
as ankylosing spondylitis, osteoarthritis, and rheumatoid arthri- vere pain although it was not recommended for use in obstetric
Proprietary Preparations (details are given in Part 3)
tis. It may be used as an antipyretic to reduce fever. analgesia because of an increased risk of neonatal depression.
Multi-ingredient: Canad.: Rheumalan†. The usual adult dose is 600 to 900 mg daily by mouth in up to 3 Dextromoramide is subject to abuse.
divided doses, adjusted according to response, to a usual maxi- Dextromoramide has been given orally as the tartrate. It has also
mum of 1.2 g daily. Elderly patients should be started at the low- been given rectally as suppositories and by subcutaneous or in-
Devil’s Claw Root er end of the dose range; dosage may then be increased according tramuscular injection.
to tolerance. Dose reductions are also recommended in patients
Djävulsklorot; Harpagofytový kořen; Harpagonjuuri; Harpago- with hepatic or renal impairment, see below. Preparations
phyti radix; Harpagophyton; Harpagophyton, racine d’; Harpago- For doses in children, see below. BP 2008: Dextromoramide Tablets.
phytum; Inkaruočiu˛ šaknys; Ördögcsáklya gyökér; Raíz de harp- Proprietary Preparations (details are given in Part 3)
◊ References.
agofito; Teufelskrallenwurzel. Irl.: Palfium; Neth.: Palface; Palfium.
1. Phleps W. Overview on clinical data of dexibuprofen. Clin Rheu-
C AS — 19210-12-9 (harpagoside). matol 2001; 20 (suppl 1): S15–S21.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
40 Analgesics Anti-inflammatory Drugs and Antipyretics
Dextropropoxyphene (BAN, pINN) Adverse Effects 5. Santos Gil I, et al. Hipoglucemia secundaria a ingestión de dex-
tropropoxifeno en un paciente adicto a drogas. Med Clin (Barc)
As for Opioid Analgesics in general, p.102. 1998; 110: 475–6.
Dekstropropoksifeeni; Dextropropoxifen; Dextropropoxifeno;
In the recommended dosage the adverse effects of dex- 6. Shah P, et al. Propoxyphene-induced hypoglycemia in renal fail-
Dextropropoxyphène; Dextropropoxyphenum; Propoxyphene. ure. Endocr Pract 2006; 12: 170–3.
(+)-(1S,2R)-1-Benzyl-3-dimethylamino-2-methyl-1-phenylpropyl tropropoxyphene are less marked than those of mor-
phine. Gastrointestinal effects, dizziness, and drowsi- Overdosage. There have been several reviews or retrospective
propionate.
studies of acute self-poisoning with dextropropoxyphene.1-4 At a
Декстропропоксифен ness are the most common. Liver impairment, manifest symposium on the safety and efficacy of dextropropoxyphene5
C 22 H 29 NO 2 = 339.5. as abnormal liver function tests and, more rarely, as re- many of the participants dealt with the problems of dextropro-
C AS — 469-62-5. versible jaundice, has been reported. poxyphene overdosage, often in conjunction with paracetamol
and sometimes with alcohol. Profound and even fatal CNS de-
ATC — N02AC04. There have been a large number of fatalities from ei- pression can develop rapidly as a result of the dextropropoxy-
ATC Vet — QN02AC04. ther accidental or intentional overdosage with dextro- phene content and in many cases death has occurred within an
propoxyphene. Many reports emphasise the rapidity hour;6 it was suggested that as few as 15 to 20 tablets of co-prox-
with which death ensues; death within an hour of over- amol may be fatal.7,8 Analysis of suicides involving drugs in
H 3C dosage is not uncommon, and it can occur within 15 England and Wales between 1997 and 1999 revealed that the
CH3
odds of dying after overdose with co-proxamol were 2.3 times
N minutes. Overdosage is often complicated by patients that for tricyclic antidepressant overdose, and 28.1 times greater
H 3C also taking other CNS depressants such as alcohol and than for paracetamol.9 Another analysis of suicides due to poi-
O using mixed preparations such as dextropropoxyphene soning in 3 areas of the UK between 2000 and 2001 identified
CH3 with paracetamol or aspirin. 123 cases of fatal overdose with co-proxamol;10 those who also
consumed alcohol had generally taken fewer co-proxamol tab-
O Symptoms of overdosage are similar to those of opioid lets than those who had not, emphasising the increased toxicity
poisoning in general, but in addition patients may ex- of the combination.
perience psychotic reactions. There may be cardiac An analysis of overdosage involving combination analgesic
conduction abnormalities and arrhythmias. preparations prescribed in Scotland between 2000 and 2002 also
found that overdoses with co-proxamol were 10 times more like-
Dextropropoxyphene injections are painful and have a ly to be fatal when compared with co-dydramol or co-codamol.11
NOTE. The following terms have been used as ‘street names’ (see
p.vi) or slang names for various forms of dextropropoxyphene: very destructive effect on soft tissues and veins when In the USA12 the incidence of dextropropoxyphene-associated
Dummies. abused in this way. deaths reached a peak in 1977 and then fell at a rate that was not
Anorectal reactions have followed the prolonged use matched by a decline in prescribing.
Dextropropoxyphene Hydrochloride of suppositories containing dextropropoxyphene; the It is not clear whether the metabolite, nordextropropoxyphene,
(BANM, pINNM) plays an important role in fatalities.12 However, nordextropro-
reactions appear to be dose dependent. poxyphene, like dextropropoxyphene, is considered to have local
Dekstropropoksifeenihydrokloridi; Dekstropropoksifeno hidro- Effects on the blood. A 12-year history of haemolysis and anaesthetic activity and the membrane stabilising activity of dex-
chloridas; Dextropropoxifén-hidroklorid; Dextropropoxifenhy- subsequent significant haemolytic anaemia in an elderly woman1 tropropoxyphene has been implicated as a major factor responsi-
droklorid; Dextropropoxyfen-hydrochlorid; Dextropropoxy- was associated with chronic, periodic, and occasionally exces- ble for its severe cardiac depressant effect.13
phène, chlorhydrate de; Dextropropoxypheni hydrochloridum; sive intake of co-proxamol. In January 2005, the UK CSM found the risk of toxicity of co-
Hidrocloruro de dextropropoxifeno; Propoxyphene Hydrochlo- 1. Fulton JD, McGonigal G. Steroid responsive haemolytic anaemia proxamol in overdose to be unacceptable;14 consequently, co-
ride (USAN). due to dextropropoxyphene paracetamol combination. J R Soc proxamol has been gradually withdrawn from the UK market.
Med 1989; 82: 228. Fixed-dose combinations of dextropropoxyphene and paraceta-
Декстропропоксифена Гидрохлорид
Effects on the ears. A report of complete nerve deafness asso- mol have also been withdrawn in several other countries includ-
C 22 H 29 NO 2,HCl = 375.9. ing Sweden and Switzerland.
C AS — 1639-60-7. ciated with chronic abuse of co-proxamol was made to the UK
CSM.1 The CSM had received 2 other reports of permanent hear- 1. Young RJ. Dextropropoxyphene overdosage: pharmacological
NOTE. Compounded preparations of dextropropoxyphene hydro- ing loss attributed to co-proxamol abuse; transient hearing loss considerations and clinical management. Drugs 1983; 26: 70–9.
chloride may be represented by the following names: 2. Madsen PS, et al. Acute propoxyphene self-poisoning in 222
had also been reported in 2 patients taking usual doses; 7 further consecutive patients. Acta Anaesthesiol Scand 1984; 28: 661–5.
• Co-proxamol (BAN)—dextropropoxyphene hydrochloride 1 reports described tinnitus. 3. Segest E. Poisoning with dextropropoxyphene in Denmark.
part and paracetamol 10 parts (w/w). 1. Ramsay BC. Complete nerve deafness after abuse of co-proxam- Hum Toxicol 1987; 6: 203–7.
ol. Lancet 1991; 338: 446–7. 4. Jonasson U, et al. Correlation between prescription of various
Pharmacopoeias. In Eur. (see p.vii) and US. dextropropoxyphene preparations and their involvement in fatal
Ph. Eur. 6.2 (Dextropropoxyphene Hydrochloride). A white or Effects on the liver. There have been occasional reports of poisonings. Forensic Sci Int 1999; 103: 125–32.
almost white crystalline powder. Very soluble in water; freely jaundice in patients taking dextropropoxyphene alone but many 5. Bowen D, et al. (ed). Distalgesic; safety and efficacy. Hum Tox-
of the 49 suspected hepatic reactions with dextropropoxyphene icol 1984; 3 (suppl): 1S–238S.
soluble in alcohol. Protect from light. 6. Proudfoot AT. Clinical features and management of Distalgesic
USP 31 (Propoxyphene Hydrochloride). A white odourless reported to the UK CSM by 19851 had involved use with para-
overdose. Hum Toxicol 1984; 3 (suppl): 85S–94S.
crystalline powder. Freely soluble in water; soluble in alcohol, in cetamol; clinical features including malaise, jaundice, raised se- 7. Whittington RM. Dextropropoxyphene deaths: coroner’s report.
acetone, and in chloroform; practically insoluble in ether and in rum transaminases, and sometimes fever, were however general- Hum Toxicol 1984; 3 (suppl): 175S–185S.
benzene. Store in airtight containers. ly characteristic of dextropropoxyphene alone. Relapsing 8. Young RJ, Lawson AAH. Distalgesic poisoning—cause for
jaundice mimicking biliary disease was attributable to the dex- concern. BMJ 1980; 280: 1045–7.
tropropoxyphene component of co-proxamol in 3 patients,2 9. Hawton K, et al. Co-proxamol and suicide: a study of national
Dextropropoxyphene Napsilate (BANM, pINNM) whereas there was no abnormality of liver function in 11 patients mortality statistics and local non-fatal self-poisonings. BMJ
2003; 326: 1006–8.
Dextropropoxyphène, Napsilate de; Dextropropoxyphene Na- on long-term co-proxamol analgesia.3 Another report of 9 cases 10. Hawton K, et al. A multicentre study of coproxamol poisoning
psylate; Dextropropoxypheni Napsilas; Napsilato de dextropro- found that the hepatotoxicity of dextropropoxyphene mimicked suicides based on coroners’ records in England. Br J Clin Phar-
poxifeno; Propoxyphene Napsylate (USAN). Dextropropoxy- symptoms of large bile duct obstruction, and suggested that such macol 2005; 59: 207–12.
phene naphthalene-2-sulphonate monohydrate. toxicity might be misdiagnosed.4 A more recent review5 also 11. Afshari R, et al. Co-proxamol overdose is associated with a 10-
concluded that hepatotoxicity with dextropropoxyphene might fold excess mortality compared with other paracetamol combi-
Декстропропоксифена Напсилат nation analgesics. Br J Clin Pharmacol 2005; 60: 444–7.
mimic a biliary tract disease, sometimes with few or no symp- 12. Finkle BS. Self-poisoning with dextropropoxyphene and dex-
C 22 H 29 NO 2,C 10H 8 O 3 S,H 2 O = 565.7. toms. tropropoxyphene compounds: the USA experience. Hum Toxi-
C AS — 17140-78-2 (anhydrous dextropropoxyphene nap- 1. CSM. Hepatotoxicity with dextropropoxyphene. Current Prob- col 1984; 3 (suppl): 115S–34S.
silate); 26570-10-5 (dextropropoxyphene napsilate mono- lems 17 1986. Available at: http://www.mhra.gov.uk/home/ 13. Henry JA, Cassidy SL. Membrane stabilising activity: a major
hydrate). idcplg?IdcService=GET_FILE&dDocName=CON2024424& cause of fatal poisoning. Lancet 1986; i: 1414–17.
RevisionSelectionMethod=LatestReleased (accessed 26/06/08) 14. MHRA. Withdrawal of co-proxamol products and interim up-
NOTE. Compounded preparations of dextropropoxyphene napsi- 2. Bassendine MF, et al. Dextropropoxyphene induced hepatotox- dated prescribing information. Message from Professor G Duff,
late may be represented by the following names: icity mimicking biliary tract disease. Gut 1986; 27: 444–9. Chairman of CSM (issued 31st January, 2005). Available at:
3. Hutchinson DR, et al. Liver function in patients on long-term http://www.mhra.gov.uk/home/groups/pl-a/documents/
• Co-proxAPAP (PEN)—dextropropoxyphene napsilate and websiteresources/con019461.pdf (accessed 28/08/08)
paracetamol (co-proxamol) analgesia. J Pharm Pharmacol
paracetamol. 1986; 38: 242–3.
Pharmacopoeias. In Br. and US. 4. Rosenberg WMC, et al. Dextropropoxyphene induced hepato- Treatment of Adverse Effects
toxicity: a report of nine cases. J Hepatol 1993; 19: 470–4. As for Opioid Analgesics in general, p.102.
BP 2008 (Dextropropoxyphene Napsilate). An odourless or al- 5. Bergeron L, et al. Dextropropoxyphène et atteintes hépatiques: à
most odourless white powder. It exhibits polymorphism. Practi- propos de 4 cas et revue de littèrature. Therapie 2002; 57: Rapid treatment of overdosage with naloxone and as-
cally insoluble in water; soluble in alcohol; freely soluble in chlo- 464–72.
roform.
sisted respiration is essential. Cardiac effects may not
Effects on the lungs. Hypersensitivity pneumonitis and skin be reversed by naloxone. Gastric lavage and activated
USP 31 (Propoxyphene Napsylate). A white powder having es- rash has been reported in a patient taking co-proxamol.1 No such
sentially no odour. Very slightly soluble in water; soluble 1 in 15 reaction occurred when the patient was subsequently given para-
charcoal may be of value within 1 hour of ingestion,
of alcohol and 1 in 10 of chloroform; soluble in acetone and in cetamol alone. but dialysis is of little use.
methyl alcohol. Store in airtight containers.
1. Matusiewicz SP, et al. Hypersensitivity pneumonitis associated Convulsions may require control with an anticonvul-
with co-proxamol (paracetamol + dextropropoxyphene) therapy. sant, bearing in mind that the CNS depressant effects of
Dependence and Withdrawal Postgrad Med J 1999; 75: 475–6.
dextropropoxyphene can be exacerbated (see also In-
As for Opioid Analgesics, p.101. Hypoglycaemia. Hypoglycaemia has occasionally been re-
ported with the use of dextropropoxyphene.1-6 teractions, below). Stimulants should not be used be-
Dextropropoxyphene has been subject to abuse (see cause of the risk of inducing convulsions.
1. Wiederholt IC, et al. Recurrent episodes of hypoglycemia in-
under Precautions, below). duced by propoxyphene. Neurology 1967; 17: 703–4. Patients taking overdoses of dextropropoxyphene with
2. Almirall J, et al. Propoxyphene-induced hypoglycemia in a pa-
◊ Reports of dextropropoxyphene dependence and its treatment. tient with chronic renal failure. Nephron 1989; 53: 273–5. paracetamol will also require treatment for paraceta-
1. Wall R, et al. Addiction to Distalgesic (dextropropoxyphene). 3. Laurent M, et al. Hypoglycémie sous dextropropoxyphène chez mol poisoning (p.108). Mixtures of dextropropoxy-
BMJ 1980; 280: 1213–14. des grands vieillards: 7 cas. Presse Med 1991; 20: 1628.
2. D’Abadie NB, Lenton JD. Propoxyphene dependence: problems 4. Lowenstein W, et al. Hypoglycémie au dextropropoxyphène:
phene and aspirin may be involved; the treatment of
in management. South Med J 1984; 77: 299–301. une urgence chez le toxicomane. Presse Med 1993; 22: 133. aspirin poisoning is described on p.20.
 Dextropropoxyphene/Diacerein 41
Precautions The elderly. The elimination half-lives of dextropropoxyphene 3. Haigh S. 12 Years on: co-proxamol revisited. Lancet 1996; 347:
and its metabolite nordextropropoxyphene were prolonged in 1840–1. Correction. ibid.; 348: 346.
As for Opioid Analgesics in general, p.103. 4. Sykes JV, et al. Coproxamol revisited. Lancet 1996; 348: 408.
healthy elderly subjects when compared with young controls.1
Abuse. There have been reports1 of the abuse of dextropropox- 5. Li Wan Po A, Zhang WY. Systematic overview of co-proxamol
After multiple dosing median half-lives of dextropropoxyphene to assess analgesic effects of addition of dextropropoxyphene to
yphene, and some2 considered that the ready availability of dex- and nordextropropoxyphene were 36.8 and 41.8 hours, respec- paracetamol. BMJ 1997; 315: 1565–71. Correction ibid. 1998;
tropropoxyphene made it liable to abuse although it was a rela- tively in the elderly compared with 22.0 and 22.1 hours in the 316: 116 and 656.
tively weak opioid analgesic. However, others3 thought there young subjects. In this study1 there was a strong correlation be- 6. Anonymous. Co-proxamol or paracetamol for acute pain? Drug
was no evidence that dextropropoxyphene was frequently asso- tween half-life of nordextropropoxyphene and estimated creati- Ther Bull 1998; 36: 80.
ciated with abuse, or concluded that, although there was abuse nine clearance. 7. MHRA. Withdrawal of co-proxamol products and interim updat-
potential, it was of relatively low importance in terms of the com- ed prescribing information. Message from Professor G Duff,
1. Flanagan RJ, et al. Pharmacokinetics of dextropropoxyphene
Chairman of CSM (issued 31st January, 2005). Available at:
munity as a whole.4 and nordextropropoxyphene in young and elderly volunteers af-
http://www.mhra.gov.uk/home/groups/pl-a/documents/
ter single and multiple dextropropoxyphene dosage. Br J Clin
A severe withdrawal syndrome has been reported5 in an elderly Pharmacol 1989; 28: 463–9.
websiteresources/con019461.pdf (accessed 28/08/08)
patient who covertly consumed a daily dose of dextropropoxy-
phene of 1 to 3 g for at least 12 months. The patient was treated Hepatic impairment. Plasma concentrations of dextropro- Preparations
by a gradually decreasing dosage schedule of dextropropoxy- poxyphene were higher in patients with cirrhosis given the drug BP 2008: Co-proxamol Tablets; Dextropropoxyphene Capsules;
phene over 9 weeks. than in healthy subjects whereas concentrations of nordextropro- USP 31: Propoxyphene Hydrochloride and Acetaminophen Tablets; Pro-
poxyphene were lower.1 poxyphene Hydrochloride Capsules; Propoxyphene Hydrochloride, Aspi-
1. Tennant FS. Complications of propoxyphene abuse. Arch Intern rin, and Caffeine Capsules; Propoxyphene Napsylate and Acetaminophen
Med 1973; 132: 191–4. 1. Giacomini KM, et al. Propoxyphene and norpropoxyphene plas- Tablets; Propoxyphene Napsylate and Aspirin Tablets; Propoxyphene Nap-
2. Lader M. Abuse of weak opioid analgesics. Hum Toxicol 1984; ma concentrations after oral propoxyphene in cirrhotic patients sylate Oral Suspension; Propoxyphene Napsylate Tablets.
3 (suppl): 229S–36S. with and without surgically constructed portacaval shunt. Clin
Pharmacol Ther 1980; 28: 417–24. Proprietary Preparations (details are given in Part 3)
3. Finkle BS. Self-poisoning with dextropropoxyphene and dextro- Arg.: Gobbigesic; Austral.: Doloxene; Belg.: Depronal; Canad.: 642†;
propoxyphene compounds: the USA experience. Hum Toxicol Renal impairment. Higher and more persistent plasma con- Darvon-N; Denm.: Abalgin; Doloxene; Fin.: Abalgin; Gr.: Romidon; Zi-
1984; 3 (suppl): 115S–34S. centrations of dextropropoxyphene and nordextropropoxyphene deron; India: Parvodex; Irl.: Doloxene†; Ital.: Liberen†; Mex.: Darvon
4. Turner P. Final remarks. Hum Toxicol 1984; 3 (suppl): 237S–8S. Simple; Neth.: Depronal; NZ: Doloxene†; S.Afr.: Doloxene; Spain: Dar-
in anephric patients when compared with healthy subjects1 were
5. Hedenmalm K. A case of severe withdrawal syndrome due to von†; Deprancol; Swed.: Dexofen; Doloxene; USA: Darvon; Darvon-N.
dextropropoxyphene. Ann Intern Med 1995; 123: 473. attributed to decreased first-pass metabolism of dextropropoxy-
phene and decreased renal excretion of nordextropropoxyphene Multi-ingredient: Arg.: Artifene; Calmopirin; Canovex†; D-P†; Dexpro-
Breast feeding. No adverse effects have been seen in breast- feno; Dextro + Dipirona; Dextrodip; Dorixina Forte; Gobbicalm; Klosidol;
in the anephric patients. Klosidol B1 B6 B12; Supragesic; Vicefeno; Austral.: Capadex; Di-Gesic; Pa-
fed infants whose mothers were receiving dextropropoxyphene, 1. Gibson TP, et al. Propoxyphene and norpropoxyphene plasma radex; Austria: APA; Contraforte†; Sigmalin B forte; Belg.: Algophene;
and the American Academy of Pediatrics considers1 that it is concentrations in the anephric patient. Clin Pharmacol Ther Distalgic†; Braz.: Doloxene-A; Fin.: Paraflex comp†; Fr.: Dextroref; Di
therefore usually compatible with breast feeding. The BNF also 1980; 27: 665–70. Dolko; Di-Antalvic; Diadupsan†; Dialgirex; Dioalgo; Propofan; Hong Kong:
considers that the amount of dextropropoxyphene in breast milk Cosalgesic; Distalgesic†; Dolocin; Dolpocetmol; Medonol; Hung.: Novopy-
rin; India: Buta-Proxyvon; Ibu-Proxyvon; Parvon; Parvon Forte; Parvon-N;
is too small to be harmful. Uses and Administration Parvon-Spas; Proxytab; Proxyvon; Spasmo-Proxyvon; Spasmocip; Spasmo-
1. American Academy of Pediatrics. The transfer of drugs and oth- Dextropropoxyphene is an opioid analgesic (p.104) cip Plus; Sudhinol; Walagesic†; Wygesic; Irl.: Distalgesic†; Israel: Algolysin;
er chemicals into human milk. Pediatrics 2001; 108: 776–89. Proxol; Rogaan; Mex.: Darvon-N Compuesto†; Neo-Percodan; Qual;
Correction. ibid.; 1029. Also available at: structurally related to methadone (p.82). It has mild Norw.: Aporex; NZ: Apo-Paradex†; Capadex; Paradex; Port.: Algifene;
h tt p : // a a p p o l ic y. a a p p u b li c a t i o n s. o rg / c g i /c on t e n t /f u l l / analgesic activity and is given orally as the hydrochlo- S.Afr.: Distalgesic; Doloxene Co; Doxyfene; Lentogesic; Synap; Swed.: Dis-
pediatrics%3b108/3/776 (accessed 26/06/08) talgesic†; Doleron†; Paraflex comp†; Switz.: Distalgesic†; UK: Cosalgesic†;
ride or napsilate to alleviate mild to moderate pain. Distalgesic†; USA: Balacet; Darvocet; Darvocet-N; Darvon Compound†;
Porphyria. Dextropropoxyphene has been associated with Unlike the laevo-isomer (levopropoxyphene), dextro- PC-Cap; Propacet; Trycet; Wygesic†.
acute attacks of porphyria and is considered unsafe in porphyric propoxyphene has little antitussive activity.
patients.
Dextropropoxyphene is mainly used with other analge-
sics that have anti-inflammatory and antipyretic ef- Diacerein (rINN)
Interactions
fects, such as aspirin or paracetamol. In the USA the Diacereína; Diacéréine; Diacereinum; Diacerhein; Diacetylrhein;
For interactions associated with opioid analgesics, see
usual dose is 65 mg of the hydrochloride or 100 mg of 2,4-dichlorobenzylique, alcool; Rhein Diacetate; SF-277; SF-277.
p.103. 9,10-Dihydro-4,5-dihydroxy-9,10-dioxo-2-anthroic acid diace-
Plasma concentrations of dextropropoxyphene are in- the napsilate given every 4 hours up to a maximum
tate.
creased by ritonavir, with a resultant risk of toxicity; total daily dose of 390 mg or 600 mg, respectively. In
Диацереин
they should not be given together. the UK similar doses have been given three or four
C 19 H 12 O 8 = 368.3.
times daily. C AS — 13739-02-1.
CNS depressants, including alcohol, may contribute to
The combination preparation co-proxamol (dextropro- ATC — M01AX21.
the hazards of dextropropoxyphene, see also Overdos- ATC Vet — QM01AX21.
poxyphene with paracetamol) has been gradually with-
age, above. The convulsant action of high doses of
drawn from the UK market (see also Pain, below) al-
dextropropoxyphene may be enhanced by CNS stimu-
though such combinations may remain available in a O CH3
lants.
number of countries.
Dextropropoxyphene interacts with several other drugs
Pain. A detailed review1 of the analgesic effectiveness of dextro- O
through inhibition of liver metabolism. Drugs reported propoxyphene suggested that with respect to single oral doses,
to be affected include antidepressants (see p.379), ben- recommended doses of dextropropoxyphene were no more (and
zodiazepines (see p.989), beta blockers (see p.1229), probably less) effective than usual doses of paracetamol, aspirin, O
carbamazepine (see p.474), phenobarbital (see p.493), or other NSAIDs. However, the comparative effectiveness may
phenytoin (see p.497), and warfarin (see p.1427). vary substantially depending on the cause of the pain. H3C O
When it comes to comparative studies involving combinations of O
Antimuscarinics. A suggested interaction between orphen- dextropropoxyphene with other analgesics, findings are even
adrine and dextropropoxyphene has been questioned (see less clear-cut.2 The effectiveness of co-proxamol has long been a O
p.812). matter of controversy yet despite this a survey3 conducted in 30
UK teaching hospitals found that co-proxamol was the most
Pharmacokinetics widely used paracetamol-containing analgesic. It was suggested HO O
Dextropropoxyphene is readily absorbed from the gas- that the popularity of co-proxamol was purely down to prescrib-
ing habits passed on to new medical staff, rather than hard evi- Profile
trointestinal tract, the napsilate tending to be more dence regarding efficacy. This view has been refuted by others4
slowly absorbed than the hydrochloride, but both are Diacerein is an anthraquinone derivative that is used in osteoar-
who say that a large number of studies have shown clear analge- thritis (p.11) in oral doses of 50 mg twice daily. Doses should be
subject to considerable first-pass metabolism. Peak sic effects for dextropropoxyphene. However, any assumption halved in patients with creatinine clearance less than
plasma concentrations occur about 2 to 2.5 hours after that the combination was widely used because it was more effec- 30 mL/minute. Diarrhoea is a common adverse effect with diac-
ingestion. It is rapidly distributed and concentrated in tive than paracetamol alone was not supported by a systematic erein. Its active metabolite, rhein, a constituent of rhubarb
overview of single-dose studies.5 This concluded that while co- (p.1768), is reported to act as an interleukin-1 inhibitor.
the liver, lungs, and brain. About 80% of dextropro- proxamol was indeed an effective analgesic it was no better than
poxyphene and its metabolites are reported to be bound paracetamol alone. Although the evidence from this and other Administration in renal impairment. See above and Phar-
to plasma proteins. Dextropropoxyphene crosses the systematic reviews indicate that co-proxamol should be replaced macokinetics, below.
placenta. It has been detected in breast milk. by paracetamol alone for acute pain, the position for chronic use Musculoskeletal and joint disorders. Diacerein is thought
is considered to be not so clear (but see below).6 to act via inhibition of interleukin-1β,1 which plays a role in in-
Dextropropoxyphene is N-demethylated to nordextro- In January 2005, the UK CSM found the efficacy of co-proxamol flammatory processes. Systematic reviews2,3 on the use of diac-
propoxyphene (norpropoxyphene) in the liver. It is to be poorly established and its risk of toxicity in overdose to be erein in the treatment of osteoarthritis have indicated that diac-
excreted in the urine mainly as metabolites. It is unacceptable;7 they considered that there was no robust evidence erein produces a small, but consistent, improvement in pain.
now recognised that dextropropoxyphene and nor- of the superior efficacy of co-proxamol to full-strength paraceta- Further research is necessary to confirm its short- and long-term
mol alone in either acute or chronic pain. Consequently, co-prox- effectiveness and safety but there is some evidence of residual
dextropropoxyphene have prolonged elimination half- amol has been gradually withdrawn from the UK market. Fixed- benefit on stopping treatment,3 which has been postulated to rep-
lives; values of 6 to 12 hours and 30 to 36 hours, re- dose combinations of dextropropoxyphene and paracetamol resent an improvement in the disease process.
spectively, have been reported. Accumulation of dex- have also been withdrawn in several other countries including 1. Van den Berg WB. Les mécanismes d’action de la diacerhéine,
tropropoxyphene and its metabolites may occur with Sweden and Switzerland. premier inhibiteur de l’interleukine 1 dans l’arthrose. Presse
1. Beaver WT. Analgesic efficacy of dextropropoxyphene and dex- Med 2004; 33: 10–12.
repeated doses and nordextropropoxyphene may con- tropropoxyphene-containing combinations: a review. Hum Toxi- 2. Fidelix TSA, et al. Diacerein for osteoarthritis. Available in The
tribute to the toxicity seen with overdosage. col 1984; 3 (suppl): 191S–220S. Cochrane Database of Systematic Reviews; Issue 1. Chichester:
2. Collins SL, et al. Single dose dextropropoxyphene, alone and John Wiley; 2006 (accessed 06/10/06).
◊ Reviews. with paracetamol (acetaminophen), for postoperative pain. 3. Rintelen B, et al. A meta-analysis of controlled clinical studies
1. Pearson RM. Pharmacokinetics of propoxyphene. Hum Toxicol Available in The Cochrane Database of Systematic Reviews; Is- with diacerein in the treatment of osteoarthritis. Arch Intern Med
1984; 3 (suppl): 37S–40S. sue 1. Chichester: John Wiley; 1999 (accessed 26/06/08). 2006; 166: 1899–1906.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
42 Analgesics Anti-inflammatory Drugs and Antipyretics
Pharmacokinetics. References. Old Steve; One way; Orange line; Outfit; Pack; Pakistanaise; Pa- kept at 31° when stability was only maintained for a minimum of
1. Debord P, et al. Influence of renal function on the pharmacoki- ko; Pangonadalot; Parachute; P-dope; Peg; Pepper; Perfect high; 2 days. When stored in glass syringes both strengths of diamor-
netics of diacerein after a single oral dose. Eur J Drug Metab P-funk; Pluto; Po; Poeira; Poison; Polvo; Poppy; Poudre; Pow- phine hydrochloride were stable for 15 days at 4° and at room
Pharmacokinet 1994; 19: 13–19. der; Predator; Primo; Produto; Pulborn; Pure; Quill; Race horse temperature the 1 mg/mL solution was stable for a minimum of
2. Nicolas P, et al. Clinical pharmacokinetics of diacerein. Clin Charlie; Racehorse Charlie; Ragweed; Rain; Rambo; Rane; 7 days and the 20 mg/mL solution was stable for a minimum of
Pharmacokinet 1998; 35: 347–59. Raw; Raw fusion; Raw hide; Raw Opportunities; Ready rock; 12 days. There were no substantial changes in physical appear-
Red chicken; Red devil; Red eagle; Red rock; Red rum; Reindeer ance or pH.
Preparations dust; Rhine; Ring of Turd; Rob Flaherty; Rock; Rocks; Rush
1. Davey EA, Murray JB. Hydrolysis of diamorphine in aqueous
Proprietary Preparations (details are given in Part 3) hour; Sack; Salt; Scag; Scat; Scate; Schmack; Schmeck; solutions. Pharm J 1969; 203: 737.
Arg.: Artrodar; Artroglobina†; Austria: Artrolyt; Verboril; Braz.: Artro- Schmeek; Scott; Scramble; Second to none; Shit; Shmeck; 2. Davey EA, Murray JB. Determination of diamorphine in the
dar; Chile: Artrizona; Cz.: Artrodar; Fr.: Art; Zondar; Gr.: Arthrofar; Ar- Shmeek; Shmek; Shoot; Silk; Skag; Skid; Skunk; Slack-dad-eat-
throrein; Deserein; Diacer; Diaceril; Idealite; Inflabion; Myobloc; Ostirein; presence of its degradation products using gas liquid chromatog-
your-heart-out; Slam; Sleeper; Sleepers; Slime; Slow; Sludge; raphy. Pharm J 1971; 207: 167.
Pentacrin; Reumanisal; Verboril; Indon.: Artrodar; Israel: Art; Diatrim; Smack; Snotty; Snow; Spider; Spider blue; Stuff; Stunna; Sugar;
Ital.: Fisiodar; Malaysia: Artrodar; Port.: Artrolyt; Cartivix; Spain: Gal- 3. Cooper H, et al. Stability of diamorphine in chloroform water
axdar; Glizolan; Thai.: Artrodar; Venez.: Artrodar. Suicide; Sweet dreams; Sweet Jesus; Sweet stuff; Synthe; Tang; mixture. Pharm J 1981; 226: 682–3.
Tar; Taste; Tecata; Tecate; Thailandaise; Thanie; The beast; The 4. Twycross RG. Stability of diamorphine in chloroform water.
Multi-ingredient: Mex.: Dolocartigen. fake throwdown; The Jack Bauer; The Loud-House Permadillo; Pharm J 1981; 227: 218.
The Nax; The witch; Thing; Thunder; Tiger; Tigre; Tigre Blan- 5. Beaumont IM. Stability of diamorphine in chloroform water.
co; Tigre del Norte; Tits; TNT; T.N.T.; Tongs; Tootsie roll; Top Pharm J 1981; 227: 41.
drool; Train; Trash; Twin towers; Twists; Vidrio; Whack; 6. Jones VA, et al. Diamorphine stability in aqueous solution for
Diamorphine Hydrochloride Whicked; White; White Bitch; White boy; White dragon; White subcutaneous infusion. Br J Clin Pharmacol 1987; 23: 651P.

⊗ dynamite; White girl; White horse; White junk; White lady; 7. Omar OA, et al. Diamorphine stability in aqueous solution for
(BANM) White nurse; "White Pony"; White stuff; White Tiger; Wicked; subcutaneous infusion. J Pharm Pharmacol 1989; 41: 275–7.
Wings; Witch; Witch hazel; WTC; Zoquete. 8. Kleinberg ML, et al. Stability of heroin hydrochloride in infu-
Diacetilmorfina, hidrocloruro de; Diacetylmorphine Hydrochlo- sion devices and containers for intravenous administration. Am J
ride; Heroin Hydrochloride; Hidrocloruro de diamorfina; Hidro- Pharmacopoeias. In Br. and Swiss. Swiss also includes the Hosp Pharm 1990; 47: 377–81.
cloruro de heroína. 4,5-Epoxy-17-methylmorphinan-3,6-diyl dia- anhydrous form.
cetate hydrochloride monohydrate. BP 2008 (Diamorphine Hydrochloride). A white or almost Dependence and Withdrawal
white crystalline powder, odourless when freshly prepared but As for Opioid Analgesics, p.101.
Героина Гидрохлорид; Диаморфина Гидрохлорид develops an odour characteristic of acetic acid on storage. Freely
C 21 H 23 NO 5,HCl,H 2 O = 423.9. soluble in water and in chloroform; soluble in alcohol; practical- Diamorphine is subject to abuse (see under Adverse
C AS — 561-27-3 (diamorphine); 1502-95-0 (diamorphine ly insoluble in ether. Protect from light. Effects, Treatment, and Precautions, below).
hydrochloride). Diamorphine is used for substitution therapy in the
Incompatibility. Diamorphine hydrochloride is incompatible
ATC — N02AA09. with mineral acids and alkalis and with chlorocresol.1 management of opioid dependence (see under Uses
ATC Vet — QN02AA09. The BNF notes that cyclizine may precipitate from mixtures with and Administration, below).
diamorphine hydrochloride at concentrations of cyclizine greater
than 10 mg/mL, or in the presence of sodium chloride 0.9%, or Adverse Effects, Treatment, and Precau-
H 3C O as the concentration of diamorphine relative to cyclizine increas- tions
es; mixtures of diamorphine and cyclizine are also liable to pre-
cipitate after 24 hours. As for Opioid Analgesics in general, p.102.
O
It also considers that mixtures of diamorphine and haloperidol Pulmonary oedema after overdosage is a common
O H are liable to precipitate after 24 hours if the haloperidol concen- cause of fatalities among diamorphine addicts. Nausea
O NCH3 tration is above 2 mg/mL. Under some conditions mixtures of and hypotension are claimed to be less common than
metoclopramide and diamorphine may become discoloured and with morphine.
should be discarded.
H 3C O 1. McEwan JS, Macmorran GH. The compatibility of some bacte-
There are many reports of adverse effects associated
ricides. Pharm J 1947; 158: 260–2. with the abuse of diamorphine, usually obtained illicit-
(diamorphine) ly in an adulterated form.
Stability. Diamorphine is relatively unstable in aqueous solu-
tion and is hydrolysed to 6-O-monoacetylmorphine and then Abuse. Most of the reports of adverse effects with diamorphine
NOTE. The following terms have been used as ‘street names’ (see morphine to a significant extent at room temperature; 3-O- involve its abuse. In addition to the central effects, there are ef-
p.vi) or slang names for various forms of diamorphine: monoacetylmorphine is only occasionally detected. The rate of fects caused by the administration methods and by the adulter-
57 Chevy; A Sidani; AIP; Al Capone; Amelia; Antifreeze; Aries; decomposition is at a minimum at about pH 4.1,2 ants.1,2 Thus in many instances it is difficult to identify the factor
Aunt Hazel; Auntie Hazel; Aunty Hazel; Bacalhau; Bad bundle; causing the toxicity. Most body systems are involved including
Bad seed; Ball; Ballot; Bart Simpson; Batman; Beast; Big Bad In a study of the stability of aqueous solutions of diamorphine in
chloroform water it was concluded that such solutions should be the immune system,3 kidneys,4,5 liver,6 respiratory system,7-10
Boy; Big bag; Big doodig; Big H; Big Harry; Bin laden; Bindle;
Birdie powder; Black; Black Dragon; Black eagle; Black Girl; used within 3 weeks of preparation when stored at room temper- and the nervous system.11-16
Black pearl; Black stuff; Black tar; Black tootsie roll; Blanche; ature.3 Another study4 noted that the degradation products of Other aspects of the illicit use of diamorphine include fatal
Blanco; Blast; Bleue; Block busters; Blow; Blows; Blue bag; diamorphine were not devoid of analgesic activity. Using a more overdose17 and smuggling by swallowing packages of drug18,19
Blue hero; Blue star; Bobby Brown; Bomb; Bomba; Bombe; sensitive analytical method it was reported that although the pH or other methods of internal bodily concealment.
Bombido; Bombita; Bombitas; Bombs away; Bone; Bonita; range of maximum stability of diamorphine in aqueous solution 1. Hendrickse RG, et al. Aflatoxins and heroin. BMJ 1989; 299:
Boy; Bozo; Brad; Brain damage; Brea; Brick gum; Broja; Broth- was 3.8 to 4.4, the addition of buffers reduced stability.5 Simple 492–3.
er; Brown; Brown crystal; Brown rhine; Brown sugar; Brown unbuffered chloroform water gave maximum stability, the shelf- 2. CDC. Atypical reactions associated with heroin use: five states,
tape; Bugger; Bull dog; Bundle; Burra; Butu; Caballo; Caca; life of such a solution being 4 weeks at room temperature. January–April 2005. MMWR 2005; 54: 793–6. Correction.
Calbo; Capital H; Caps; Captain Jack; Carga; Carne; Cavalo; ibid.; 852.
Chang; Chapopote; Charley; Chatarra; Cheese; Cheva; Cheval; The BP 2008 recommends that solutions for injection be pre- 3. Husby G, et al. Smooth muscle antibody in heroin addicts. Ann
pared immediately before use by dissolving Diamorphine Hy- Intern Med 1975; 83: 801–5.
Chi; Chiba; Chick; Chicken; Chicle; Chieva; China cat; China 4. Cunningham EE, et al. Heroin-associated nephropathy. JAMA
white; Chinche; Chinese H; Chinese red; Chinese Rocks; Chi- drochloride for Injection in Water for Injections. This may pose 1983; 250: 2935–6.
noise; Chip; Chiva; Chocofan; Choco-fan; Chueva; Chunks; Cli- a problem with solutions for subcutaneous infusion when con- 5. do Sameiro Faria M, et al. Nephropathy associated with heroin
max; Cocofan; Coffee; Cotics; Cotton Candy; Courage pills; centrated solutions may remain in infusion pump reservoirs for abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18:
Crank; Crap; Crop; Crown crap; Cura; Dead on arrival; Dead some time.6 Investigation of 9 concentrations of diamorphine 2308–13.
president; Deuce; Diesel; Diggidy; Dirt; DOA; Dog food; Dog- stored at 4 different temperatures for 8 weeks7 revealed instabil- 6. Weller IVD, et al. Clinical, biochemical, serological, histologi-
ee; Dogie; Doogie; Doojee; Dookey Rocks; Dooley; Doosey; ity under conditions of concentration, time, and temperature cal and ultrastructural features of liver disease in drug abusers.
Dope; Downtown; Dr. Feelgood; Dragon; Dreck; DT; Dugee; Gut 1984; 25: 417–23.
prevalent during subcutaneous infusion. Degradation of diamor- 7. Anderson K. Bronchospasm and intravenous street heroin. Lan-
Dugie; Duji; Dujra; Dujre; Dust; Dyno; Dyno-pure; Eggs; Eight; phine occurred at all concentrations (0.98 to 250 mg/mL) at tem- cet 1986; i: 1208.
Eighth; Elephant; Estuffa; Fachiva; Ferry dust; Fix; Flea powder; peratures of 4° and above; the effect of temperature was signifi- 8. Cygan J, et al. Inhaled heroin-induced status asthmaticus: five
Foil; Foo foo stuff; Foolish powder; Furra; Galloping horse; Gal- cant at 21° and 37°. The percentage fall in diamorphine cases and a review of the literature. Chest 2000; 117: 272–5.
lup; Gamot; Garbage; Gato; Gear; George; George smack; concentration was directly related to initial concentration and 9. Boto de los Bueis A, et al. Bronchial hyperreactivity in patients
Ghost; Girl; Glacines; Glass; Goat; Gold; Golden Brown; Gold- was accompanied by a corresponding increase in 6-O- who inhale heroin mixed with cocaine vaporized on aluminium
en girl; Golpe; Goma; Good; Good H; Good Horse; Good and foil. Chest 2002; 121: 1223–30.
plenty; Goods; Goop; Grape Jolly Rancher; Gravy; Grey shields; monoacetylmorphine and, to a lesser extent, morphine; other 10. Sporer KA, Dorn E. Heroin-related noncardiogenic pulmonary
H; H22; H-bomb; H Caps; Hache; Hair; Hairpiece; Hairy; Ham- possible breakdown products such as 3-O-monoacetylmorphine edema: a case series. Chest 2001; 120: 1628–32.
mer; Hard candy; Hard stuff; Harriet Tubman; Harry; Harry were not present in detectable quantities. Diamorphine degrada- 11. Sempere AP, et al. Spongiform leucoencephalopathy after in-
Jones; Hayron; Hazel; Heaven; Heaven dust; Heavy stuff; tion was associated with a fall in pH and the development of a haling heroin. Lancet 1991; 338: 320.
Helen; Hell dust; Henry; Hera; Hero; Hero of the underworld; strong acetic acid-like odour. Precipitation and a white turbidity 12. Roulet Perez E, et al. Toxic leucoencephalopathy after heroin
was seen in solutions of 15.6 mg/mL and above after incubation ingestion in a 2 ⁄ -year-old child. Lancet 1992; 340: 729.
Heroa; Heroina; Heron; Herone; Hessle; Him; Holy terror; Hom-
for 2 weeks at 21° and 37°. It has been noted that solutions for 13. Zuckerman GB. Neurologic complications following intranasal
bre; Homebake; Homicide; Hong-yen; Hood; Hop; Horning; administration of heroin in an adolescent. Ann Pharmacother
Horse; Horsebite; Hot dope; Hot heroin; HRN; Isda; Jack; Jee infusion are generally freshly prepared and used within 24 hours, 1996; 30: 778–81.
gee; Jerry Springer; Jesus; Jive; Jive doo jee; Joharito; Jojee; but that signs of precipitation should be watched for, especially 14. Kriegstein AR, et al. Heroin inhalation and progressive spongi-
Jones; Joy; Joy dust; Joy flakes; Joy powder; Judas; Junco; Junk; when using longer-term infusions and high concentrations of form leukoencephalopathy. N Engl J Med 1997; 336: 589–90.
Kabayo; Kaka Water; Karachi; Kermit the Frog; La Buena; La diamorphine.7 15. Long H, et al. A fatal case of spongiform leukoencephalopathy
Chiva; Lady H; Layne; LBJ; Lemonade; Life saver; Little bomb; linked to "chasing the dragon". J Toxicol Clin Toxicol 2003; 41:
Man; Manteca; Matsakow; Mayo; Mexican Black Tar; Mexican In another stability study8 diamorphine hydrochloride in concen- 887–91.
brown; Mexican Dirt; Mexican horse; Mexican mud; Mister trations of both 1 and 20 mg/mL in sodium chloride 0.9% was 16. Dabby R, et al. Acute heroin-related neuropathy. J Peripher
stable for a minimum of 15 days at room temperature (23° to 25°) Nerv Syst 2006; 11: 304–9.
Brownstone; Mojo; Money talks; Monkey; Montego; Morse
and 4° when stored in a PVC container. In one type of disposable 17. Kintz P, et al. Toxicological data after heroin overdose. Hum
Code Features; Morotgara; Mortal combat; Mother pearl; Mr. Toxicol 1989; 8: 487–9.
Brownstone; Mud; Murotugora; Muzzle; Nanoo; Nice and easy; infusion device (Infusor) similar solutions were stable for 15
18. Stewart A, et al. Body packing—a case report and review of the
Nickel bag; Nickel deck; Nixon; Noddy Brown; Noise; Nose; days even at 31°. In another infusion device (Intermate 200) literature. Postgrad Med J 1990; 66: 659–61.
Nose drops; Number 3; Number 4; Number 8; Nurse; Oddy diamorphine was stable for a minimum of 15 days at both con- 19. Traub SJ, et al. Pediatric "body packing". Arch Pediatr Adolesc
Noddy; Of course my horse; Ogoy; Oil; Old garbage; Old navy; centrations and all temperatures except for the 1 mg/mL solution Med 2003; 157: 174–7.
 Diamorphine Hydrochloride 43
Administration. Although generally free from complications, The pharmacokinetics of inhaled diamorphine fumes ("chasing preferred to morphine salts for intraspinal use because it is more
sterile abscess formation was reported in 2 patients with ad- the dragon") has been studied2 in diamorphine addicts receiving lipid-soluble.
vanced cancer receiving diamorphine by continuous subcutane- substitution therapy with diamorphine and methadone. Absorp- As a guide to relative potency diamorphine hydrochloride 5 mg
ous infusions.1 Acute dysphoric reactions have been reported af- tion through the lungs occurred very rapidly and was virtually given intramuscularly is equivalent to about 10 mg given orally,
ter the use of epidural diamorphine.2 complete immediately after inhalation; bioavailability was esti- which in turn is equivalent to about 15 mg of oral morphine sul-
1. Hoskin PJ, et al. Sterile abscess formation by continuous subcu- mated to be about 53%. fate. When given by subcutaneous infusion, diamorphine hydro-
taneous infusion of diamorphine. BMJ 1988; 296: 1605. 1. Kendall JM, Latter VS. Intranasal diamorphine as an alternative chloride 10 mg every 24 hours is equivalent to about 15 mg
2. Holder KJ, Morgan BM. Dysphoria after extradural diamor- to intramuscular morphine: pharmacokinetic and pharmacody- every 24 hours of morphine sulfate.
phine. Br J Anaesth 1994; 72: 728. namic aspects. Clin Pharmacokinet 2003; 42: 501–13.
2. Rook EJ, et al. Population pharmacokinetics of heroin and its Administration in children. In the treatment of acute or
Breast feeding. The American Academy of Pediatrics has major metabolites. Clin Pharmacokinet 2006; 45: 401–17. chronic pain in children, the BNFC suggests the following doses
stated1 that, when used as a drug of abuse by breast-feeding according to age:
mothers, diamorphine has caused adverse effects in the infant, INTRASPINAL ROUTE. Diamorphine is much more lipid-soluble
and has a more rapid onset and shorter duration of action than by continuous intravenous infusion
notably tremors, restlessness, vomiting, and poor feeding. How-
ever, the BNF considers that diamorphine when given in thera- morphine. Although deacetylation to morphine occurs rapidly • neonates with spontaneous respiration may be given 2.5 to
peutic doses to a breast-feeding mother is unlikely to affect the in the blood it occurs only slowly in the CSF after intraspinal 7 micrograms/kg per hour
breast-fed infant. injection of diamorphine.1 After intrathecal injection diamor- • ventilated neonates may be given 50 micrograms/kg initially
See also Opioid Dependence under Uses and Administration, be- phine was removed from the CSF much more rapidly than by intravenous injection over 30 minutes followed by
low. morphine.2 Peak plasma concentrations of morphine after 15 micrograms/kg per hour by continuous intravenous infu-
epidural diamorphine injection were significantly higher and sion
1. American Academy of Pediatrics. The transfer of drugs and oth-
er chemicals into human milk. Pediatrics 2001; 108: 776–89. were achieved significantly faster than after epidural injection • 1 month to 12 years, 12.5 to 25 micrograms/kg per hour
Correction. ibid.; 1029. Also available at: of morphine.3 by intravenous injection
h tt p : // a a p p o l ic y. a a p p u b li c a t i o n s. o rg / c g i /c on t e n t /f u l l / 1. Morgan M. The rational use of intrathecal and extradural opio- • 1 to 3 months, 20 micrograms/kg every 6 hours if necessary
pediatrics%3b108/3/776 (accessed 26/06/08) ids. Br J Anaesth 1989; 63: 165–88.
2. Moore A, et al. Spinal fluid kinetics of morphine and heroin. • 3 to 6 months, 25 to 50 micrograms/kg every 6 hours if neces-
Hypersensitivity. Anaphylaxis occurred in a patient given in- Clin Pharmacol Ther 1984; 35: 40–5. sary
trathecal diamorphine and bupivacaine for surgical anaesthesia;1 3. Watson J, et al. Plasma morphine concentrations and analgesic • 6 to 12 months, 75 micrograms/kg every 4 hours if necessary
the authors noted that the patient received patient-controlled effects of lumbar extradural morphine and heroin. Anesth Analg • 1 to 12 years, 75 to 100 micrograms/kg every 4 hours if nec-
analgesia with morphine shortly after the reaction without prob- 1984; 63: 629–34.
essary
lem. Subsequent skin prick tests identified diamorphine as the Children. Loading doses of either 50 micrograms/kg or
likely causative agent. by mouth
200 micrograms/kg of diamorphine were given as an infusion • 1 month to 12 years, 100 to 200 micrograms/kg (maximum of
1. Gooch I, Gwinnutt C. Anaphylaxis to intrathecal diamorphine. over 30 minutes to 19 ventilated neonates followed by a contin-
Resuscitation 2006; 70: 470–3. 10 mg) every 4 hours if necessary
uous infusion of 15 micrograms/kg per hour, and the pharmacok- In a study1 of the effects of diamorphine in 34 premature infants
Phaeochromocytoma. Diamorphine can liberate endog- inetics of the products of diamorphine metabolism (morphine,
(gestational age 26 to 40 weeks), a loading dose of
enous histamine which may in turn stimulate release of catecho- morphine-6-glucuronide, and morphine-3-glucuronide) stud-
50 micrograms/kg given as an intravenous infusion over 30 min-
lamines. Its use provoked hypertension and tachycardia in a pa- ied.1 Although the overall elimination of morphine was reduced utes followed by a continuous infusion at a rate of
tient with phaeochromocytoma.1 compared with adults, the relative contributions of the various 15 micrograms/kg per hour was considered to be safe and result-
1. Chaturvedi NC, et al. Diamorphine-induced attack of paroxys- metabolic routes of morphine remained similar between neo- ed in plasma concentrations of morphine comparable with those
mal hypertension in phaeochromocytoma. BMJ 1974; 2: 538. nates and adults. Data from this study did not indicate any advan- that usually produce adequate analgesia in children and adults;
Pregnancy and the neonate. Some references to diamor- tage for the higher loading dose (see also under Uses and Admin- the duration of the infusion ranged from 14 to 149 hours. Small
phine dependence in pregnant women and the effects on the fetus istration, below). but significant reductions in heart rate and mean blood pressure
and neonate. 1. Barrett DA, et al. Morphine, morphine-6-glucuronide and mor- were noted but these were not associated with any clinical dete-
phine-3-glucuronide pharmacokinetics in newborn infants re-
1. Fricker HS, Segal S. Narcotic addiction, pregnancy, and the new- ceiving diamorphine infusions. Br J Clin Pharmacol 1996; 41: rioration. The fall in respiration rate reflected the desired inten-
born. Am J Dis Child 1978; 132: 360–6. 531–7. tion to encourage synchronisation of the infants’ breathing with
2. Ostrea EM, Chavez CJ. Perinatal problems (excluding neonatal the ventilator. The authors concluded that intravenous diamor-
withdrawal) in maternal drug addiction: a study of 830 cases. J phine could be given safely to neonates and would provide ade-
Pediatr 1979; 94: 292–5. Uses and Administration
quate analgesia. A later study2 indicated that the use of a
3. Lifschitz MH, et al. Fetal and postnatal growth of children born Diamorphine hydrochloride is an acetylated morphine 200 micrograms/kg loading dose conferred no benefit over a
to narcotic-dependent women. J Pediatr 1983; 102: 686–91.
4. Klenka HM. Babies born in a district general hospital to mothers
derivative and is a more potent opioid analgesic 50 micrograms/kg dose and might produce undesirable physio-
taking heroin. BMJ 1986; 293: 745–6. (p.104) than morphine (p.89). Diamorphine is used for logical effects. In a comparative study3 with morphine
5. Gregg JEM, et al. Inhaling heroin during pregnancy: effects on the relief of severe pain especially in palliative care. It (200 micrograms/kg loading dose over 2 hours, followed by
the baby. BMJ 1988; 296: 754. maintenance infusion of 25 micrograms/kg per hour) in ventilat-
6. Little BB, et al. Maternal and fetal effects of heroin addiction is also used similarly to morphine for the relief of dys-
ed preterm neonates requiring sedation, diamorphine
during pregnancy. J Reprod Med 1990; 35: 159–62. pnoea due to pulmonary oedema resulting from left (120 micrograms/kg over 2 hours and then 15 micrograms/kg
7. Mur Sierra A, et al. Asociación entre el consumo de heroína du- ventricular failure. Diamorphine has a powerful cough
rante la gestación y anomalías estructurales de los cilios respira- per hour) was as effective as morphine in producing sedation and
torios en el período neonatal. An Esp Pediatr 2001; 55: 335–8. suppressant effect and has been given as Diamorphine also had a faster onset of action. The small but significant drop in
Linctus (BPC 1973) to control cough associated with blood pressure noted during morphine infusions was not seen
Interactions with diamorphine infusions.
terminal lung cancer although morphine is now pre-
For interactions associated with opioid analgesics, see The subcutaneous route appeared to be as effective and safe as
ferred. the intravenous route for infusions in children for postoperative
p.103. In the treatment of acute pain usual doses of diamor- pain relief after elective abdominal surgery.4 The dose of diamor-
phine hydrochloride by subcutaneous or intramuscular phine used in both groups of children was 1 mg/kg given at a rate
Pharmacokinetics injection are 5 to 10 mg every 4 hours. Doses equiva- of 20 micrograms/kg per hour.
Diamorphine hydrochloride is well absorbed from the Intranasal diamorphine has been investigated in adults and chil-
lent to one-quarter to one-half of the corresponding dren, and appears to be effective and well tolerated; because it
gastrointestinal tract, although this may be erratic, and intramuscular dose may be given by slow intravenous does not require a needle it may offer particular advantages in
after subcutaneous or intramuscular injection. On in- injection. children.5 Guidelines6 for analgesia in children in Accident and
jection it is rapidly hydrolysed to the active metabolite Emergency departments in the UK recommend the use of intra-
For the pain of myocardial infarction doses of 5 mg are
6-O-monoacetylmorphine (6-acetylmorphine) in the nasal diamorphine for severe pain such as that associated with
given by slow intravenous injection at a rate of large burns, long bone dislocation, appendicitis, or sickle-cell
blood and then to morphine (p.88). Oral doses are sub-
1 mg/minute with a further dose of 2.5 to 5 mg if re- crisis. A suggested dose to be instilled into one nostril is
ject to extensive first-pass metabolism to morphine;
quired; doses may be reduced by one-half for elderly or 100 micrograms/kg given in 0.2 mL of sterile water.
neither diamorphine nor 6-acetylmorphine have been 1. Elias-Jones AC, et al. Diamorphine infusion in the preterm ne-
frail patients. Doses of 2.5 to 5 mg may be given intra-
detected in the blood after giving diamorphine by this onate. Arch Dis Child 1991; 66: 1155–7.
venously at the same rate for acute pulmonary oede- 2. Barker DP, et al. Randomised, double blind trial of two loading
route. Both diamorphine and 6-acetylmorphine readily
ma. dose regimens of diamorphine in ventilated newborn infants.
cross the blood-brain barrier. Morphine glucuronides Arch Dis Child 1995; 73: F22–F26.
are the main excretion products in the urine. A small For chronic pain 5 to 10 mg may be given by subcu- 3. Wood CM, et al. Randomised double blind trial of morphine ver-
taneous or intramuscular injection every 4 hours; the sus diamorphine for sedation of preterm neonates. Arch Dis
amount is excreted in the faeces. Child Fetal Neonatal Ed 1998; 79: F34–F39.
dose may be increased according to needs. Similar dos- 4. Semple D, et al. Comparison of iv and sc diamorphine infusions
◊ References. es may be given orally, although it is converted to mor- for the treatment of acute pain in children. Br J Anaesth 1996;
1. Boerner U, et al. The metabolism of morphine and heroin in 76: 310–12.
man. Drug Metab Rev 1975; 4: 39–73. phine by first-pass metabolism (see Pharmacokinetics, 5. Kendall JM, Latter VS. Intranasal diamorphine as an alternative
2. Inturrisi CE, et al. The pharmacokinetics of heroin in patients above). Diamorphine hydrochloride may also be given to intramuscular morphine: pharmacokinetic and pharmacody-
with chronic pain. N Engl J Med 1984; 310: 1213–17. by continuous subcutaneous or intravenous infusion or namic aspects. Clin Pharmacokinet 2003; 42: 501–13.
3. Moore RA, et al. Opiate metabolism and excretion. Baillieres 6. British Association for Emergency Medicine. Clinical Effective-
Clin Anaesthesiol 1987; 1: 829–58. intraspinally. ness Committee guideline for the management of pain in chil-
4. Barrett DA, et al. Morphine kinetics after diamorphine infusion dren (2004). Available at: http://www.emergencymed.org.uk/
in premature neonates. Br J Clin Pharmacol 1991; 32: 31–7.
For details of doses in children, see below. BAEM/CEC/assets/cec_pain_in_children.pdf (accessed
5. Girardin F, et al. Pharmacokinetics of high doses of intramuscu- Action. Because of its abuse potential, supply of diamorphine is 26/06/08)
lar and oral heroin in narcotic addicts. Clin Pharmacol Ther carefully controlled and in many countries it is not available for Opioid dependence. The treatment of opioid dependence is
2003; 74: 341–52.
clinical use; morphine can provide equivalent analgesia by dose discussed on p.101. Many opiate misusers have expressed a pref-
Administration. INHALATIONAL ROUTE. A literature review1 adjustment. There has been much debate regarding the relative erence for withdrawal using diamorphine rather than methadone.
found that intranasal diamorphine had a similar pharmacoki- merits of analgesia with diamorphine or morphine. Many now In a comparative study stabilisation was achieved using either
netic profile to that of intramuscular diamorphine. It is rapidly regard oral morphine to be the opioid analgesic of choice al- diamorphine or methadone 1 mg/mL oral solutions;1 patients
absorbed, as a dry powder, via the nasal mucosa although this though diamorphine hydrochloride may be preferred for injec- could not identify which they had been given. Whenever signs of
is not as complete as by intramuscular injection; intranasal tion because it is more soluble in water thus allowing the use of physical withdrawal were seen 10 mL of either solution was giv-
absorption appeared to be dose dependent. smaller dose volumes. Diamorphine hydrochloride may also be en and the total amount over the first 24 hours taken as the pa-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
44 Analgesics Anti-inflammatory Drugs and Antipyretics
tient’s daily requirement. The mean dose of diamorphine re- 5. Bailey CR, et al. Diamorphine-bupivacaine mixture compared
quired for stabilisation was 55 mg compared with 36 mg for with plain bupivacaine for analgesia. Br J Anaesth 1994; 72:
58–61. COOH
methadone. Some centres have given diamorphine in the form of 6. Gopinathan C, et al. A comparative study of patient-controlled
reefers. Diamorphine has also been prescribed with methadone epidural diamorphine, subcutaneous diamorphine and an epi-
Cl
H
in the management of addicts.2 A systematic review3 that includ- dural diamorphine/bupivacaine combination for postoperative
N
ed this study failed to produce conclusive results about the effec- pain. Eur J Anaesthesiol 2000; 17: 189–96.
tiveness of diamorphine (alone or with methadone) in mainte- 7. Lee A, et al. Postoperative analgesia by continuous extradural
infusion of bupivacaine and diamorphine. Br J Anaesth 1988;
nance treatment; however, since the studies were not directly 60: 845–50.
comparable, continued evaluation in clinical studies is required. 8. Madej TH, et al. Hypoxaemia and pain relief after lower abdom- Cl
Oral tablets4 and intravenous injection5 of diamorphine have also inal surgery: comparison of extradural and patient-controlled
been tried in severely dependent, treatment-resistant patients. analgesia. Br J Anaesth 1992; 69: 554–7.
9. Reay BA, et al. Low-dose intrathecal diamorphine analgesia Diclofenac Diethylamine (BANM)
Breast feeding has been used to treat diamorphine dependence in following major orthopaedic surgery. Br J Anaesth 1989; 62:
the offspring of dependent mothers but this is no longer consid- 248–52. Diclofenac Diethylammonium; Diclofenaco dietilamina; Dik-
ered to be the best method and some authorities recommend that 10. Kestin IG, et al. Analgesia for labour and delivery using incre- lofenak Dietilamonyum.
breast feeding should be stopped. mental diamorphine and bupivacaine via a 32-gauge intrathecal
catheter. Br J Anaesth 1992; 68: 244–7. Диклофенак Диэтиламин
1. Ghodse AH, et al. Comparison of oral preparations of heroin and C 18 H 22Cl 2 N 2 O 2 = 369.3.
methadone to stabilise opiate misusers as inpatients. BMJ 1990; 11. Vaughan DJA, et al. Choice of opioid for initiation of combined
300: 719–20.
spinal epidural analgesia in labour—fentanyl or diamorphine. C AS — 78213-16-8.
Br J Anaesth 2001; 86: 567–9. ATC — D11AX18.
2. van den Brink W, et al. Medical prescription of heroin to treat- 12. Hallworth SP, et al. Comparison of intrathecal and epidural
ment resistant heroin addicts: two randomised controlled trials. ATC Vet — QD11AX18.
diamorphine for elective Caesarean section using a combined
Abridged version: BMJ 2003; 327: 310–12. Correction. ibid.; spinal-epidural technique. Br J Anaesth 1999; 82: 228–32. Pharmacopoeias. In Br.
724. Full version: http://www.bmj.com/cgi/reprint/327/7410/ 13. Cowan CM, et al. Comparison of intrathecal fentanyl and BP 2008 (Diclofenac Diethylamine). A white to light beige, crys-
310 (accessed 26/06/08) diamorphine in addition to bupivacaine for Caesarean section
3. Ferri M, et al. Heroin maintenance for chronic heroin depend- talline powder. Sparingly soluble in water and in acetone; freely
under spinal anaesthesia. Br J Anaesth 2002; 89: 452–8.
ents. Available in The Cochrane Database of Systematic Re- 14. Lane S, et al. A comparison of intrathecal fentanyl and diamor-
soluble in alcohol and in methyl alcohol; practically insoluble in
views; Issue 2. Chichester: John Wiley; 2005 (accessed phine as adjuncts in spinal anaesthesia for Caesarean section. 1M sodium hydroxide. The pH of a 1% solution in alcohol (10%)
26/06/08). Anaesthesia 2005; 60: 453–7. is between 6.4 and 8.4. Store in airtight containers. Protect from
4. Frick U, et al. A prospective cohort study on orally administered 15. Saravanan S, et al. Minimum dose of intrathecal diamorphine light.
heroin substitution for severely addicted opioid users. Addiction required to prevent intraoperative supplementation of spinal an-
2006; 101: 1631–9. aesthesia for Caesarean section. Br J Anaesth 2003; 91: 368–72.
5. March JC, et al. Controlled trial of prescribed heroin in the treat- 16. Wrench IJ, et al. Dose response to intrathecal diamorphine for Diclofenac Epolamine
ment of opioid addiction. J Subst Abuse Treat 2006; 31: 203–11. elective caesarean section and compliance with a national audit DHEP; Diclofenac Hydroxyethylpyrrolidine.
standard. Int J Obstet Anesth 2007; 16: 17–21.
Pain. ACUTE PAIN. Rapid pain relief may be obtained with the 17. Poullis M. Diamorphine and British cardiology: so we are right! Диклофенак Эполамин
intravenous injection of diamorphine. Other routes include Heart 1999; 82: 645–6. C 14 H 11Cl 2 NO 2 , C 6 H 13 NO = 411.3.
the intraspinal route for which diamorphine is well suited be- C AS — 119623-66-4.
CHRONIC PAIN. Patients with chronic opioid-sensitive pain are
cause of its lipid solubility and pharmacokinetics. Epidural ATC — D11AX18.
doses of diamorphine have ranged from 0.5 to 10 mg. 1 often treated with diamorphine given by continuous subcuta-
neous infusion using a small battery-operated syringe driver. ATC Vet — QD11AX18.
Analgesia was significantly more prolonged and more intense
after epidural rather than intramuscular injection of diamor- The following technique has been described.1 Diamorphine
hydrochloride 1 g could be dissolved in 1.6 mL of water to Diclofenac Potassium (BANM, USAN, rINNM)
phine 5 mg in women who had had caesarean section;2 itch-
ing was reported by 50% of patients undergoing epidural give a solution with a volume of 2.4 mL (415 mg/mL), but the CGP-45840B; Diclofénac potassique; Diclofenaco potásico; Di-
analgesia. Epidural diamorphine alone3 or with bupivacaine4 maximum suggested concentration was 250 mg/mL. If the clofenacum kalicum; Diklofenaakkikalium; Diklofenak draselná sůl;
has been used for analgesia during labour; addition of adren- analgesic requirement was not known the following protocol Diklofenak Potasyum; Diklofenakkalium; Diklofenák-kálium; Dik-
aline appeared to improve the quality and duration of analge- was recommended: lofenako kalio druska; Kalii Diclofenacum. Potassium [o-(2,6-
sia with diamorphine.3 In another study addition of diamor- • Start injections every 4 hours of 2.5 or 5 mg diamorphine, or, dichloroanilino)phenyl]acetate.
phine to bupivacaine produced a high incidence of pruritus if the patient has already been taking opioids, a dose that is Калия Диклофенак
and drowsiness.5 A study6 of patient-controlled analgesia for equivalent to the last dose C 14 H 10Cl 2 KNO 2 = 334.2.
postoperative pain found that although epidural diamorphine, • If this is unsatisfactory increase this dose in 50% increments C AS — 15307-81-0.
used alone or with bupivacaine, reduced the analgesic dose until the patient reports even a little pain relief ATC — D11AX18.
requirement, there was little clinical advantage over the sub- • Calculate the 24-hour requirement by multiplying by six, and ATC Vet — QD11AX18.
cutaneous route. start the infusion at this level Pharmacopoeias. In Eur. (see p.vii) and US.
Continuous epidural infusion of diamorphine • Increase the 24-hour dosage in the pump by 50% increments Ph. Eur. 6.2 (Diclofenac Potassium). A white or slightly yellow-
500 micrograms/hour in 0.125% bupivacaine provided postop- until the pain is controlled. Note that requirements may vary ish, slightly hygroscopic, crystalline powder. Sparingly soluble
erative analgesia superior to that with either drug alone in pa- from less than 20 mg to more than 5 g per 24 hours in water; soluble in alcohol; slightly soluble in acetone; freely
tients undergoing major abdominal gynaecological surgery.7 A When starting an infusion it is important not to allow any break- soluble in methyl alcohol. Store in airtight containers. Protect
similar infusion produced analgesia superior to that with either through pain. This may be achieved either by starting the infu- from light.
epidural bolus injection or patient-controlled intravenous sion more than 2 hours before the previous oral dose wears off or USP 31 (Diclofenac Potassium). pH of a 1% solution in water is
diamorphine in patients undergoing total abdominal hysterecto- by giving a loading dose injection of the 4-hourly requirement. between 7.0 and 8.5. Store at a temperature of 20° to 25°. Protect
my.8 However, more patients receiving the continuous epidural from light.
Although generally free from complications, sterile abscess for-
infusion were hypoxaemic than in the other 2 groups.
mation was reported in 2 patients with advanced cancer receiv-
Diamorphine has also been given intrathecally for postoperative ing diamorphine by continuous subcutaneous infusions.2 Diclofenac Sodium (BANM, USAN, rINNM)
analgesia and should be effective at lower doses than with the
epidural route because of greater CSF concentrations. Diamor- The intraspinal3 and intraventricular4 routes have also been used Diclofénac sodique; Diclofenaco sódico; Diclofenacum natricum;
phine 250 or 500 micrograms given intrathecally with bupi- successfully in patients with intractable pain. Topical application Diclophenac Sodium; Diklofenaakkinatrium; Diklofenak sodná
vacaine spinal anaesthesia both provided greater postoperative of diamorphine has also been tried5,6 for the control of pressure sůl; Diklofenak Sodyum; Diklofenaknatrium; Diklofenák-nátrium;
analgesia than bupivacaine alone,9 but the incidence of adverse ulcer pain in a small number of palliative care patients. Diklofenako natrio druska; GP-45840; Natrii Diclofenacum. So-
effects, especially nausea, vomiting, and urinary retention, was 1. Dover SB. Syringe driver in terminal care. BMJ 1987; 294: dium [2-(2,6-dichloroanilino)phenyl]acetate.
553–5.
still high with either dose and routine use of this technique was 2. Hoskin PJ, et al. Sterile abscess formation by continuous subcu- Натрий Диклофенак
not recommended. Intrathecal diamorphine with bupivacaine taneous infusion of diamorphine. BMJ 1988; 296: 1605. C 14 H 10Cl 2 NNaO 2 = 318.1.
has also been used for analgesia during labour10,11 and caesarean 3. Baker L, et al. Evolving spinal analgesia practice in palliative C AS — 15307-79-6.
section.12-16 In a study12 in patients undergoing caesarean sec- care. Palliat Med 2004; 18: 507–15. ATC — D11AX18.
tion, intrathecal diamorphine 250 micrograms showed compara- 4. Reeve WG, Todd JG. Intraventricular diamorphine via an Om- ATC Vet — QD11AX18.
ble postoperative analgesia with a 5-mg epidural dose and was maya shunt for intractable cancer pain. Br J Anaesth 1990; 65:
544–7. NOTE. DICL is a code approved by the BP 2008 for use on single
associated with less postoperative nausea and vomiting. Other unit doses of eye drops containing diclofenac sodium where the
5. Flock P. Pilot study to determine the effectiveness of diamor-
studies13,14 found that intrathecal diamorphine reduced supple- phine gel to control pressure ulcer pain. J Pain Symptom Manage individual container may be too small to bear all the appropriate
mental analgesic requirements during and after caesarean section 2003; 25: 547–54. labelling information.
when compared with intrathecal fentanyl. Intrathecal diamor- 6. Abbas SQ. Diamorphine-Intrasite dressings for painful pressure
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, US, and Viet.
phine 400 micrograms was considered by some15 to be the low- ulcers. J Pain Symptom Manage 2004; 28: 532–4.
est dose required to reduce intraoperative analgesic supplemen- Ph. Eur. 6.2 (Diclofenac Sodium). A white to slightly yellowish,
tation to below 5%; however, lower doses of 300 micrograms
Preparations slightly hygroscopic, crystalline powder. Sparingly soluble in
have been used in practice.16 BP 2008: Diamorphine Injection; water; soluble in alcohol; slightly soluble in acetone; freely solu-
BPC 1973: Diamorphine Linctus. ble in methyl alcohol. Store in airtight containers. Protect from
Diamorphine has been extensively used by cardiologists in the light.
UK for the management of pain in acute left ventricular failure, Proprietary Preparations (details are given in Part 3)
Switz.: Diaphin. USP 31 (Diclofenac Sodium). A white to off-white, hygroscopic,
unstable angina, and myocardial infarction. It has been theorised crystalline powder. Sparingly soluble in water; soluble in alco-
that diamorphine may offer benefits over morphine because its
hol; practically insoluble in chloroform and in ether; freely solu-
stimulatory effects at opioid δ receptors on the myocardium may
ble in methyl alcohol. pH of a 1% solution in water is between
reduce the extent of myocardial damage.17 Evidence to support
this theory is, however, lacking. Diclofenac (BAN, rINN) 7.0 and 8.5. Store in airtight containers. Protect from light.
1. Morgan M. The rational use of intrathecal and extradural opio- Diclofénac; Diclofenaco; Diclofenacum; Diklofenaakki; Dik-
ids. Br J Anaesth 1989; 63: 165–88. lofenak. [2-(2,6-Dichloroanilino)phenyl]acetic acid.
Adverse Effects and Treatment
2. Macrae DJ, et al. Double-blind comparison of the efficacy of As for NSAIDs in general, p.96.
extradural diamorphine, extradural phenoperidine and im Диклофенак
diamorphine following caesarean section. Br J Anaesth 1987; C 14 H 11Cl 2 NO 2 = 296.1. There may be pain and, occasionally, tissue damage at
59: 354–9. the site of injection when diclofenac is given intramus-
3. Keenan GMA, et al. Extradural diamorphine with adrenaline in C AS — 15307-86-5.
labour: comparison with diamorphine and bupivacaine. Br J ATC — D11AX18; M01AB05; M02AA15; S01BC03. cularly. Diclofenac suppositories can cause local irrita-
Anaesth 1991; 66: 242–6. tion. Transient burning and stinging may occur with di-
4. McGrady EM, et al. Epidural diamorphine and bupivacaine in ATC Vet — QD11AX18; QM01AB05; QM02AA15;
labour. Anaesthesia 1989; 44: 400–3. QS01BC03. clofenac ophthalmic solution; more serious corneal
 Diclofenac 45
adverse effects have also occurred (see Effects on the 2. Deakin M, et al. Small bowel perforation associated with an ex- haemorrhagic diathesis, cerebrovascular bleeding (in-
cessive dose of slow release diclofenac sodium. BMJ 1988; 297:
Eyes, below). Topical preparations of diclofenac, such 488–9. cluding suspected), or asthma nor in patients undergo-
as plasters and gel, may cause application site reac- 3. Gentric A, Pennec YL. Diclofenac-induced pseudomembranous ing surgery with a high risk of haemorrhage.
colitis. Lancet 1992; 340: 126–7.
tions. Ophthalmic preparations containing diclofenac should
Effects on the kidneys. Renal papillary necrosis1 and nephrot-
Incidence of adverse effects. A review of worldwide clinical ic syndrome2-4 have been reported in patients taking diclofenac.
not be used by patients who wear soft contact lenses.
studies with diclofenac1 has reported the incidence of drug-asso- See also Effects on Electrolytes, above. Breast feeding. Diclofenac is distributed into breast milk al-
ciated adverse effects to be about 12%; about 16% of patients 1. Scott SJ, et al. Renal papillary necrosis associated with di- though the BNF and some licensed product information consider
who had adverse effects stopped treatment (a figure correspond- clofenac sodium. BMJ 1986; 292: 1050. the amount to be too small to be harmful to breast-fed infants.
ing to about 2% of the entire patient sample). The most frequent- 2. Beun GDM, et al. Isolated minimal change nephropathy associ-
ly reported adverse effects were gastrointestinal and were report- ated with diclofenac. BMJ 1987; 295: 182–3. Porphyria. Diclofenac sodium has been associated with acute
ed in 7.6% of patients. CNS-related adverse effects were 3. Yinnon AM, et al. Nephrotic syndrome associated with di- attacks of porphyria and is considered unsafe in porphyric pa-
reported in 0.7% of patients and allergy or local reactions in clofenac sodium. BMJ 1987; 295: 556. tients.
4. Tattersall J, et al. Membranous nephropathy associated with di-
0.4%. This and other reviews2 have shown that adverse effects clofenac. Postgrad Med J 1992; 68: 392–3. Veterinary use. Veterinary use of diclofenac in cattle in South
associated with diclofenac are usually mild and transient and ap- Asia has been associated with severe decline in the numbers of
pear to be unrelated to the dose given. Effects on the liver. Elevations of serum aminotransferase ac-
vultures, to whom the residues are highly toxic if they consume
1. Willkens RF. Worldwide clinical safety experience with di- tivity and clinical hepatitis,1-8 including fatal fulminant
the carcasses.1,2 Meloxicam (p.80) has been suggested as an al-
clofenac. Semin Arthritis Rheum 1985; 15 (suppl 1): 105–10. hepatitis2,5 have occurred in patients taking diclofenac. There has
also been a case report of hepato-renal damage attributed to di- ternative.
2. Small RE. Diclofenac sodium. Clin Pharm 1989; 8: 545–8.
clofenac.9 Analysis10 of 180 of the cases of diclofenac-associated 1. Shultz S, et al. Diclofenac poisoning is widespread in declining
Effects on the blood. Results of a large survey undertaken to vulture populations across the Indian subcontinent. Proc Biol Sci
assess the relation between agranulocytosis, aplastic anaemia, hepatic injury received by the FDA between November 1988 2004; 271 (suppl 6): S458–S460.
and drug exposure indicated that diclofenac was significantly as- and June 1991 suggested an increased risk of hepatotoxicity in 2. Sharp D. Meloxicam to prevent rabies? Lancet 2006; 367:
sociated with aplastic anaemia, providing an estimated tenfold female patients and those taking diclofenac for osteoarthritis. 887–8.
increase in risk.1 There are reports of other haematological ab- Hepatotoxicity had been detected within 6 months of starting di-
normalities including haemolytic anaemia,2,3 thrombocytope- clofenac in 85% of the patients. The biochemical pattern of inju- Interactions
nia,4,5 neutropenia,5 and agranulocytosis6 occurring in patients ry was hepatocellular or mixed hepatocellular in 66% of patients For interactions associated with NSAIDs, see p.99.
given diclofenac. and cholestatic injury was found in 8% of patients. Signs of hy-
persensitivity were uncommon and it was considered that the Diclofenac should not be given intravenously to pa-
Localised spontaneous bleeding,7 bruising,8 inhibition of platelet
aggregation,7 and prolonged bleeding time8 have been reported.
mechanism of hepatic injury was likely to be a metabolic idio- tients already receiving other NSAIDs or anticoagu-
syncratic reaction rather than due to intrinsic toxicity of di- lants including low-dose heparin.
1. The International Agranulocytosis and Aplastic Anemia Study. clofenac.
Risks of agranulocytosis and aplastic anemia: a first report of Ciclosporin. Deterioration in renal function has been attributed
their relation to drug use with special reference to analgesics. 1. Dunk AA, et al. Diclofenac hepatitis. BMJ 1982; 284: 1605–6.
JAMA 1986; 256: 1749–57. 2. Breen EG, et al. Fatal hepatitis associated with diclofenac. Gut to the use of diclofenac with ciclosporin.1 Increased concentra-
2. López A, et al. Autoimmune hemolytic anemia induced by di- 1986; 27: 1390–3. tions of diclofenac were also noted with ciclosporin;2 licensed
clofenac. Ann Pharmacother 1995; 29: 787. 3. Schapira D, et al. Diclofenac-induced hepatotoxicity. Postgrad product information for ciclosporin recommends that the dosage
Med J 1986; 62: 63–5.
3. Ahrens N, et al. Misdiagnosis in patients with diclofenac-in- 4. Ryley NG, et al. Diclofenac associated hepatitis. Gut 1989; 30: of diclofenac should be reduced by about one-half when the two
duced hemolysis: new cases and a concise review. Am J Hematol A708. are given together.
2006; 81: 128–31. 5. Helfgott SM, et al. Diclofenac-associated hepatotoxicity. JAMA 1. Branthwaite JP, Nicholls A. Cyclosporin and diclofenac interac-
4. George S, Rahi AHS. Thrombocytopenia associated with di- 1990; 264: 2660–2. tion in rheumatoid arthritis. Lancet 1991; 337: 252.
clofenac therapy. Am J Health-Syst Pharm 1995; 52: 420–1. 6. Purcell P, et al. Diclofenac hepatitis. Gut 1991; 32: 1381–5. 2. Kovarik JM, et al. Cyclosporine and nonsteroidal antiinflamma-
5. Kim HL, Kovacs MJ. Diclofenac-associated thrombocytopenia 7. Bhogaraju A, et al. Diclofenac-associated hepatitis. South Med tory drugs: exploring potential drug interactions and their impli-
and neutropenia. Ann Pharmacother 1995; 29: 713–15. J 1999; 92: 711–13. cations for the treatment of rheumatoid arthritis. J Clin Pharma-
6. Colomina P, Garcia S. Agranulocytosis caused by diclofenac. 8. Greaves RRSH, et al. Inadvertent diclofenac rechallenge from col 1997; 37: 336–43.
DICP Ann Pharmacother 1989; 23: 507. generic and non-generic prescribing, leading to liver transplan-
7. Price AJ, Obeid D. Spontaneous non-gastrointestinal bleeding tation for fulminant liver failure. Eur J Gastroenterol Hepatol Diuretics. Deterioration in renal function has been attributed to
associated with diclofenac. Lancet 1989; ii: 1520. 2001; 13: 71–3. the use of diclofenac with triamterene.1
8. Khazan U, et al. Diclofenac sodium and bruising. Ann Intern 9. Diggory P, et al. Renal and hepatic impairment in association
with diclofenac administration. Postgrad Med J 1989; 64: 1. Härkönen M, Ekblom-Kullberg S. Reversible deterioration of re-
Med 1990; 112: 472–3. nal function after diclofenac in patient receiving triamterene.
507–8.
Effects on the cardiovascular system. For a discussion of 10. Banks AT, et al. Diclofenac-associated hepatotoxicity: analysis BMJ 1986; 293: 698–9.
the cardiovascular effects of NSAIDs, including diclofenac, see of 180 cases reported to the Food and Drug Administration as Gastrointestinal drugs. A decrease in the plasma concentra-
adverse reactions. Hepatology 1995; 22: 820–7.
p.96. tion of diclofenac has been reported1 when given after sucralfate.
Effects on electrolytes. A syndrome resembling the syn- Effects on the skin. Self-limiting skin reactions such as rash or 1. Pedrazzoli J, et al. Short-term sucralfate administration alters
drome of inappropriate antidiuretic hormone secretion has been pruritus may occur in patients given diclofenac. More serious potassium diclofenac absorption in healthy male volunteers. Br
reported in elderly women given diclofenac.1,2 Also the UK skin reactions attributed to diclofenac include bullous dermatitis1 J Clin Pharmacol 1997; 43: 104–108.
CSM had received a report of fatal hyponatraemia in another eld- and erythema multiforme.2,3 Local irritation and necrosis has oc- Lipid regulating drugs. Colestyramine appears substantially
erly woman.2 curred on intramuscular injection of diclofenac.4-7 to reduce the bioavailability of diclofenac when the two drugs are
1. Petersson I, et al. Water intoxication associated with non-steroi-
1. Gabrielsen TØ, et al. Drug-induced bullous dermatosis with lin- given together;1 colestipol produces a similar but smaller effect.
ear IgA deposits along the basement membrane. Acta Derm Ve-
dal anti-inflammatory drug therapy. Acta Med Scand 1987; 221: 1. al-Balla SR, et al. The effects of cholestyramine and colestipol
nereol (Stockh) 1981; 61: 439–41.
221–3. on the absorption of diclofenac in man. Int J Clin Pharmacol
2. Morris BAP, Remtulla SS. Erythema multiforme major follow- Ther 1994; 32: 441–5.
2. Cheung NT, et al. Syndrome of inappropriate secretion of anti- ing use of diclofenac. Can Med Assoc J 1985; 133: 665.
diuretic hormone induced by diclofenac. BMJ 1993; 306: 186.
3. Young J. Erythema multiforme-like eruption as a result of ‘So- Misoprostol. The plasma concentration of diclofenac was re-
Effects on the eyes. A patient who had been taking oral di- laraze’ treatment. J Dermatol Treat 2003; 14: 189. duced when it was given as a 100-mg dose daily in the form of a
clofenac for several years and had increasingly complained of 4. Stricker BHC, van Kasteren BJ. Diclofenac-induced isolated modified-release preparation to subjects receiving misoprostol
myonecrosis and the Nicolau syndrome. Ann Intern Med 1992;
dry, gritty eyes noticed that eye irritation disappeared within 3 117: 1058. 800 micrograms daily.1 Use together was also associated with an
days when diclofenac had to be stopped because of gastrointesti- 5. Pillans PI, O’Connor N. Tissue necrosis and necrotising fasciitis increase in the incidence and severity of gastrointestinal effects.
nal effects.1 after intramuscular administration of diclofenac. Ann Pharmaco- Studies by the manufacturer2 had failed to find any significant
Ocular diclofenac and related drugs have been implicated in re- ther 1995; 29: 264–6. pharmacokinetic interactions between diclofenac and misopros-
ports of corneal toxicity. Ulceration of the conjunctiva or cornea, 6. Ezzedine K, et al. Nicolau syndrome following diclofenac ad- tol when given in a formulation containing diclofenac 50 mg and
ministration. Br J Dermatol 2004; 150: 385–7. misoprostol 200 micrograms.
corneal or scleral melts, and perforations have been reported in 7. Mutalik S, Belgaumkar V. Nicolau syndrome: a report of 2 cases.
patients using diclofenac eye drops, particularly after cataract J Drugs Dermatol 2006; 5: 377–8. 1. Dammann HG, et al. Differential effects of misoprostol and ran-
surgery.2-5 Keratitis and perforations were also reported with itidine on the pharmacokinetics of diclofenac and gastrointesti-
ketorolac eye drops,4 although less frequently. For mention of Hypersensitivity. Aspirin-sensitive asthmatic patients have nal symptoms. Br J Clin Pharmacol 1993; 36: 345–9.
corneal melting with bromfenac, see p.28. developed reactions (rhinorrhoea, tightness of chest, wheezing, 2. Karim A. Pharmacokinetics of diclofenac and misoprostol when
dyspnoea) when challenged with diclofenac in doses of 10 to administered alone or as a combination product. Drugs 1993; 45
1. Reid ALA, Henderson R. Diclofenac and dry, irritable eyes. Med (suppl 1): 7–14.
J Aust 1994; 160: 308. 25 mg1 and the UK CSM has received a report of an aspirin-sen-
2. Lin JC, et al. Corneal melting associated with use of topical non- sitive patient who died from acute asthma 4 hours after a single Parasympathomimetics. Licensed product information for
steroidal anti-inflammatory drugs after ocular surgery. Arch 25-mg dose of diclofenac.2 acetylcholine chloride ophthalmic preparations has stated that
Ophthalmol 2000; 118: 1129–32. Anaphylactic shock has been reported.3 there have been reports that acetylcholine and carbachol have
3. Congdon NG, et al. Corneal complications associated with topi- been ineffective when used in patients treated with topical (oph-
1. Szczeklik A, et al. Asthmatic attacks induced in aspirin-sensitive
cal ophthalmic use of nonsteroidal antiinflammatory drugs. J thalmic) NSAIDs.
patients by diclofenac and naproxen. BMJ 1977; 2: 231–2.
Cataract Refract Surg 2001; 27: 622–31.
2. CSM/MCA. Avoid all NSAIDs in aspirin-sensitive patients.
4. Guidera AC, et al. Keratitis, ulceration, and perforation associ- Current Problems 1993; 19: 8. Also available at:
ated with topical nonsteroidal anti-inflammatory drugs. Oph- http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ Pharmacokinetics
thalmology 2001; 108: 936–44.
5. Flach AJ. Corneal melts associated with topically applied nons-
FILE&dDocName=CON2024455&RevisionSelectionMethod= Diclofenac is rapidly absorbed when given as an oral
LatestReleased (accessed 01/11/07)
teroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc 3. Dux S, et al. Anaphylactic shock induced by diclofenac. BMJ
solution, sugar-coated tablets, rectal suppository, or by
2001; 99: 205–10. 1983; 286: 1861. intramuscular injection. It is absorbed more slowly
Effects on the gastrointestinal tract. The most frequent ad- when given as enteric-coated tablets, especially when
verse effects reported in patients given diclofenac systemically Precautions this dosage form is given with food. Although di-
are gastrointestinal in nature. Typical reactions include epigastric As for NSAIDs in general, p.98. Systemic diclofenac
pain, nausea, vomiting, and diarrhoea. Rarely peptic ulcer and clofenac given orally is almost completely absorbed, it
gastrointestinal bleeding have occurred. Diclofenac has also is contra-indicated in patients with severe hepatic or re- is subject to first-pass metabolism so that about 50% of
been implicated as the causative agent in colonic ulceration,1 nal impairment. the drug reaches the systemic circulation in the
small bowel perforation,2 and pseudomembranous colitis.3 Di- In addition, use of intravenous diclofenac is contra-in- unchanged form. Diclofenac is also absorbed percuta-
clofenac suppositories may cause local reactions such as itching, dicated in patients with moderate or severe renal im- neously. At therapeutic concentrations it is more than
burning, or exacerbation of haemorrhoids.
1. Carson J, et al. Colonic ulceration and bleeding during di-
pairment, hypovolaemia, or dehydration; it should also 99% bound to plasma proteins. Diclofenac penetrates
clofenac therapy. N Engl J Med 1990; 323: 135. not be given intravenously in patients with a history of synovial fluid where concentrations may persist even
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
46 Analgesics Anti-inflammatory Drugs and Antipyretics
when plasma concentrations fall; small amounts are mended for parenteral use is 2 days. Diclofenac sodi- to 2 days. Again, a maximum daily dose of 150 mg should not be
distributed into breast milk. The terminal plasma half- um is also used intramuscularly in renal colic in a dose exceeded.
life is about 1 to 2 hours. Diclofenac is metabolised to of 75 mg repeated once after 30 minutes if necessary. Diclofenac potassium has also been used in children aged over
14 years for the treatment of rheumatic disease, musculoskeletal
4′-hydroxydiclofenac, 5-hydroxydiclofenac, 3′-hy- For dosage details in children see below. disorders, and postoperative pain; it is given in an oral dose of 75
droxydiclofenac and 4′,5-dihydroxydiclofenac. It is Diclofenac sodium is used as a 0.1% ophthalmic solu- to 100 mg daily in 2 to 3 divided doses.
then excreted in the form of glucuronide and sulfate tion in a number of situations: TOPICAL. References to the use of plasters providing sustained
conjugates, mainly in the urine (about 60%) but also in topical release of diclofenac epolamine,1-6 and a systematic
the bile (about 35%); less than 1% is excreted as • for the prevention of intra-operative miosis during review of the use of a topical solution of diclofenac with
unchanged diclofenac. cataract surgery, it is instilled in the appropriate eye dimethyl sulfoxide to treat osteoarthritis.7 The latter was
4 times during the 2 hours before surgery found to be effective and better tolerated than oral use.
◊ References. 1. Galeazzi M, Marcolongo R. A placebo-controlled study of the
1. Fowler PD, et al. Plasma and synovial fluid concentrations of • for the treatment of postoperative inflammation after efficacy and tolerability of a nonsteroidal anti-inflammatory
diclofenac sodium and its major hydroxylated metabolites dur- cataract surgery, it is instilled 4 times daily for up to drug, DHEP plaster, in inflammatory peri- and extra-articular
ing long-term treatment of rheumatoid arthritis. Eur J Clin Phar- rheumatological diseases. Drugs Exp Clin Res 1993; 19: 107–15.
macol 1983; 25: 389–94. 28 days starting 24 hours after surgery 2. Dreiser RL, Tisne-Camus M. DHEP plasters as a topical treat-
2. Maggi CA, et al. Comparative bioavailability of diclofenac hy- • for the control of post-photorefractive keratectomy ment of knee osteoarthritis—a double-blind placebo-controlled
droxyethylpyrrolidine vs diclofenac sodium in man. Eur J Clin study. Drugs Exp Clin Res 1993; 19: 117–23.
Pharmacol 1990; 38: 207–8. pain, it is instilled twice in the hour before surgery, 3. Affaitati G, et al. Effects of topical diclofenac (DHEP plaster) on
3. Davies NM, Anderson KE. Clinical pharmacokinetics of di- then one drop twice at 5-minute intervals immediate- skin, subcutis and muscle pain thresholds in subjects without
clofenac: therapeutic insights and pitfalls. Clin Pharmacokinet spontaneous pain. Drugs Exp Clin Res 2001; 27: 69–76.
1997; 33: 184–213. ly after the procedure, and then every 2 to 5 hours 4. Jenoure P-J. Évaluation d’un anti-inflammatoire non stéroïdien
4. Brenner SS, et al. Influence of age and cytochrome P450 2C9 while awake for up to 24 hours topique dans le traitement de la douleur et de l’inflammation:
genotype on the steady-state disposition of diclofenac and exemple de Flector Tissugel 1% dispositif local bioadhésif de
celecoxib. Clin Pharmacokinet 2003; 42: 283–92. • for pain control after accidental trauma one drop is diclofénac épolamine. Presse Med 2004; 33: 10–13.
5. Hinz B, et al. Bioavailability of diclofenac potassium at low dos- instilled 4 times daily for up to 2 days 5. Brühlmann P, et al. Short-term treatment with topical diclofenac
es. Br J Clin Pharmacol 2005; 59: 80–4. epolamine plaster in patients with symptomatic knee osteoarthri-
• in the treatment of inflammation and discomfort af- tis: pooled analysis of two randomised clinical studies. Curr Med
ter strabismus surgery one drop is instilled 4 times Res Opin 2006; 22: 2429–38.
Uses and Administration 6. Alessandri F, et al. Topical diclofenac patch for postoperative
Diclofenac, a phenylacetic acid derivative, is an daily for the first week; this is reduced to 3 times dai- wound pain in laparoscopic gynecologic surgery: a randomized
NSAID (p.99). It is used mainly as the sodium salt for ly in the second week, twice daily in the third week, study. J Minim Invasive Gynecol 2006; 13: 195–200.
7. Towheed TE. Pennsaid therapy for osteoarthritis of the knee: a
the relief of pain and inflammation in various condi- and as required for the fourth week systematic review and metaanalysis of randomized controlled
tions: musculoskeletal and joint disorders such as rheu- trials. J Rheumatol 2006; 33: 567–73.
• for the control of inflammation after argon laser
matoid arthritis, osteoarthritis, and ankylosing spond- trabeculoplasty one drop is instilled 4 times during Actinic keratoses. Diclofenac sodium 3% in hyaluronic acid
ylitis; peri-articular disorders such as bursitis and gel is used1-3 in the treatment of actinic keratoses (see Basal Cell
the 2 hours before the procedure followed by one and Squamous Cell Carcinoma, p.673), and a meta-analysis4
tendinitis; soft-tissue disorders such as sprains and drop 4 times daily for up to 7 days after the proce- found it to be of benefit, despite previous concerns that the prep-
strains; and other painful conditions such as renal colic, dure aration may not be significantly more effective than hyaluronic
acute gout, dysmenorrhoea, migraine, and after some • for the treatment of pain and discomfort after radial acid gel alone.5 An open-label comparison involving 30 patients
surgical procedures. It has also been used in some with multiple actinic keratoses suggested that 90 days of treat-
keratotomy one drop is instilled before surgery fol- ment with diclofenac sodium 3% gel (to lesions on one side of
countries for the management of actinic keratoses and lowed by one drop immediately after surgery and the face and scalp) was better tolerated, but slightly less effective,
fever. Eye drops of diclofenac sodium are used for the then one drop 4 times daily for up to 2 days than 28 days of treatment with fluorouracil 5% cream (to lesions
prevention of intra-operative miosis during cataract ex- on the other side).6
traction, for the treatment of inflammation after sur- • to relieve symptoms of seasonal allergic conjunctivi- 1. Rivers JK, McLean DI. An open study to assess the efficacy and
gery or laser treatment of the eye, for pain in corneal tis one drop is instilled 4 times daily as necessary safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for
the treatment of actinic keratoses. Arch Dermatol 1997; 133:
epithelial defects after surgery or accidental trauma, Diclofenac diethylamine is used topically as a gel con- 1239–42.
and for the relief of ocular signs and symptoms of taining the equivalent of 1% of diclofenac sodium for 2. Rivers JK, et al. Topical treatment of actinic keratoses with 3.0%
diclofenac in 2.5% hyaluronan gel. Br J Dermatol 2002; 146:
seasonal allergic conjunctivitis. the local symptomatic relief of pain and inflammation; 94–100.
The usual oral or rectal dose of diclofenac sodium is it is applied to the affected site 3 or 4 times daily; treat- 3. Ulrich C, et al. Treatment of multiple actinic keratoses with top-
ment should be reviewed after 14 days or after 28 days ical diclofenac 3% gel in organ transplant recipients: a series of
75 to 150 mg daily in divided doses. In the UK the six cases. Br J Dermatol 2007; 156 (suppl 3): 40–2.
maximum dose regardless of route or indication is if used for osteoarthritis. A topical solution of di- 4. Pirard D. et al. Three percent diclofenac in 2.5% hyaluronan gel
clofenac sodium 1.6% is also available for the treat- in the treatment of actinic keratoses: a meta-analysis of the re-
150 mg daily; however, in the USA a maximum oral cent studies. Arch Dermatol Res 2005; 297: 185–9.
dose of 200 mg daily is allowed in the treatment of ment of osteoarthritis in superficial joints such as the 5. McEwan LE, Smith JG. Topical diclofenac/hyaluronic acid gel in
rheumatoid arthritis. Modified-release preparations of wrist or knee; it is applied in small aliquots to achieve the treatment of solar keratoses. Australas J Dermatol 1997; 38:
187–9.
diclofenac sodium are available for oral use. Di- a total of 20 or 40 drops, depending on the size of the 6. Smith SR, et al. Bilateral comparison of the efficacy and tolera-
clofenac has also been given in equivalent oral doses as joint, and repeated four times daily. Diclofenac is also bility of 3% diclofenac sodium gel and 5% 5-fluorouracil cream
used in the management of actinic keratoses; it is ap- in the treatment of actinic keratoses of the face and scalp. J
the free acid in dispersible preparations for short-term Drugs Dermatol 2006; 5: 156–9.
treatment up to 3 months long. Diclofenac is also given plied twice daily as diclofenac sodium gel 3% for 60 to
Pain. Reviews.
orally as the potassium salt. Doses of the potassium salt 90 days but the optimum therapeutic effect may not be 1. Barden J, et al. Single dose oral diclofenac for postoperative
are similar to those for diclofenac sodium. Diclofenac seen until 30 days after the end of treatment. Di- pain. Available in The Cochrane Database of Systematic Re-
clofenac epolamine is also used topically as a plaster views; Issue 2. Chichester: John Wiley; 2004 (accessed
potassium is also used in the treatment of migraine in 07/11/06).
an initial dose of 50 mg taken at the first signs of an containing the equivalent of 1% of diclofenac sodium
for local symptomatic pain relief in ankle sprain and Preparations
attack; an additional dose of 50 mg may be taken after BP 2008: Diclofenac Gel; Gastro-resistant Diclofenac Tablets; Prolonged-
2 hours if symptoms persist. If necessary further doses epicondylitis. In the treatment of ankle sprain, 1 plaster release Diclofenac Capsules; Prolonged-release Diclofenac Tablets;
of 50 mg may be taken every 4 to 6 hours to a maxi- is applied once daily for a maximum of 3 days and for USP 31: Diclofenac Potassium Tablets; Diclofenac Sodium Delayed-release
Tablets; Diclofenac Sodium Extended-Release Tablets.
mum daily dose of 200 mg. epicondylitis, 1 plaster is applied twice daily for a max-
Proprietary Preparations (details are given in Part 3)
imum of 14 days. Arg.: Ainedif; Aktiosan†; Aldoron NF; Algicler; Algioxib; Anaflex; Atomo
Diclofenac sodium may also be given by deep intra- Desinflamante Geldic; Banoclus; Befol; Blokium; Calmoflex; Cataflam†; Cur-
muscular injection into the gluteal muscle in a dose of Diclofenac is available in combination with misopros- inflam; Damixa†; Desinflam†; DFN; Diastone; Diclac; Diclogesic; Diclogrand;
75 mg once daily or, if required in severe conditions, tol (see p.2013) for patients at risk of NSAID-induced Diclomar; Diclonex; Difenac; Difenac Forte; Dilam; Dioxaflex; Disipan;
peptic ulceration. Dolo Tomanil; Dolofenac; Doloneitor; Dolvan; Doxtran; Faboflem; Flexin;
75 mg twice daily. Diclofenac sodium may also be giv- Flexiplen; Flogenac†; Flogolisin; Flotac†; Fluxpiren; Gel Antiinflamatorio†;
en as a continuous or intermittent intravenous infusion Administration. IN CHILDREN. In children 1 to 12 years old Gentisalyl; Iglodine; Imanol; Indofeno†; Ingeclof; Klonafenac; Lenitil†; Leve-
dad; Lorbifenac; Metaflex NF; Miocalm; Nalgiflex; Natura Fenac; Norviken;
in glucose 5% or sodium chloride 0.9% (both previous- the licensed UK oral or rectal dose of diclofenac sodium for Oxa; Oxaprost; Pronix; Quer-Out; Rati Salil D; Rodinac; Salicrem Forte;
ly buffered with sodium bicarbonate) or as a bolus in- juvenile idiopathic arthritis is 1 to 3 mg/kg daily in divided Silfox; Tomanil; Vesalion; Viartril NF; Vimultisa; Virobron Gel; Virobron NF;
doses. In children 6 to 12 years old diclofenac sodium may Volforte; Voltaren; Voltaren Colirio; Voltaren Migra; Xedenol; Xina†; Aus-
travenous injection.. For the treatment of postoperative also be given rectally for the treatment of acute postoperative tral.: Arthrotec; Clonac; Dencorub Anti-Inflammatory†; Diclac; Diclohexal;
pain a dose of 75 mg may be given over 30 to 120 min- Dinac; Fenac; Imflac; Solaraze; Voltaren; Voltaren Ophtha; Austria: Ag-
pain, either alone or as an adjunct to opiate therapy; a usual ilomed; Algefit; Arthrotec; Dedolor; Deflamat; Deflamm; Diclac; Diclaxol;
utes or as a bolus injection. The dose may be repeated dose is 1 to 2 mg/kg daily in divided doses for a maximum of Diclo-B; Diclobene; Diclomelan; Diclostad; Diclosyl; Difene; Dolo-Voltaren;
once after 4 to 6 hours if necessary. To prevent postop- 4 days. The parenteral route is not licensed for use in children Dolpasse; Fenaren; Flector; Magluphen†; Rheumabene†; Tratul; Voltaren;
although it has been used (see below). Zymamed; Belg.: Arthrotec; Cataflam; Diclofemed; Diclotop; Docdiclofe;
erative pain, an initial dose of 25 to 50 mg diclofenac Flector; Motifene; Polyflam; Voltapatch; Voltaren; Braz.: Ana-Flex; Artren;
sodium may be given after surgery over 15 to 60 min- The BNFC suggests slightly different doses of diclofenac sodi- Augelit†; Bel-Gel†; Benevran; Biofenac; Cataflam; Cataflex; Cataflexym; Cat-
um: in the management of rheumatic disease, including juvenile algem†; Cinaflan†; Clofaren†; Clofen†; Clofenak; Clofenid; Deltaflogin; Del-
utes followed by 5 mg/hour to a maximum of 150 mg idiopathic arthritis, in children from 6 months of age, it recom- taren; Desinflex†; Diclac†; Diclo P; Diclof†; Diclofen†; Diclofenax†; Diclog-
daily. Alternatively, the initial dose may be given as a enom; Diclokalium†; Diclonaco; Diclonatrium†; Diclonax; Diclonil;
mends an oral dose of 3 to 5 mg/kg daily, in 2 or 3 divided doses, Diclosod†; Diclosodico; Difenan†; Dioxaflex; Dnaren; Dorflan; Dorgen;
bolus injection over 5 to 60 seconds followed by addi- up to a maximum of 150 mg daily. For relief of pain and inflam- Doriflan†; Fenaflan; Fenaren; Fenburil; Fisioren; Fladon; Flamalgen†; Flanakin;
tional injections up to the maximum daily dosage; this mation in, for example, soft-tissue disorders, the recommended Flanaren; Flexamina†; Flodin Duo; Flogan; Flogesic†; Flogiren; Flogonac†;
oral or rectal dose in children from 6 months of age is 0.3 to Flotac; Infladoren†; Inflamax; Kindaren; Lifaren†; Luparen†; Maxilerg; Neo-
may be repeated after 4 to 6 hours if necessary al- 1 mg/kg given three times daily; children 2 years of age and older coflan; Neotaflan; Neotaren; Olfen; Optamax†; Ortoflan; Poltax; Probenxil;
though the total dose should not exceed the maximum Prodofenaco; Profenac†; Sintofenac†; Sodix; Still; Tonaflan†; Tricin†; Ven-
may be given a similar dose once or twice daily by intravenous drex; Voltaflan; Voltaflex; Voltaren; Voltaren Colirio; Voltrix; Canad.: Apo-
daily dose of 150 mg. The maximum period recom- infusion or deep intramuscular (gluteal) injection instead, for up Diclo; Arthrotec; Diclotec†; Novo-Difenac; Nu-Diclo; Pennsaid; Voltaren;
 Diclofenac/Diflunisal 47
Voltaren Ophtha; Chile: 3A Ofteno; Amofen; Artren; Autdol; Cataflam; robion; Neodolpasse; Neurofenac; Voltamicin; Belg.: Ocubrax; Braz.: Algi- Adverse Effects and Treatment
Deflamat; Diclotaren; Dicogel; Dignofenac†; Elitiran; Exflam; Flector; Flotac; Butazolon†; Algi-Tanderil†; Beserol; Cedrilax†; Codaten; Diclofetamol; Flex- As for NSAIDs in general, p.96. The commonest adverse effects
Lertus; Merpal; Noxiflex†; Oftic; Pirexyl; Piroflam; Pro Lertus; Sipirac; Tur- algin; Mioflex A; Sedilax; Tandene; Tanderalgin; Tandriflan; Tandrilax; Torsilax;
bogesic; Voltaren; Cz.: Almiral; Apo-Diclo; Arthrotec†; Diclofen; Di- Trilax†; Cz.: Neodolpasse; Voltamicin†; Ger.: Combaren; Voltaren Plus; occurring with diflunisal are gastrointestinal disturbances, head-
cloreum; DIKY; Dolmina; Dorosan; Feloran†; Flector; Inflamac†; Monoflam; Gr.: Tobrafen; Hong Kong: Neurofenac†; Vartelon-B; Vidaclofen-Plus; ache, and rash. Peptic ulceration and gastrointestinal bleeding
Myogit; Naclof†; Naklofen; Olfen; Rewodina; Uniclophen; Uno; Veral; Hung.: Neodolpasse; Ocubrax†; Voltamicin†; India: Actimol; Buta-Proxy- have been reported. Dizziness, drowsiness, insomnia, and tinni-
Voltaren; Denm.: Arthrotec; Diclodan; Diclogea†; Diclon; Difenet; Flector; von; Cip-Zox; Cipzen D; Cofenac; Diclogenta; Diclomol; Dicloran MS; Di- tus may also occur.
Modifenac; Solaraze; Voltaren; Vostar; Fin.: Arthrotec; Diclometin; Diclom- cloran-A†; Diclospa; Diser; Doflex Plus; Dolocide KP; Dolocide MR; DP
ex; Eeze; Flector; Motifene; Solaraze; Trabona†; Voltaren; Fr.: Artotec; Flec- Gesic; Duoflam Gel; Esgipyrin; Fenaplus; Fenaplus-MR; Fensaide-P†; Flamar- Effects on the blood. Haematological adverse effects associ-
tor; Solaraze; Voldal; Voltarendolo; Voltarene; Xenid; Ger.: Allvoran; Artho- MX; Flanzen-D; Inflazone; Myospaz Forte; New Panazox; Nicip D; Omnigel; ated with diflunisal appear to be infrequent. Thrombocytopenia
tec; Benfofen†; Delphinac†; Diclac; Diclo; Diclo-Divido; Diclo-Gel; Diclo- Osteoflam-MR; Oxalgin-DP; Pacizox; Paracip Plus; Parvon Forte; Reactine
Puren; Diclo-saar; Diclodoc; Diclofenbeta; Diclophlogont†; Difen; Dolgit- Forte; Reactine Plus; Relaxyl Plus; Spasmo-Proxyvon Forte; Systaflam; In- associated with diflunisal-induced peripheral platelet destruction
Diclo; duravolten†; Effekton; Jenafenac; Jutafenac; Lexobene†; Monoflam; don.: Dolofenac; Ital.: Voltamicin†; Malaysia: Voren Plus; Mex.: Ariflam has been reported in a patient with rheumatoid arthritis.1 Heinz-
Myogit; Rewodina; Sigafenac†; Solaraze; Voltaren; Voltaren Ophtha; Gr.: Forte; Diclovith-B; Dolaren; Dolo-Neurobion; Dolo-Pangavit; Duciclon; body haemolytic anaemia has also been reported, see Hypersen-
Anthraxiton; Arthrotec; Cataflam†; Clonac†; Declofon; Delimon; Denaclof; Duoflex; Empatil; Lertus CD; Ortocol; Tafirol AC; Trazinac; Tribedoce sitivity, below.
Diclofast; Diclophlogont†; Dicloplast; Difend†; Dinaclon†; Evinopon; Eye- Compuesto; Uni-Dox; Voltaren Forte; Pol.: Venozel; Rus.: Diclofenacol
clof; Fenoclof; Figrel†; Flefarmin; Optobet; Pengon†; Pennsaid; Relipain; (Диклофенакол); Dicloran Plus (Диклоран Плюс); Singapore: Vol- 1. Bobrove AM. Diflunisal-associated thrombocytopenia in a pa-
Rheumavek; Ruvominox; Sfinac; Topalgon; Urigon; Vilacril†; Vilonit; Voltaren; tamicin†; Spain: Ocubrax; Switz.: Tobrafen; Voltamicin; Turk.: Ocubrax; tient with rheumatoid arthritis. Arthritis Rheum 1988; 31: 148–9.
Vurdon; Hong Kong: Almiral; Analpan; Apo-Diclo; Arthrotec; Cataflam; Venez.: Combaren; Painfort; Todenac; Trazinac.
Clofec; Clofenac; Curinflam; Diclo-Denk; Diclofen; Diclogesic; Diclowal†; Effects on the kidneys. Acute interstitial nephritis, presenting
Difenac; Difenol; Erdon; Eurofenac; Flector; Flogofenac; Grofenac; Inflanac; as acute oliguric renal failure, erythroderma, and eosinophilia
Novo-Difenac†; Olfen; Remafen; Remethan; Ren; Rhemofenax; Uniren; has followed the use of diflunisal.1
Vartelon; Voltaren; Voltaren Ophtha; Votalen; Zolterol; Hung.: Cataflam; Diethylamine Salicylate 1. Chan LK, et al. Acute interstitial nephritis and erythroderma as-
Diclac; Diclomel; Flameril; Flector; Fortedol; Huma-Difenac†; Olfen†; Ver- sociated with diflunisal. BMJ 1980; 280: 84–5.
al†; Voltaren; Voltaren Ophta; India: Cofenac; Diclomol; Diclonac; Di- Diaethylamini Salicylas; Dietylaminsalicylat; Dietyyliamiinisalisy-
cloran†; Doflex; Dolocide K; Dolocide Plus; Esgipyrin DS; Fenlodac†; Fen- laatti; Salicilato de dietilamina; Salisilat Dietilamin. Effects on the lungs. For reference to pneumonitis associated
saide†; I-Gesic; Jonac; K-Fenac; Nac; Nac Gel; Oxalgin; Oxalgin-D; Oxalgin- with diflunisal therapy, see Hypersensitivity, below.
SR; Profenac; Reactine; Relaxyl; Solunac; Tromagesic; Tromax; Voveran; In- Диэтиламин Салицилат; Салицилат Диэтиламина
don.: Abdiflam; Alflam; Atranac; Berifen; Cataflam; Catanac; Deflamat; Di- C 11 H 17 NO 3 = 211.3. Effects on the skin. Reports of Stevens-Johnson syndrome as-
cloflam; Diclomec; Diflam; Divoltar; Eflagen; Exaflam; Fenaren; Fenavel;
Flamar; Flamenac; Kadiflam; Kaflam; Kamaflam; Klotaren; Laflanac; Linac; C AS — 4419-92-5. sociated with diflunisal.1,2 See also Hypersensitivity, below.
Matsunaflam; Merflam; Nadifen; Neurofenac; Nichoflam; Nilaren; Potazen; 1. Hunter JA, et al. Diflunisal and Stevens-Johnson syndrome. BMJ
Prostanac; Provoltar; Reclofen; Renadinac; Renvol; Scanaflam; Scantaren; 1978; 2: 1088.
Tirmaclo; Valto; Volmatik; Voltadex; Voltaren; Voltaren Ophtha; Voren; X- 2. Grom JA, et al. Diflunisal-induced erythema multiforme major.
Flam; Xepathritis; Yariflam; Zegren; Irl.: Arthrotec; Cataflam; Diclac; Diclo; CH3
Hosp Formul 1986; 21: 353–4.
Diclomax; Diclomel; Difene; Solaraze; Vologen†; Voltarol; Voltarol Ophtha; HO
Israel: Abitren; Arthrotec; Betaren; Cataflam; Dicloplast; Diclorengel; Hypersensitivity. Three cases of hypersensitivity to diflunisal
-
Olfen; Voltaren; Voltaren Ophtha; Ital.: Algosenac; Artrofenac†; Artrotec; H2N+ O in which the main clinical features were fever, elevated liver en-
Dealgic; Deflamat; Diclocular; Diclofan; Dicloftil; Dicloral; Dicloreum; Di-
clotears; Dolaut; Doroxan; Dropflam; Fenadol; Fender; Flector; Flogofenac; zyme values, erythroderma, and eosinophilia, have been report-
Forgenac; Itami; Leviogel; Lisiflen†; Misofenac; Molfenac; Novapirina; ed.1 Heinz-body haemolytic anaemia occurred in one of the pa-
Pennsaid; Ribex Flu†; Solaraze; Topfans; Voltadol; Voltaren; Voltfast; Zero- CH3 O tients. Other hypersensitivity reactions associated with diflunisal
flog; Jpn: Anavan; Malaysia: Almiral; Apo-Diclo†; Cataflam; Clofec; therapy have included pneumonitis2 and fulminant necrotising
Clofenac; Difnal; Fenac; Fenadium†; Inflanac; Lesflam; Neo-Pyrazon; Olfen; fasciitis.3
Remafen†; Remethan; Rhewlin†; Taks†; Uniren; Voltaren; Voren; Wari-Di- Pharmacopoeias. In Br. and Chin.
clowal†; Zolterol; Mex.: 3A Ofteno; Alsidexten; Ariflam; Artrenac; Ar- BP 2008 (Diethylamine Salicylate). White or almost white, 1. Cook DJ, et al. Three cases of diflunisal hypersensitivity. Can
trenac Pro; Artrene; Artrotec; Atalak; Cataflam; Clo-Far; Clonodifen; Coral; odourless or almost odourless crystals. Very soluble in water; Med Assoc J 1988; 138: 1029–30.
Deflox; Dicfafena; Diclac; Dicloran; Diclosol; Dioxaflex; Dirret; Docril; freely soluble in alcohol and in chloroform. Protect from light. 2. Rich MW, Thomas RA. A case of eosinophilic pneumonia and
Dofen; Dolaren; Dolflam; Dolofenac; Doltarac; Evadol; Fenagel; Fenalgin; vasculitis induced by diflunisal. Chest 1997; 111: 1767–9.
Fervex; Flamydol; Flamygel; Flankol; Flogoken; Flotac; Fortical; Fustaren; Gal- Avoid contact with iron or iron salts. 3. Krige JEJ, et al. Necrotising fasciitis after diflunisal for minor
edol; Hipo Sport; Lertus; Lifenac; Liroken; Lodyfen; Logesic†; Lonatec; Lu- injury. Lancet 1985; ii: 1432–3.
fac-Z; Mafena; Manacon; Merxil; Metracin; Musol; Nediclon; Neo-Dolaren; Profile
Pharmaflam; Practiser; Precifenac; Selectofen; Solof; Still; Uni-Fenil†; Vicma- Diethylamine salicylate is a salicylic acid derivative used topi- Overdosage. Diflunisal poisoning has sometimes been fatal.1,2
fen; Volfenac; Voltaren; Neth.: Arthrotec; Artrotec; Cataflam; Itami; Mis- cally in rubefacient preparations similarly to methyl salicylate A dose of 15 g has been reported to have caused death when no
ofenac; Naclof; Normulen; Otriflu; Voltaren; Norw.: Arthrotec; Cataflam; (p.85) for rheumatic and muscular pain.
Modifenac; Otriflu; Solaraze; Voltaren; Voltaren Ophtha; NZ: Apo-Diclo; other drugs were involved but a dose of 7.5 g has also been fatal
Cataflam; Diclax; Diclohexal; Flameril; Voltaren; Voltaren Ophtha; Voltfast; Preparations when taken with other drugs.
Philipp.: Acuflam; Cataflam; Clofenix; Clofil; Clonaren; Difenax; Diflapane; 1. Court H, Volans GN. Poisoning after overdose with non-steroi-
Doloflam; Dycon; Eslofen; Fenaspec; Lobafen; Lofenax; Neo-Pyrazon; BP 2008: Diethylamine Salicylate Cream.
dal anti-inflammatory drugs. Adverse Drug React Acute Poison-
Nepenthe; Parafortan; Rheuflam; Uniclonax; Volfenn; Voltaren; Voren; Zo- Proprietary Preparations (details are given in Part 3) ing Rev 1984; 3: 1–21.
bid; Pol.: Apo-Diclo; Arthrotec; Cataflam; Diclac; Dicloberl; DicloDuo; Di- Belg.: Algesal; Canad.: Physiogesic; Fin.: Algesal; Hung.: Aciphen; India:
cloratio; Dicloreum; Difadol; Diklonat P; Dikloziaja; Felogel; Majamil; Naclof; 2. Levine B, et al. Diflunisal related fatality: a case report. Forensic
Multigesic†; Ital.: Algesal†; Neth.: Algesal; Norw.: Algesal; Pol.: Saldiam; Sci Int 1987; 35: 45–50.
Naklofen; Olfen; Ratiogel; Rewodina; Veral; Voltaren; Voltenac; Port.: Ar- Port.: Algicum; Algiderma; Massagim; Swed.: Algesal; Turk.: Algesal;
throtec; Cataflam; Clofen; Dicloabak; Diclodent; Dicloftal; Diclospray; Di- Reparil N; UK: Algesal; Lloyd’s Cream; Venez.: Alesal. Precautions
clotec; Difnan; Dofene; Dolacen; Dorcalor; Fenac; Fenil-V; Flameril; Flector;
Olfen; Otriflu; Painex; Pennsaid; Solaraze; Voltaren; Rus.: Almiral Multi-ingredient: Arg.: Algesal; Cartiflex; Crema Antiinflamatoria; Fepar- As for NSAIDs in general, p.98. Diflunisal may need to be given
(Алмирал); Apo-Diclo (Апо-дикло); Arthrotec (Артротек)†; Diclac il†; Rati Salil Flex; Salicrem; Austral.: Rubesal; Austria: Algesal; Derivon; in reduced dosage in patients with significant renal impairment
(Диклак); Diclo-F (Дикло-ф); Diclobene (Диклобене); Dicloberl Dolo-Menthoneurin; Dolorex†; Igitur-antirheumatische; Igitur-Rheumafluid; and should not be given when renal impairment is severe. Aspi-
(Диклоберл); Diclonat (Диклонат); Dicloran (Диклоран); Diclovit Latesyl; Pasta rubra salicylata; Reparil; Rheugesal; Thermal; Belg.: Reparil;
Braz.: Reparil; Chile: Repariven; Cz.: Algesal; Reparil-Gel N; Fr.: Algesal rin and other acetylated salicylates are not recommended for use
(Дикловит); Feloran (Фелоран)†; Naclof (Наклоф); Naklofen (Наклофен); in children unless specifically indicated, because of the risk of
Naklofen Duo (Наклофен Дуо); Rapten Rapid (Раптен Рапид); Voltaren Suractive; Reparil; Traumalgyl; Ger.: Algesal; Algesalona†; Dolo-Menthone-
(Вольтарен); S.Afr.: Adco-Clofelam; Arcanafenac; Arthrotec; Arthru- urin†; Doloneuro†; Reparil-Gel N; Gr.: Algesal Suractive; Ponostop; Hong Reye’s syndrome. Although this precaution has not been specif-
Derm; Cataflam; Dicloflam; Diclohexal; Dynak; Flexagen; Fortfen; Infla-Ban; Kong: Reparil; Rubesal; Hung.: Algesal; Reparil N; Indon.: Algesal Super- ically extended to diflunisal it is not generally licensed for use in
K-Fenak; Panamor; Pharmaflam†; Veltex; Voltaren; Voltaren Ophtha; Singa- active; Ital.: Edeven; Reparil; Sedalpan; Via Mal Traumagel; Mex.: Algesal†;
Neth.: Algesal Forte; Norw.: Thermal†; Pol.: Reparil N; Port.: Algesal; children.
pore: Almiral; Cataflam; Clofec; Clofenac; Diclo; Diclo-Denk†; Dicloran; Di-
clowal†; Difenac; Difnal; Inac; Inflanac; Lesflam; Neo-Pyrazon†; Olfen; Pri- Latesil; Medalginan; Venoparil; S.Afr.: Reparil; Spain: Algesal; Contusin; Interactions
taren; Remafen; Remethan†; Rhewlin; Ultrafen; Uniren; Voltaren; Voltaren Doctomitil†; Dolmitin; Feparil; Radio Salil; Switz.: Algesal†; Algesalona†;
Mavena Proctal-Gen; Reparil; Thai.: Reparil; Veno Gel; Turk.: Algesal Su- For interactions associated with NSAIDs, see p.99.
Ophtha; Voren; Zolterol; Spain: Artrotec; Di Retard; Dolo Nervobion;
Dolo-Voltaren; Dolotren; Luase; Normulen; Sulexon; Voltaren; Swed.: Ar- ractive; Prepagel; UAE: Rubicalm; UK: Fiery Jack; Transvasin Heat Spray; Aspirin may produce a small decrease in the plasma concentra-
throtec; Flector; Modifenac†; Solaraze; Voltaren; Voltaren Ophtha; Voltaren Venez.: Lemazol. tion of diflunisal. Diflunisal has been reported to increase the
T; Switz.: Agofenac†; Arthrotec; Athrofen; Deflamat†; Diclac; diclo-basan; plasma concentrations of indometacin and paracetamol; diflunis-
Diclo†; Diclosifar; Ecofenac; Effigel; Flector; Fortenac; Grofenac; Inflamac; al with indometacin has been associated with fatal gastrointesti-
Olfen; Primofenac; Relova; Tonopan; Vifenac; Voltaren Dolo; Voltaren
Emulgel; Voltaren Ophta; Voltarene; Thai.: Almiral†; Ammi-Votara; Ammi- Diflunisal (BAN, USAN, rINN) nal haemorrhage and therefore the combination should not be
nac; Arclonac; Arthrotec†; Cataflam; Catanac; Cencenag; Chinclonac; used. Regular use of antacids may reduce the absorption of dif-
Clofec; Clofon; Demac; Diclofen†; Diclogel; Diclolan; Diclomol; Diclosian; Diflunisaali; Diflunisalis; Diflunisalum; Difluniszal; MK-647. 5-(2,4- lunisal.
Difelene†; Difen; Difenac; Difengesic; Difeno; Dinac; Dinefec†; Dosanac; Difluorophenyl)salicylic acid.
Fenac; Fenagel; Flexy; Inflanac; Lesflam; Lofenac; Masaren; Medaren†; My-
Дифлунисал Benzodiazepines. For the effect of diflunisal on plasma con-
fenax; Myonac; N-Zen; Naclof; Olfen†; Ostaren; Posnac; Putaren†; Remeth- centrations of oxazepam, see p.989.
an; Rhumanol; Rumatab†; Sefnac; Silflam†; Subsyde; Taks; Tarjen†; Tarjena; C 13 H 8 F 2 O 3 = 250.2.
Uniren; Vasalen; Veenac; Ventarone; Volfenac; Volnac; Volta; Voltanac; C AS — 22494-42-4. Probenecid. Average steady-state plasma concentrations of di-
Voltaren; Volverac; Votamed; Turk.: Actinoma; Cataflam; Deflamat; Diclo- flunisal were increased by 65% when it was given with probene-
flam; Diclomec; Difenak; Dikloron; Dolorex; Inflased; Kalidren; Miyadren; ATC — N02BA11.
Voltaren; Voltaren Ophta; UAE: Clofen; UK: Acoflam†; Arthrotec; ATC Vet — QN02BA11. cid.1 This was due mainly to reduced formation of the phenolic
Defanac; Defenac; Dexomon; Dicloflex; Diclomax; Diclovol; Diclozip; Dy- and acyl glucuronides. However, plasma concentrations of these
loject; Econac; Fenactol; Flamatak; Flamrase; Lofensaid†; Motifene; Pennsaid; glucuronides and the sulfate conjugate were also increased even
Rheumatac; Rhumalgan; Slofenac; Solaraze; Volraman; Volsaid; Voltarol; COOH more because probenecid also reduced their renal clearance.
Voltarol Ophtha; USA: Arthrotec; Cataflam; Flector; Solaraze; Voltaren;
Venez.: 3A Ofteno; Ar throtec; Ar tren; Campal; Cataflam; Clofen; 1. Macdonald JI, et al. Effect of probenecid on the formation and
Clofenac; Diagesic; Diclofen P; Diclosal; Diclostan†; Difenac; Diklason; Di- elimination kinetics of the sulphate and glucuronide conjugates
ralon; Dival; Doltren†; Flogaren; Flotac; Klafenac; Viavox; Voltaren; Volten; F OH of diflunisal. Eur J Clin Pharmacol 1995; 47: 519–23.
Votaxil.
Pharmacokinetics
Multi-ingredient: Arg.: Albesine Biotic; Algicler; Algio Nervomax; Algio
Diflunisal is well absorbed from the gastrointestinal tract and
F peak plasma concentrations occur about 2 to 3 hours after inges-
Nervomax Fuerte; Amixen Plus; Befol Plus; Belmalen; Blokium B12; Blokium
Flex; Blokium Gesic; Corteroid Gesic; Curinflam Plus; Delta Tomanil B12; tion of a single dose. It is more than 99% bound to plasma protein
Desinflam Biotic†; Diclogesic Forte; Diclogesic Plus B12; Diclogesic Relax; Pharmacopoeias. In Chin., Eur. (see p.vii), and US. and has a plasma half-life of about 8 to 12 hours. Diflunisal ex-
Diclomar Flex; Diclonex Relax; Dioxaflex B12; Dioxaflex Forte; Dioxaflex Ph. Eur. 6.2 (Diflunisal). A white or almost white, crystalline hibits non-linear pharmacokinetics so that doubling the dose
Gesic; Dioxaflex Plus; Dolo Nervobion; Dolo Nervobion 10000; Dolvan
Flex; Doxtran B12; Doxtran Flex; Doxtran Gesic; Flaval; Glifapen; Hyanac†; powder. Practically insoluble in water; soluble in alcohol; dis- more than doubles drug accumulation. Due to the long half-life
Iglodine Flex; Ingebrax; Lertus Biotic†; Metaflex Gesic; Metaflex Plus NF; solves in dilute solutions of alkali hydroxides. Protect from light. and non-linear kinetics, several days are required to reach steady-
Meticil; Mio Aldoron NF; Mio-Virobron NF; Nalgiflex Relax; Oxa B12; Oxa USP 31 (Diflunisal). A white to off-white, practically odourless, state plasma concentrations after multiple dosing. The time to
Forte; Oxa Sport; Oxadisten; Oxafem; Oxagesic; Pancloflex; Panclogesic; powder. Insoluble in water and in hexane; freely soluble in alco- steady-state concentrations can be reduced by giving an initial
Rodinac B12; Rodinac Biotic; Rodinac Flex; Rodinac Gesic; Silfox Flex; Tafirol hol and in methyl alcohol; soluble in acetone and in ethyl acetate; loading dose. Concentrations of diflunisal in synovial fluid reach
Artro; Tobradiclo; Tobratlas; Tomanil Flex; Vesalion B12; Vesalion Flex; Ve-
salion Gesic; Viartril Flex; Virobron B12 NF; Voltaren Flex; Voltaren Forte; slightly soluble in carbon tetrachloride, in chloroform, and in about 70% of those in plasma. Diflunisal is excreted in the urine
Xedenol B12; Xedenol Flex; Xedenol Gesic; Austria: Diclovit; Dolo-Neu- dichloromethane. mainly as glucuronide conjugates. Some biliary recycling may
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
48 Analgesics Anti-inflammatory Drugs and Antipyretics
also occur. Diflunisal is distributed into breast milk with concen- NOTE. Compounded preparations of dihydrocodeine tartrate may subjects did not find any reduced analgesic activity when dihy-
trations reported to be about 2 to 7% of those in plasma. be represented by the following names: drocodeine was given with quinidine, despite a three- to fourfold
reduction in plasma concentrations of the metabolite dihydro-
◊ References. • Co-dydramol (BAN)—dihydrocodeine tartrate 1 part and pa-
racetamol 50 parts (w/w). morphine.1
1. Loewen GR, et al. Effect of dose on the glucuronidation and sul-
phation kinetics of diflunisal in man: single dose studies. Br J The following terms have been used as ‘street names’ (see 1. Wilder-Smith CH, et al. The visceral and somatic antinocicep-
Clin Pharmacol 1988; 26: 31–9. p.vi) or slang names for various forms of dihydrocodeine tar- tive effects of dihydrocodeine and its metabolite, dihydromor-
trate: phine: a cross-over study with extensive and quinidine-induced
2. Eriksson L-O, et al. Influence of renal failure, rheumatoid arthri- poor metabolizers. Br J Clin Pharmacol 1998; 45: 575–81.
tis and old age on the pharmacokinetics of diflunisal. Eur J Clin DFs; Diffs; Duncan Flockharts.
Pharmacol 1989; 36: 165–74. Pharmacopoeias. In Eur. (see p.vii) and US.
3. Verbeeck RK, et al. The effect of multiple dosage on the kinetics Ph. Eur. 6.2 (Dihydrocodeine Hydrogen Tartrate; Dihydroco- Pharmacokinetics
of glucuronidation and sulphation of diflunisal in man. Br J Clin After oral doses peak concentrations of dihydroco-
Pharmacol 1990; 29: 381–9. deine Tartrate BP 2008). A white or almost white crystalline
4. Macdonald JI, et al. Sex-difference and the effects of smoking powder. Freely soluble in water; sparingly soluble in alcohol; deine occur after about 1.2 to 1.8 hours; oral bioavaila-
and oral contraceptive steroids on the kinetics of diflunisal. Eur practically insoluble in cyclohexane. A 10% solution in water bility is only about 20%, probably because of substan-
J Clin Pharmacol 1990; 38: 175–9. has a pH of 3.2 to 4.2. Protect from light. tial first-pass metabolism in the gut wall or liver.
5. Nuernberg B, et al. Pharmacokinetics of diflunisal in patients. USP 31 (Dihydrocodeine Bitartrate). pH of a 10% solution in
Clin Pharmacokinet 1991; 20: 81–9. water is between 3.2 and 4.2. Store in airtight containers. Dihydrocodeine is metabolised in the liver via the cy-
Uses and Administration tochrome P450 isoenzyme CYP2D6, to dihydromor-
Diflunisal is a salicylic acid derivative (see Aspirin, p.23) but it Dependence and Withdrawal phine, which has potent analgesic activity, although the
is not hydrolysed to salicylate and its clinical effects resemble As for Opioid Analgesics, p.101. analgesic effect of dihydrocodeine appears to be pri-
more closely those of propionic acid derivative NSAIDs such as marily due to the parent compound; some is also con-
ibuprofen (p.65). Diflunisal is given in the acute or long-term Dihydrocodeine has been subject to abuse (see under
management of mild to moderate pain, and pain and inflamma- Precautions, below). verted via CYP3A4 to nordihydrocodeine. Dihydroco-
tion associated with osteoarthritis and rheumatoid arthritis. The deine is excreted in urine as unchanged drug and
usual initial oral dose for pain relief is 1 g followed by a mainte- Adverse Effects and Treatment metabolites, including glucuronide conjugates. Elimi-
nance dose of 500 mg every 12 hours. In some patients 250 mg As for Opioid Analgesics in general, p.102; adverse ef- nation half-life is reported to range from about 3.5 to 5
every 8 to 12 hours may be sufficient but others may require hours.
500 mg every 8 hours. Maintenance doses greater than 1.5 g dai- fects of dihydrocodeine are less pronounced than those
ly are not recommended. The usual oral dose for arthritis is of morphine. ◊ References.
500 mg to 1 g daily in 2 divided doses. Doses may need to be Overdosage. A 29-year-old man who had taken 2.1 g of dihy- 1. Rowell FJ, et al. Pharmacokinetics of intravenous and oral dihy-
reduced in patients with renal impairment, see below. drocodeine had biochemical evidence of acute renal and hepatic drocodeine and its acid metabolites. Eur J Clin Pharmacol 1983;
25: 419–24.
Diflunisal arginine has been used similarly given by mouth or by impairment when admitted 13 hours after the overdose.1 Severe 2. Fromm MF, et al. Dihydrocodeine: a new opioid substrate for the
intramuscular or intravenous injection. life-threatening respiratory depression subsequently developed polymorphic CYP2D6 in humans. Clin Pharmacol Ther 1995;
Administration in renal impairment. Diflunisal may need 36 hours after the overdose and only responded to treatment with 58: 374–82.
to be given in reduced dosage in patients with significant renal naloxone after large doses (a total of 46.6 mg of naloxone) over 3. Ammon S, et al. Pharmacokinetics of dihydrocodeine and its ac-
a long period (106 hours). Commenting on this report some tive metabolite after single and multiple dosing. Br J Clin Phar-
impairment and should not be given when renal impairment is macol 1999; 48: 317–22.
severe. questioned the evidence for hepatic impairment and considered
that the raised liver enzyme values were of muscular origin as a 4. Webb JA, et al. Contribution of dihydrocodeine and dihydromor-
phine to analgesia following dihydrocodeine administration in
Preparations result of rhabdomyolysis.2-4 Rhabdomyolysis may also have man: a PK-PD modelling analysis. Br J Clin Pharmacol 2001;
BP 2008: Diflunisal Tablets; contributed to renal failure. 52: 35–43.
USP 31: Diflunisal Tablets. An anaphylactoid reaction after an overdose with an unspecified Renal impairment. The pharmacokinetics of dihydrocodeine
Proprietary Preparations (details are given in Part 3) number of dihydrocodeine tablets5 appeared to respond to intra- tartrate, given as a single oral 60-mg dose, were affected in 9
Austral.: Dolobid†; Austria: Fluniget; Belg.: Biartac†; Diflusal; Denm.: venous naloxone. patients with chronic renal failure treated with haemodialysis
Donobid†; Fin.: Donobid†; Fr.: Dolobis†; Gr.: Analeric; Irl.: Dolobid†; Is- 1. Redfern N. Dihydrocodeine overdose treated with naloxone in-
rael: Dolobid†; Ital.: Artrodol; Dolobid†; Mex.: Dolobid†; Neth.: Dolo- when compared with 9 healthy subjects.1 Time to peak plasma
fusion. BMJ 1983; 287: 751–2.
bid; Dolocid; Norw.: Donobid; Port.: Dolobid†; Flunidor†; Spain: Dolo- 2. Buckley BM, Vale JA. Dihydrocodeine overdose treated with concentration in those with renal failure was 3 hours compared
bid; Swed.: Donobid; Switz.: Unisal†; Thai.: Dolobid; Turk.: Dolphin; UK: naloxone infusion. BMJ 1983; 287: 1547. with 1 hour in healthy subjects; the area under the plasma con-
Dolobid†; USA: Dolobid†; Venez.: Dolobid†. centration-time curve was greater in those with renal failure; and
3. Blain PG, Lane RJM. Dihydrocodeine overdose treated with
naloxone infusion. BMJ 1983; 287: 1547. after 24 hours dihydrocodeine was still detectable in the plasma
4. Wen P. Dihydrocodeine overdose treated with naloxone infusion. of all renal failure patients, but in only 3 of the healthy subjects.
BMJ 1983; 287: 1548.
1. Barnes JN, et al. Dihydrocodeine in renal failure: further evi-
Dihydrocodeine Phosphate 5. Panos MZ, et al. Use of naloxone in opioid-induced anaphylac-
toid reaction. Br J Anaesth 1988; 61: 371. dence for an important role of the kidney in the handling of opi-
oid drugs. BMJ 1985; 290: 740–2.
(BANM, rINNM) Pain. For reference to increased postoperative pain associated
Dihydrocodéine, Phosphate de; Dihydrocodeini Phosphas; Fos- with the use of dihydrocodeine, see under Uses and Administra- Uses and Administration
fato de dihidrocodeína; Hydrocodeine Phosphate. tion, below.
Dihydrocodeine is an opioid analgesic (p.104). It is re-
Дигидрокодеина Фосфат lated to codeine (p.38) and has similar analgesic activ-
Precautions
C 18 H 23 NO 3,H 3PO 4 = 399.4. ity. Dihydrocodeine is used for the relief of moderate to
As for Opioid Analgesics in general, p.103.
C AS — 24204-13-5. severe pain, often in combination preparations with pa-
ATC — N02AA08. Abuse. Dihydrocodeine has been reported to be widely abused racetamol. It has also been used as a cough suppres-
by opiate addicts.1-4
ATC Vet — QN02AA08. sant.
1. Swadi H, et al. Misuse of dihydrocodeine tartrate (DF 118)
among opiate addicts. BMJ 1990; 300: 1313. For analgesia the usual oral dose of dihydrocodeine
2. Robertson JR, et al. Misuse of dihydrocodeine tartrate (DF 118)
H3CO among opiate addicts. BMJ 1990; 301: 119. tartrate is 30 mg after food every 4 to 6 hours; up to
3. Strang J, et al. Misuse of dihydrocodeine tartrate (DF 118) 240 mg daily may be given for severe pain. Modified-
among opiate addicts. BMJ 1990; 301: 119.
4. Seymour A, et al. The role of dihydrocodeine in causing death
release preparations are available for twice daily dos-
among drug users in the west of Scotland. Scott Med J 2001; 46: age in patients with chronic severe pain.
O H 143–6.
Dihydrocodeine tartrate may also be given by deep
NCH3 The elderly. Despite some renal impairment an elderly group subcutaneous or intramuscular injection in doses of up
of patients1 appeared to handle dihydrocodeine similarly to
healthy young subjects. There was marked variability in all to 50 mg every 4 to 6 hours.
HO measurements and on the basis of this study no clear conclusions For details of doses in children, see below.
on guidelines for dosage in elderly patients could be drawn.
(dihydrocodeine) However, the recommendation that small doses be given initially As a cough suppressant dihydrocodeine tartrate may
with subsequent doses according to response was endorsed. be given in oral doses of 10 to 30 mg up to three times
Pharmacopoeias. In Jpn. 1. Davies KN, et al. The effect of ageing on the pharmacokinetics daily.
of dihydrocodeine. Eur J Clin Pharmacol 1989; 37: 375–9.
Dihydrocodeine phosphate has also been used. Other
Renal impairment. Caution is necessary when giving dihy- salts of dihydrocodeine used, mainly for their antitus-
Dihydrocodeine Tartrate (BANM, rINNM) drocodeine to patients with severe renal impairment. Severe nar-
Dihidrokodein-hidrogén-tartrát; Dihidrokodeino-vandenilio tar- cosis occurred in a patient with anuria and on maintenance sive effects, include the hydrochloride, the polistirex,
tratas; Dihydrocodeine Acid Tartrate; Dihydrocodeine haemodialysis after she had received dihydrocodeine orally for 4 and the thiocyanate. Dihydrocodeine polistirex has
Bitartrate; Dihydrocodeine Hydrogen Tartrate; Dihydrocodéine, days.1 She responded to treatment with naloxone. also been used in modified-release preparations.
hydrogénotartrate de; Dihydrocodéine, Tartrate de; Dihydroco- See also under Pharmacokinetics, below.
Administration in children. In the UK, dihydrocodeine
deini Bitartras; Dihydrocodeini hydrogenotartras; Dihydrocodei- 1. Barnes JN, Goodwin FJ. Dihydrocodeine narcosis in renal fail-
tartrate may be given orally, or by deep subcutaneous or intra-
ni Tartras; Dihydrokodeiinivetytartratti; Dihydrokodein-tartarát; ure. BMJ 1983; 286: 438–9.
muscular injection, for analgesia in children aged from 4 to 12
Dihydrokodeinvätetartrat; Dihydrokodeiny wodorowinian; years in usual doses of 0.5 to 1 mg/kg (to a maximum of 30 mg)
Drocode Bitartrate; Hydrocodeine Bitartrate; Tartrato de dihid- Interactions every 4 to 6 hours; older children may be given the usual adult
rocodeína. 4,5-Epoxy-3-methoxy-17-methylmorphinan-6-ol hy- For interactions associated with opioid analgesics, see dose (see above). Although unlicensed in children under 4 years,
drogen tartrate. p.103. the BNFC suggests giving those aged 1 to 4 years
Дигидрокодеина Тартрат 500 micrograms/kg every 4 to 6 hours.
Quinidine. Dihydrocodeine is metabolised via the cytochrome
C 18 H 23 NO 3,C 4 H 6 O 6 = 451.5. P450 isoenzyme CYP2D6 to active metabolites, which may per- Dyspnoea. Dihydrocodeine has been reported1 to have pro-
C AS — 125-28-0 (dihydrocodeine); 5965-13-9 (dihydroc- haps play a role in its analgesic activity in extensive metabolis- duced benefit in normocapnic patients severely disabled by
odeine tartrate). ers; quinidine impairs this metabolism, but a study in 11 healthy breathlessness due to chronic airflow obstruction. A dose of
 Dihydrocodeine Phosphate/Dipyrone 49
15 mg was taken 30 minutes before exercise up to three times a Preparations Pharmacokinetics
day. BP 2008: Dipipanone and Cyclizine Tablets. After oral doses dipyrone is rapidly hydrolysed in the gastroin-
1. Johnson MA, et al. Dihydrocodeine for breathlessness in ‘pink Proprietary Preparations (details are given in Part 3) testinal tract to the active metabolite 4-methyl-amino-antipyrine,
puffers’. BMJ 1983; 286: 675–7. which after absorption undergoes metabolism to 4-formyl-ami-
Multi-ingredient: Hong Kong: Wellconal†; Irl.: Diconal†; S.Afr.: Well-
conal; UK: Diconal. no-antipyrine and other metabolites. Dipyrone is also rapidly
Pain. Dihydrocodeine is used in the management of moderate to undetectable in plasma after intravenous doses. None of the
severe pain. However, dose-related increase in postoperative metabolites of dipyrone are extensively bound to plasma pro-
pain has been seen1 in patients given 25 or 50 mg dihydroco- teins. Most of a dose is excreted in the urine as metabolites.
deine tartrate intravenously after dental surgery, and it has been Dipyrone (BAN, USAN) Dipyrone metabolites are also distributed into breast milk.
proposed that dihydrocodeine might act as an antagonist in situ- Metamizole Sodium (pINN); Aminopyrine-sulphonate Sodium;
ations where acute pain was accompanied by high opioid activi- ◊ References.
Analginum; Dipiron; Dipyron; Dipyroni; Dipyronum; Metamitsoli- 1. Heinemeyer G, et al. The kinetics of metamizol and its metabo-
ty.2 Systematic review of the use of single oral doses of dihydroc-
natrium; Metamizol; Metamizol sódico; Metamizol sodná sůl lites in critical-care patients with acute renal dysfunction. Eur J
odeine has indicated that these are insufficient to provide Clin Pharmacol 1993; 45: 445–50.
adequate relief of postoperative pain, and that dihydrocodeine is monohydrát; Metamizol sodowy; Metamizol Sodyum; Métami-
zole sodique; Metamizolnatrium; Metamizol-nátrium; Metamizo- 2. Levy M, et al. Clinical pharmacokinetics of dipyrone and its me-
less effective than ibuprofen.3 tabolites. Clin Pharmacokinet 1995; 28: 216–34.
lo natrio druska; Metamizolum natricum; Metamizolum Natri- 3. Zylber-Katz E, et al. Dipyrone metabolism in liver disease. Clin
1. Seymour RA, et al. Dihydrocodeine-induced hyperalgesia in
postoperative dental pain. Lancet 1982; i: 1425–6. cum Monohydricum; Methampyrone; Methylmelubrin; Natrium Pharmacol Ther 1995; 58: 198–209.
2. Henry JA. Dihydrocodeine increases dental pain. Lancet 1982; Novaminsulfonicum; Noramidazophenum; Novamidazofen; No- Uses and Administration
ii: 223. vaminsulfone Sodium; NSC-73205; Sodium Noramidopyrine Dipyrone is the sodium sulfonate of aminophenazone (p.19) and
3. Edwards JE, et al. Single dose dihydrocodeine for acute postop- Methanesulphonate; Sulpyrine. Sodium N-(2,3-dimethyl-5-oxo- has similar properties. Because of the risk of serious adverse ef-
erative pain. Available in The Cochrane Database of Systematic 1-phenyl-3-pyrazolin-4-yl)-N-methylaminomethanesulphonate fects, in many countries its use is considered justified only in se-
Reviews; Issue 2. Chichester: John Wiley; 2000 (accessed monohydrate. vere pain or fever where no alternative is available or suitable.
26/06/08).
Метамизол Натрий Dipyrone has been given orally in doses of 0.5 to 4 g daily in
Preparations C 13 H 16 N 3 NaO 4 S,H 2 O = 351.4. divided doses. It has also been given by intramuscular or intrave-
C AS — 68-89-3 (anhydrous dipyrone); 5907-38-0 (dipy- nous injection and rectally as a suppository.
BP 2008: Co-dydramol Tablets; Dihydrocodeine Injection; Dihydrocodeine
Oral Solution; Dihydrocodeine Tablets. rone monohydrate). A magnesium congener of dipyrone, metamizole magnesium
ATC — N02BB02. has been used similarly to dipyrone as has the calcium congener
Proprietary Preparations (details are given in Part 3) metamizole calcium.
ATC Vet — QN02BB02.
Austral.: Paracodin; Rikodeine; Austria: Codidol; Dehace; Paracodin;
Belg.: Codicontin; Paracodine; Cz.: DHC Continus; Fr.: Dicodin; Ger.: Preparations
DHC; Paracodin; Paracodin N; Remedacen†; Tiamon Mono; Gr.: Condug- Proprietary Preparations (details are given in Part 3)
esic†; Hong Kong: DF 118; Hung.: DHC; Hydrocodin; Irl.: DF 118; DHC CH3
Arg.: Algiopiret†; Analgina; Dioxadol; Dipigrand; Ditral; Integrobe; Lisalgil;
Continus; Paracodin; Ital.: Paracodina; Malaysia: Codesic†; DF 118; NZ: Novacler; Novalgina; Novemina; Unibios Simple; Austria: Inalgon Neu;
DHC Continus; Pol.: DHC Continus; Port.: Didor†; S.Afr.: DF 118; Para- N Novalgin; Spasmo Inalgon Neu; Belg.: Analgine; Novalgine; Braz.: Algirona;
codin; Spain: Contugesic†; Paracodina; Tosidrin; Switz.: Codicontin; Para- H 3C
N Anador; Analgesil; Analgex†; Apiron; Baralgin; Conmel; Difebril; Dipimax;
codin; UK: DF 118; DHC Continus. •
H 2O Dipirex†; Dipiron; Dipironax†; Dipix; Diprin; Doralex†; Dorfebril†; Dori-
Multi-ingredient: Arg.: Lentusin; Austral.: Codox; Austria: Paracodin; lan†; Dornal†; Dorona; Dorpinon; DS500†; Findor†; Magnodor†; Magnopy-
+− rol; Maxiliv; Multiralgim†; Nofebrin; Novagreen; Novalgex†; Novalgina; Piro-
Ger.: Antitussivum Burger N†; Makatussin Tropfen forte†; Paracodin re- Na O3S N O
tard†; Hong Kong: Codaewon; Irl.: Paramol; Ital.: Cardiazol-Paracodina; febran†; Pirogina; Prodopirona; Sifpirona†; Termonal; Termopirona;
Paracodina; Jpn: Colgen Kowa IB Toumei; Malaysia: Dihydrocodeine P; Termoprin; Toloxin†; Zitalgin†; Chile: Baralgina M; Conmel; Novalgina†;
Switz.: Escotussin; Makatussin Comp; Paracodin retard†; UK: Paramol; CH3 Cz.: Novalgin; Fr.: Novalgine†; Ger.: Analgin; Berlosin; Metalgin†; Nopain;
Remedeine; USA: DHC Plus; DiHydro-CP; DiHydro-GP; DiHydro-PE; Du- Novalgin; Novaminsulfon; Hong Kong: Metilon†; Hung.: Algopyrin; Algo-
ohist DH; Novahistine DH; Pancof; Pancof PD; Pancof-EXP; Panlor; Synal- zone; Novalgin; Panalgorin; India: Novalgin; Indon.: Antalgin; Antrain; Cor-
gos-DC.
NOTE. Confusingly the term dipyrone sodium also appears to be nalgin; Foragin; Licogin; Norages; Novalgin; Panstop; Pragesol; Pyronal; Ro-
used synonymously for dipyrone itself. Dipyrone is referred to in nalgin; Scanalgin; Unagen; Israel: Novalgin; Optalgin; Phanalgin; V-Talgin;
some countries by the colloquial name ‘Mexican aspirin’. The Ital.: Novalgina; Mex.: Alnex; Anaprol; Anapyrol; Apixol†; Avafontan; Av-
names noraminophenazonum and novaminsulfon have appar- aldrian†; Ayoral Simple†; Carofril†; Conmel; Dalmasin; Dalsin; Defin; Dime-
ently been applied to dipyrone, but it is not clear whether these tirol; Dipydol; Dofisan; Dolgan; Dolizol; Dolofur; Domenal; Exalgin†; Exo-
Dipipanone Hydrochloride (BANM, rINNM) are the sodium salt.
dalina; Fandall; Fardolpin; Farlin; Indigon; Lozima; Mach-2; Macodin; Magnil;
Magnol; Magnolonas; Magnopyrol; Magsons; Mayoprina; Mecoten†;
Dipipanone, Chlorhydrate de; Dipipanoni Hydrochloridum; Hid- Pharmacopoeias. In Chin., Eur. (see p.vii), and Jpn. Medipirol; Mermid; Messelfenil; Metapirona; Midelin; Minoral; Mizoltec;
rocloruro de dipipanona; Phenylpiperone Hydrochloride; Piperi- Ph. Eur. 6.2 (Metamizole Sodium; Dipyrone BP 2008). A white Modimet; Neo-Melubrina; Neomelin; Neosedal; Paleodina; Pifrol; Piramag-
no†; Pirandall; Pirasod; Pirinovag; Piromebrina; Poloren†; Precidona; Pro-
dyl Methadone Hydrochloride; Piperidylamidone Hydrochlo- or almost white crystalline powder. Very soluble in water; solu- dolina; Prolubrin; Pyranol; Pyron; Suprin; Termonil; Utidol; Vegal; Neth.:
ride. (±)-4,4-Diphenyl-6-piperidinoheptan-3-one hydrochloride ble in alcohol. Protect from light. Novalgin; Pol.: Pyrahexal; Pyralgin; Pyralginum; Port.: Conmel†; Dolocal-
monohydrate. ma; Nolotil; Novalgina†; Rus.: Analgin (Анальгин); Baralgin M (Баралгин
Adverse Effects and Precautions М); Spain: Algi; Citdolal†; Dolemicin; Lasain; Neo Melubrina; Nolotil;
Дипипанона Гидрохлорид Use of dipyrone is associated with an increased risk of agranulo- Switz.: Minalgine; Novalgine; Thai.: Acodon†; Centagin; Deparon; Gen-
cytosis and with shock. ergin; Invoigin; Kno-Paine; Medalgin†; Mezabox; Nivagin; Novalgin; Olan-
C 24 H 31NO,HCl,H 2 O = 404.0. Gin; Turk.: Adepiron; Andolor; Baralgin M; Devaljin; Feninox; Geralgine;
◊ References. Kafalgin; Nogesic; Novakom-S; Novalgin; Novo-Plan; Novopyrine; Sebon;
C AS — 467-83-4 (dipipanone); 856-87-1 (dipipanone hy- Veraljin; Urug.: Dolanet; Venez.: Bral; Buscadol†; Combanal†; Combaron†;
drochloride). 1. Levy M. Hypersensitivity to pyrazolones. Thorax 2000; 55 (sup-
pl 2): S72–S74. Conmel; Delsal; Dipamona; Dipidol; Klinomel†; Nimel†; Noval†; Novalcina;
Piradro†; Piradrops Simple†; Promel; Rosadol†.
Effects on the blood. Data collected from 8 population groups Multi-ingredient: Arg.: Antispasmina; Apasmo; Apasmo Compuesto;
in Europe and Israel by the International Agranulocytosis and Artifene; Bellatotal; Buscapina Compositum; Calmopirin; Canovex†; Cifes-
Aplastic Anemia Study1 revealed that there was a significant re- pasmo Compuesto; Colobolina D; Craun†; Cronopen Balsamico; D-P†;
gional variability in the rate-ratio estimate for agranulocytosis Dentolina Plus; Dextro + Dipirona; Dextrodip; Dioxadol; Dresan Biotic†;
CH3 and dipyrone (0.9 in Budapest to 33.3 in Barcelona). Although a Dresan†; Espasmo Biotenk; Espasmo Dioxadol; Fadagrip; Febrimicina†;
Flexicamin A; Gastrolina Compuesta; Gobbicalm; Integrobe Plus; Keptan
large relative increase in risk between agranulocytosis and use of Compuesto†; Klosidol; Klosidol B1 B6 B12; Lisalgil Compuesto; Luar-G
N dipyrone was found, the incidence was less than some previous Compositum; Migra Dioxadol; Migral; Migral Compositum; Multin; Novo-
CH3 reports had suggested. pasmil Compuesto; Paratropina Compuesta; Pasmodina Compuesta; Pas-
mosedan Compuesto†; Rupe-N Compuesto; Saldeva†; Solacil; Sumal; Te-
Blood dyscrasias such as agranulocytosis and granulocytopenia tralgin; Tetralgin Novo; Vicefeno; Austria: Buscopan Compositum;
O
have continued to be reported where dipyrone remains availa- Spasmium comp; Belg.: Buscopan Compositum; Braz.: Algexin; Algice;
ble.2-7 Aminocid†; Analgin C-R; Analgosedan†; Analverin Composto†; Analverin†;
1. The International Agranulocytosis and Aplastic Anemia Study. Anapirol†; Baldin-CE†; Banidor†; Bicavine; Binospan; Bioscina Composta†;
Risks of agranulocytosis and aplastic anemia: a first report of Bromalgina†; Broncopinol†; Buscopan Composto; Buscoveran Composto;
(dipipanone) their relation to drug use with special reference to analgesics. Butilamin; Cafalena†; Cefaldina; Cefaliv; Codeverin†; Dalgex; Dexalgen;
JAMA 1986; 256: 1749–57. Dimex†; Dipirol†; Disbuspan; Doralgex; Doralgina; Dorciflex; Dorflex; Dor-
icin; Doridina; Dorilen; Doriless; Dorscopena†; Dorsedin; Dorspan; Dor-
2. Hedenmalm K, Spigset O. Agranulocytosis and other blood dy- zone; Ductopan†; Enxak; Espasmocron; Espasmodid Composto; Eucal-
Pharmacopoeias. In Br. scrasias associated with dipyrone (metamizole). Eur J Clin
BP 2008 (Dipipanone Hydrochloride). An odourless or almost iptan†; Flexalgex; Flexdor; Gripanil†; Gripion†; Gripomatine†; Griponia†;
Pharmacol 2002; 58: 265–74. Gripsay; Hioariston; Hiospan Composto; Inib-Dor†; Itaiflex†; Killgrip†; Kind-
odourless, white, crystalline powder. Sparingly soluble in water; 3. Maj S, Lis Y. The incidence of metamizole sodium-induced pasm; Lisador; Melpaz†; Migraliv; Migranette; Mionevrix; Miorrelax; Neoco-
freely soluble in alcohol and in acetone; practically insoluble in agranulocytosis in Poland. J Int Med Res 2002; 30: 488–95. pan; Neomigran†; Neosaldina; Neuralgina; Nevralgex; Par; Pasmalgin†;
ether. A 2.5% solution in water has a pH of 4.0 to 6.0. 4. Maj S, Centkowski P. A prospective study of the incidence of Plenocedan†; Pulmorien†; Relaflex; Rielex; Sedabel†; Sedalene; Sedalex;
agranulocytosis and aplastic anemia associated with the oral use Sedalgina; Sedalin; Sedol; Spasmotropin; Tensaldin; Tetrapulmo; Theopiri-
Profile of metamizole sodium in Poland. Med Sci Monit 2004; 10: na†; Tropinal; Uzara†; Veratropan Composto; Chile: Bramedil Compuesto;
PI93–PI95. Buscapina Compositum; Cefalmin; Cinabel; Dioran†; Dolcopin; Dolnix;
Dipipanone hydrochloride is an opioid analgesic (p.101) struc- 5. Ibanez L, et al. Agranulocytosis associated with dipyrone (met- Dolo-Neurobionta†; Dolonase; Fredol; Migragesic; Migranol; Migratam;
turally related to methadone (p.82). Used alone it is reported to amizol). Eur J Clin Pharmacol 2005; 60: 821–9. Neo Butartrol; Nospasmin Compuesto; Piretanyl; Scopanil; Silartrin†; Silre-
be less sedating than morphine. It is used in the treatment of mod- 6. Hamerschlak N, Cavalcanti AB. Neutropenia, agranulocytosis lax†; Sistalgina†; Ultrimin; Viadil Compuesto; Viplan Compuesto; Viproxil
erate to severe pain. and dipyrone. Sao Paulo Med J 2005; 123: 247–9. Compuesto; Cz.: Algifen; Algifen Neo; Analgin; Quarelin†; Fin.: Litalgin; Fr.:
7. Garcia S, et al. Dipyrone-induced granulocytopenia: a case for Avafortan†; Cefaline-Pyrazole†; Salgydal a la noramidopyrine†; Visceralgine
Dipipanone hydrochloride is usually given in combination prep- awareness. Pharmacotherapy 2006; 26: 440–2. Forte†; Hung.: Algopyrin Complex; Quarelin; Ridol†; Indon.: Analsik; Ars-
arations with the antiemetic cyclizine hydrochloride to reduce inal; Biomega; Cetalgin; Cetalgin-T; Corsanural; Dactron; Danalgin; Depar-
the incidence of nausea and vomiting, but the use of such prepa- Effects on the skin. Dipyrone has been considered responsible on; Dolo Scanneuron; Dolo-Licobion; Foraneural; Goralgin; Hedix; Ikaneu-
rations is not recommended for the management of chronic pain, for a case of drug-induced toxic epidermal necrolysis.1 ron Plus; Neuralgin RX; Neuro Panstop; Neurobat A; Neurodial;
Neurogen; Neurosanbe Plus; Neurotropic Plus; Neuroval; Opineuron;
as the antiemetic is usually only required for the first few days of 1. Roujeau J-C, et al. Sjögren-like syndrome after drug-induced Penagon; Pritagesic; Procolic; Proneuron; Spaslic; Spasmal; Spasminal; Stiler-
treatment. The usual oral dose of dipipanone hydrochloride is toxic epidermal necrolysis. Lancet 1985; i: 609–11. an; Supranal; Tropineuron; Unthecol; Ital.: Soma Complex†; Mex.: Algos-
10 mg, repeated every 6 hours. The dose may be increased if nec- Hypersensitivity. Cross-sensitivity between aspirin and dipy- far; Anadil; Ayoral†; Benfol; Biomesina Compuesta; Bipasmin Compuesto;
rone occurred in a patient.1 Dipyrone produced an exacerbation Bipasmin Compuesto N; Buscapina Compositum; Busconet; Busepan; Bus-
essary in increments of 5 mg; it is seldom necessary to exceed a prina; Colepren; Dolnefort; Dolo-Tiaminal; Espasmogress; Hiosinotil Com-
dose of 30 mg. After an oral dose the analgesic effect begins of dyspnoea, cyanosis, and respiratory arrest. puesto†; Hiosultrina-F; Korifen; Neo-Brontyl; Neo-Pasmonal; Ortran†; Pas-
within an hour and lasts about 4 to 6 hours. 1. Bartoli E, et al. Drug-induced asthma. Lancet 1976; i: 1357. modil; Pirobutil; Respicil; Retodol Compositum; Selpiran; Serralpina
Compuesta; Singril; Pol.: Gardan P; Scopolan Compositum; Spasmalgon;
Preparations of dipipanone hydrochloride with cyclizine hydro- Porphyria. Dipyrone has been associated with acute attacks of Tolargin; Rus.: Analgin-Chinin (Анальгин-Хинин); Antigrippin-ANVI
chloride are subject to abuse. porphyria and is considered unsafe in porphyric patients. (Антигриппин-АНВИ); Baralgetas (Баралгетас)†; Benalgin (Бенальгин);

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
50 Analgesics Anti-inflammatory Drugs and Antipyretics
Maxigan (Максиган); Nebalgan (Небалган); Pentalgin-N (Пенталгин-Н); flammatory disorders of the skin, mouth, throat, and rectum. Adverse Effects and Precautions
Revalgin (Ревалгин); Sedal-M (Седал-М); Sedalgin-Neo (Седальгин-Нео); Enoxolone potassium (potassium glycyrrhetinate) has been used
Spasgan (Спазган); Spasmalgon (Спазмалгон); Spasmalin (Спазмалин); As for Infliximab, p.69.
Tempalgin (Темпалгин); Tempanginol (Темпангинол); S.Afr.: Baralgan†; similarly.
Buscopan Compositum; Norifortan†; Scopex Co; Spain: Buscapina Com- Derivatives of enoxolone, including its aluminium salt (p.1729) Mild to moderate injection site reactions with symp-
positum; Nolotil Compositum†; Thai.: Butarion; Novapam; Turk.: Busco- and carbenoxolone (p.1714) have been used in the treatment of toms of erythema, itching, pain, or swelling are com-
pan Compositum; Peraljin; Skopolin; Venez.: Bort†; Buscapina Composi- benign peptic ulcer disease and other gastrointestinal disorders. mon with etanercept. Other common reactions include
tum; Butilamina Compuesta; Cotar†; Diezol Compuesto†; Flemibar;
Hioscinol Compuesto†; Praxona; Sarifan Compuesto†; Sistalcin Composi- ◊ Enoxolone is a potent inhibitor of the enzyme 11β-hydroxys- headache, dizziness, asthenia, nausea and vomiting,
tum. teroid dehydrogenase, which inactivates cortisol, and use with abdominal pain, dyspepsia, and allergic reactions. Anti-
hydrocortisone has been shown in animal studies to potentiate bodies to etanercept may develop.
the activity of hydrocortisone in skin.1 Whether this also in-
creased the systemic absorption and toxicity of hydrocortisone Etanercept should be used with caution in patients with
Eltenac (rINN)
was unclear.2 However, for reference to adverse effects attributed heart failure.
Elténac; Eltenaco; Eltenacum. 4-(2,6-Dichloroanilino)-3-thiophe- to systemic inhibition of cortisol when enoxolone (glycyrrhetinic
neacetic acid. ◊ References.
acid) is produced during metabolism of ingested liquorice, see 1. Sánchez Carazo JL, et al. Safety of etanercept in psoriasis: a crit-
Эльтенак Effects on Fluid and Electrolyte Homoeostasis, p.1740. ical review. Drug Safety 2006; 29: 675–85.
C 12 H 9 Cl 2 NO 2 S = 302.2. A cream containing enoxolone with hyaluronic acid, telm-
Wegener’s granulomatosis. The addition of etanercept to
C AS — 72895-88-6. esteine, and a grape extract, has been investigated with apparent
standard therapy (including cyclophosphamide or methotrexate
benefit in the management of mild to moderate eczema.3,4 How-
and corticosteroids) was not shown to be effective in patients
ever, topical application of enoxolone has been associated with
with Wegener’s granulomatosis and was associated with an in-
Cl contact dermatitis.5
creased incidence of various non-cutaneous malignancies.1 Li-
1. Teelucksingh S, et al. Potentiation of hydrocortisone activity in
skin by glycyrrhetinic acid. Lancet 1990; 335: 1060–3. censed product information recommends that etanercept should
O 2. Greaves MW. Potentiation of hydrocortisone activity in skin by not be added to therapy in patients with Wegener’s granulomato-
HN glycerrhetinic acid. Lancet 1990; 336: 876. sis.
3. Belloni G, et al. A randomised, double-blind, vehicle-controlled 1. Wegener’s Granulomatosis Etanercept Trial (WGET) Research
HO study to evaluate the efficacy and safety of MAS063D (Atopi- Group. Etanercept plus standard therapy for Wegener’s granulo-
Cl clair) in the treatment of mild to moderate atopic dermatitis. Eur matosis. N Engl J Med 2005; 352: 351–61.
S J Dermatol 2005; 15: 31–6.
4. Abramovits W, Boguniewicz M. Adult Atopiclair Study Group.
A multicenter, randomized, vehicle-controlled clinical study to Interactions
Profile examine the efficacy and safety of MAS063DP (Atopiclair) in As for Infliximab, p.71. The use of etanercept with sul-
Eltenac is an NSAID (p.96) used in veterinary medicine. the management of mild to moderate atopic dermatitis in adults.
J Drugs Dermatol 2006; 5: 236–44. fasalazine has resulted in decreased white blood cell
5. Tanaka S, et al. Allergic contact dermatitis from enoxolone. counts; however, the clinical significance of this is
Contact Dermatitis 2001; 44: 192. unknown. For an increased incidence of malignancy
Embutramide (BAN, USAN, rINN) Preparations when etanercept was added to standard immunosup-
Embutramida; Embutramidum; Hoe-18-680. N-(β,β-Diethyl-m- Proprietary Preparations (details are given in Part 3) pressive therapy in patients with Wegener’s granulo-
Belg.: Dermanox; Fr.: Arthrodont; Moustidose; PO 12; S.Afr.: Arthro-
methoxyphenethyl)-4-hydroxybutyramide. dont. matosis, see above.
Эмбутрамид Multi-ingredient: Arg.: Anastim con RTH; Empecid Pie; Chile: Gingilac-
C 17 H 27 NO 3 = 293.4. er†; Ruboril; Sebium AKN; Suavigel; Fr.: Apaisance; Erygine; Fluocaril dents Pharmacokinetics
sensibles; Hexalyse; Hyseke; Hyseke Solaire; Mousticologne; Moustidose
C AS — 15687-14-6. Bebe-Nourrisson; Night Peel; Novophane; Novophane S; Photoderm After a single subcutaneous dose of etanercept, UK li-
Flush†; Photoderm Laser†; Pyreflor; Sebium AKN; Sedorrhoide; Tiq’Aouta; censed product information states that the mean half-
Vocadys; Hong Kong: Hexalyse; Indon.: Polik; Israel: Aphtagone; Aptha-
CH3 X; Gelclair†; Ital.: Acnesan†; Bactilene; Benodent Gel Gengivale†; Biothy- life is about 70 hours, and the time to peak serum con-
mus DS; Eudent con Glysan†; Fluocaril; Lenipasta†; Lenirose†; Lisomucil centration 48 hours. In contrast, US information gives
H Gola; Neo-Stomygen; Pastiglie Valda†; Prurex; Skab 2; Viderm†; Mex.: An-
N genovag; Periodentyl; Port.: Despigmentante; Rus.: Hexalyse (Гексализ); the half-life as 102 hours and the time to peak concen-
OH Spain: Angileptol; Anginovag; Roberfarin; UK: Atopiclair; Gelclair; Xclair; tration as about 70 hours, although with a considerable
H 3C USA: Atopiclair; Gelclair; Venez.: Sebium AKN; Sensibio DS.
O range. Repeated dosing was noted to result in a two- to
sevenfold increase in serum levels of etanercept in
CH3 Epirizole (USAN, pINN) some patients.
O ◊ References.
DA-398; Epirizol; Épirizole; Epirizolum; Mepirizole. 4-Methoxy-2-
(5-methoxy-3-methylpyrazol-1-yl)-6-methylpyrimidine. 1. Korth-Bradley JM, et al. The pharmacokinetics of etanercept in
Profile healthy volunteers. Ann Pharmacother 2000; 34: 161–4.
Embutramide is an opioid analgesic used in veterinary medicine Эпиризол 2. Zhou H. Clinical pharmacokinetics of etanercept: a fully human-
for euthanasia. C 11 H 14N 4 O 2 = 234.3. ized soluble recombinant tumor necrosis factor receptor fusion
C AS — 18694-40-1. protein. J Clin Pharmacol 2005; 45: 490–7.
3. Yim D-S, et al. Population pharmacokinetic analysis and simu-
lation of the time-concentration profile of etanercept in pediatric
patients with juvenile rheumatoid arthritis. J Clin Pharmacol
Enoxolone (BAN, rINN) CH3 2005; 45: 246–56.
Enoksolonas; Enoksoloni; Enoxolon; Enoxolona; Énoxolone; O 4. Don BR, et al. The pharmacokinetics of etanercept in patients
with end-stage renal disease on haemodialysis. J Pharm Phar-
Enoxolonum; Glycyrrhetic Acid; Glycyrrhetinic Acid; Kwas gli- macol 2005; 57: 1407–13.
cyryzynowy. 3β-Hydroxy-11-oxo-olean-12-en-30-oic acid. 5. Sullivan JT, et al. Bioequivalence of liquid and reconstituted
N CH3 lyophilized etanercept subcutaneous injections. J Clin Pharma-
Эноксолон
col 2006; 46: 654–61.
C 30 H 46 O 4 = 470.7. O N 6. Nestorov I, et al. Pharmacokinetics of subcutaneously adminis-
H3C
C AS — 471-53-4. N tered etanercept in subjects with psoriasis. Br J Clin Pharmacol
ATC — D03AX10. 2006; 62: 435–45.
ATC Vet — QD03AX10. N 7. Elewski B, et al. Comparison of clinical and pharmacokinetic
profiles of etanercept 25 mg twice weekly and 50 mg once week-
ly in patients with psoriasis. Br J Dermatol 2007; 156: 138–42.
CH3
H3C COOH Uses and Administration
Pharmacopoeias. In Jpn. Etanercept is a recombinant version of soluble human
H Profile tumour necrosis factor (TNF) receptor that binds spe-
O Epirizole is an NSAID (p.96) that has been given in a usual oral cifically to tumour necrosis factor (p.783) and blocks
H 3C CH3 CH3 dose of 150 to 450 mg daily in divided doses; larger doses of up its interaction with endogenous cell-surface TNF re-
to 600 mg daily have been used in patients with rheumatoid ar- ceptors. This interaction prevents the important effect
thritis.
H CH3 of TNF in the inflammatory processes of rheumatoid
Preparations arthritis; elevated TNF levels are also found in psoriat-
HO Proprietary Preparations (details are given in Part 3)
H Braz.: Mebron†; Jpn: Mebron; Venez.: Dalex. ic plaques, in the synovium of patients with psoriatic
H 3C CH3 arthritis, and in the serum and synovium of patients
with ankylosing spondylitis.
NOTE. Do not confuse with glycyrrhizic acid (p.2316).
Etanercept (BAN, USAN, rINN) Etanercept is used in the treatment of moderately to se-
Pharmacopoeias. In Eur. (see p.vii). verely active rheumatoid arthritis and active and pro-
Ph. Eur. 6.2 (Enoxolone). A white or almost white, crystalline Étanercept; Etanerceptum; Etanersept; Etanersepti; rhu- gressive psoriatic arthritis. In the UK, it is licensed
powder. It exhibits polymorphism. Practically insoluble in water; TNFR:Fc; TNR-001. A dimer of 1-235 tumour necrosis factor re-
for use in patients who have had an inadequate re-
soluble in dehydrated alcohol; sparingly soluble in dichlo- ceptor (human) fusion protein with 236-467-immunoglobulin
romethane. Protect from light. G1 (human γ1-chain Fc fragment). sponse to standard disease-modifying antirheumatic
Этанерцепт drugs although, in severe rheumatoid arthritis, it may
Profile be used in patients not previously treated with meth-
Enoxolone is a complex triterpene prepared from glycyrrhizic C AS — 185243-69-0.
acid (p.2316), a constituent of liquorice (p.1740). Enoxolone is ATC — L04AB01. otrexate. In the USA, it is licensed to treat early rheu-
used locally in preparations for the treatment of non-infective in- ATC Vet — QL04AB01. matoid arthritis or psoriatic arthritis, to reduce the signs
 Eltenac/Ethenzamide 51
and symptoms, delay structural damage, and improve these 2 studies found that efficacy was also sustained when pa- Spondyloarthropathies. References to the use of etanercept
physical function. In both indications, it is given as a tients who had received etanercept 25 mg twice weekly for at in the treatment of ankylosing spondylitis and psoriatic arthritis
least 24 weeks had their dose altered to 50 mg once weekly. (p.13).
subcutaneous injection in a dose of 25 mg twice week- 1. Leonardi CL, et al. Etanercept as monotherapy in patients with 1. Mease PJ, et al. Etanercept in the treatment of psoriatic arthritis
ly at intervals of 3 or 4 days. The equivalent weekly psoriasis. N Engl J Med 2003; 349: 2014–22. and psoriasis: a randomised trial. Lancet 2000; 356: 385–90.
dose of 50 mg may also be given either as a single 2. Papp KA, et al. A global phase III randomized controlled trial 2. Brandt J, et al. Six-month results of a double-blind, placebo-
of etanercept in psoriasis: safety, efficacy, and effect of dose re- controlled trial of etanercept treatment in patients with active
50-mg injection or as two separate 25-mg injections duction. Br J Dermatol 2005; 152: 1304–12. ankylosing spondylitis. Arthritis Rheum 2003; 48: 1667–75.
(given at about the same time). In the UK, NICE rec- 3. NICE. Etanercept and efalizumab for the treatment of adults 3. Davis JC, et al. Enbrel Ankylosing Spondylitis Study Group.
with psoriasis: Technology Appraisal Guidance 103 (issued July Recombinant human tumor necrosis factor receptor (etanercept)
ommends, based on guidelines from the British Socie- 2006). Available at: http://www.nice.org.uk/nicemedia/pdf/ for treating ankylosing spondylitis: a randomized, controlled
ty of Rheumatology, that treatment be stopped if there TA103guidance.pdf (accessed 13/06/08) trial. Arthritis Rheum 2003; 48: 3230–6.
4. Boehncke W-H, et al. European Dermatology Expert Group. 4. Mease PJ, et al. Etanercept treatment of psoriatic arthritis: safe-
is no adequate response after 6 months. Etanercept is Recommendations for the use of etanercept in psoriasis: a Euro- ty, efficacy, and effect on disease progression. Arthritis Rheum
also indicated in the treatment of severely active pean dermatology expert group consensus. J Eur Acad Derma- 2004; 50: 2264–72.
tol Venereol 2006; 20: 988–98.
ankylosing spondylitis; in the UK, its use is again lim- 5. Woolacott N, et al. NHS Health Technology Assessment Pro- 5. Baraliakos X, et al. Outcome of patients with active ankylosing
spondylitis after two years of therapy with etanercept: clinical
ited to those who have had an inadequate response to gramme. Etanercept and efalizumab for the treatment of psoria-
and magnetic resonance imaging data. Arthritis Rheum 2005;
sis: a systematic review (issued November 2006). Available at:
conventional therapy. Doses are similar to those used http://www.hta.ac.uk/fullmono/mon1046.pdf (accessed 53: 856–63.
for rheumatoid arthritis. 13/06/08) 6. Mease PJ, et al. Continued inhibition of radiographic progres-
6. Tyring S, et al. Long-term safety and efficacy of 50 mg of sion in patients with psoriatic arthritis following 2 years of treat-
Etanercept is also used in the treatment of chronic, etanercept twice weekly in patients with psoriasis. Arch Derma- ment with etanercept. J Rheumatol 2006; 33: 712–21.
tol 2007; 143: 719–26. 7. NICE. Etanercept and infliximab for the treatment of adults
moderate to severe plaque psoriasis. In the UK, its use 7. Romero-Maté A, et al. Efficacy and safety of etanercept in pso- with psoriatic arthritis: Technology Appraisal Guidance 104 (is-
is usually limited to patients in whom other systemic riasis/psoriatic arthritis: an updated review. Am J Clin Dermatol sued July 2006). Available at: http://www.nice.org.uk/
2007; 8: 143–55. nicemedia/pdf/TA104guidance.pdf (accessed 13/06/08)
treatments are not suitable. The recommended initial 8. Elewski B, et al. Comparison of clinical and pharmacokinetic 8. Woolacott N, et al. NHS Health Technology Assessment Pro-
dose is 25 mg twice weekly. Alternatively, an initial profiles of etanercept 25 mg twice weekly and 50 mg once gramme. Etanercept and infliximab for the treatment of psoriat-
dose of 50 mg twice weekly at intervals of 3 or 4 days weekly in patients with psoriasis. Br J Dermatol 2007; 156: ic arthritis: a systematic review and economic evaluation (is-
138–42. sued September 2006). Available at: http://www.hta.ac.uk/
may be given for 12 weeks; the dose should then be 9. Ahmad K, Rogers S. Two years of experience with etanercept in fullmono/mon1031.pdf (accessed 13/06/08)
reduced to 25 mg twice weekly or 50 mg weekly. Ini- recalcitrant psoriasis. Br J Dermatol 2007; 156: 1010–14. 9. van der Heijde D, et al. Etanercept Study 314 Investigators.
10. Esposito M, et al. Treatment of erythrodermic psoriasis with Etanercept 50 mg once weekly is as effective as 25 mg twice
tial doses of 25 or 50 mg once weekly have also been etanercept. Br J Dermatol 2006; 155: 156–9. weekly in patients with ankylosing spondylitis. Ann Rheum Dis
shown to be effective. Treatment should continue until 11. Paller AS, et al. Etanercept Pediatric Psoriasis Study Group. 2006; 65: 1572–7.
Etanercept treatment for children and adolescents with plaque 10. Cantini F, et al. Switching from infliximab to once-weekly ad-
remission is achieved, for up to 24 weeks. Etanercept psoriasis. N Engl J Med 2008; 358: 241–51. ministration of 50 mg etanercept in resistant or intolerant pa-
should be stopped after 12 weeks in patients who show Rheumatoid arthritis. Some references to the use of etaner- tients with ankylosing spondylitis: results of a fifty-four-week
study. Arthritis Rheum 2006; 55: 812–6.
no response. cept in rheumatoid arthritis (p.11) and juvenile idiopathic arthri- 11. Woolacott NF, et al. Etanercept and infliximab for the treatment
For details of uses and dosage in children, see below. tis (p.10). of psoriatic arthritis: a systematic review. Clin Exp Rheumatol
1. Weinblatt ME, et al. A trial of etanercept, a recombinant tumor 2006; 24: 587–93.
Administration in children. Etanercept is used in the treat- necrosis factor receptor: Fc fusion protein, in patients with rheu- 12. Braun J, et al. Improvement in patient-reported outcomes for
ment of moderately to severely active polyarticular juvenile idi- matoid arthritis receiving methotrexate. N Engl J Med 1999; patients with ankylosing spondylitis treated with etanercept
opathic arthritis; UK licensed product information limits its use 340: 253–9. 50 mg once-weekly and 25 mg twice-weekly. Rheumatology
2. Moreland LW, et al. Etanercept therapy in rheumatoid arthritis: (Oxford) 2007; 46: 999–1004.
to those who have had an inadequate response to, or who are a randomized, controlled trial. Ann Intern Med 1999; 130: 13. Romero-Maté A, et al. Efficacy and safety of etanercept in pso-
intolerant of, the disease-modifying antirheumatic drug meth- 478–86. riasis/psoriatic arthritis: an updated review. Am J Clin Dermatol
otrexate. 3. Lovell DJ, et al. Etanercept in children with polyarticular juve- 2007; 8: 143–55.
nile rheumatoid arthritis. N Engl J Med 2000; 342: 763–9. 14. Frankel EH, et al. Etanercept improves psoriatic arthritis pa-
In the UK, it is given subcutaneously to children aged 4 years and 4. Bathon JM, et al. A comparison of etanercept and methotrexate
over in a dose of 400 micrograms/kg (up to a maximum dose of tient-reported outcomes: results from EDUCATE. Cutis 2007;
in patients with early rheumatoid arthritis. N Engl J Med 2000; 79: 322–6.
25 mg) twice weekly at intervals of 3 or 4 days. In the USA, 343: 1586–93. Correction. ibid. 2001; 344: 76. 15. McLeod C, et al. NHS Health Technology Assessment Pro-
etanercept is licensed for use in children as young as 2 years old. 5. Johnson CJ, et al. Etanercept in juvenile rheumatoid arthritis. gramme. Adalimumab, etanercept and infliximab for the treat-
Similar doses are used although they are expressed as Ann Pharmacother 2001; 35: 464–71. ment of ankylosing spondylitis: a systematic review and eco-
6. Genovese MC, et al. Etanercept versus methotrexate in patients nomic evaluation. Available at: http://www.hta.ac.uk/
800 micrograms/kg (up to a maximum dose of 50 mg) weekly: with early rheumatoid arthritis: two-year radiographic and clin-
doses to be given as 2 separate injections may either be given on fullmono/mon1128.pdf (accessed 13/06/08)
ical outcomes. Arthritis Rheum 2002; 46: 1443–50.
16. Gottlieb AB, et al. Use of etanercept for psoriatic arthritis in the
the same day or 3 to 4 days apart. 7. NICE. Guidance on the use of etanercept for the treatment of
dermatology clinic: the Experience Diagnosing, Understanding
juvenile idiopathic arthritis: Technology Appraisal Guidance 35
In the UK, NICE recommends, based on guidelines from the (issued March 2002). Available at: http://www.nice.org.uk/ Care, and Treatment with Etanercept (EDUCATE) study. J Der-
British Paediatric Rheumatology Group, that treatment be nicemedia/pdf/JIA-PDF.pdf (accessed 13/06/08) matolog Treat 2006; 17: 343–52.
stopped in children if there is no response after 6 months, or an 8. Klareskog L, et al. Therapeutic effect of the combination of 17. Hoy SM, Scott LJ. Etanercept: a review of its use in the man-
etanercept and methotrexate compared with each treatment agement of ankylosing spondylitis and psoriatic arthritis. Drugs
initial response is not maintained. 2007; 67: 2609–33.
alone in patients with rheumatoid arthritis: double-blind ran-
For references on the use of etanercept in juvenile idiopathic ar- domised controlled trial. Lancet 2004; 363: 675–81.
thritis, see Rheumatoid Arthritis, below. Vasculitic syndromes. For a preliminary report on the use of
9. Genovese MC, et al. Longterm safety, efficacy, and radiograph-
ic outcome with etanercept treatment in patients with early etanercept in Takayasu’s arteritis, see p.1514.
Asthma. TNF inhibitors such as etanercept have been investi- rheumatoid arthritis. J Rheumatol 2005; 32: 1232–42.
gated in the treatment of refractory asthma (p.1108).1,2 There is 10. Bathon JM, et al. Safety and efficacy of etanercept treatment in Preparations
some evidence that only a minority of patients will respond to elderly subjects with rheumatoid arthritis. J Rheumatol 2006; Proprietary Preparations (details are given in Part 3)
such therapy, and that the benefits and risks must therefore be 33: 234–43.
Arg.: Enbrel; Austral.: Enbrel; Belg.: Enbrel; Braz.: Enbrel; Canad.: Enbrel;
carefully assessed.3 11. van Riel PLCM, et al. ADORE (Add Enbrel or Replace Meth- Chile: Enbrel; Cz.: Enbrel; Denm.: Enbrel; Fin.: Enbrel; Fr.: Enbrel; Ger.:
otrexate) Study Investigators. Efficacy and safety of combina- Enbrel; Gr.: Enbrel; Hong Kong: Enbrel; India: Enbrel; Indon.: Enbrel; Irl.:
1. Howarth PH, et al. Tumour necrosis factor (TNFα) as a novel tion etanercept and methotrexate versus etanercept alone in pa-
therapeutic target in symptomatic corticosteroid dependent asth- Enbrel; Israel: Enbrel; Ital.: Enbrel; Malaysia: Enbrel; Mex.: Enbrel;
tients with rheumatoid arthritis with an inadequate response to Neth.: Enbrel; Norw.: Enbrel; NZ: Enbrel; Philipp.: Enbrel; Pol.: Enbrel;
ma. Thorax 2005; 60: 1012–18. methotrexate: the ADORE study. Ann Rheum Dis 2006; 65:
2. Berry MA, et al. Evidence of a role of tumor necrosis factor α in Port.: Enbrel; S.Afr.: Enbrel; Singapore: Enbrel; Spain: Enbrel; Swed.:
1478–83. Enbrel; Switz.: Enbrel; Thai.: Enbrel; Turk.: Enbrel; UK: Enbrel; USA: En-
refractory asthma. N Engl J Med 2006; 354: 697–708. 12. Moreland LW, et al. Etanercept treatment in adults with estab- brel; Venez.: Enbrel.
3. Brightling C, et al. Targeting TNF-α: a novel therapeutic ap- lished rheumatoid arthritis: 7 years of clinical experience. J
proach for asthma. J Allergy Clin Immunol 2008; 121: 5–10. Rheumatol 2006; 33: 854–61. Multi-ingredient: Hung.: Enbrel.
13. van der Heijde D, et al. Comparison of etanercept and meth-
Dementia. A small pilot study1 and individual case reports2 otrexate, alone and combined, in the treatment of rheumatoid
have suggested that perispinal injection of etanercept, in doses of arthritis: two-year clinical and radiographic results from the
25 to 50 mg weekly, may improve signs of dementia in patients TEMPO study, a double-blind, randomized trial. Arthritis Ethenzamide (BAN, rINN)
with Alzheimer’s disease. However, randomised controlled stud- Rheum 2006; 54: 1063–74.
14. Chen Y-F, et al. NHS Health Technology Assessment Pro- Aethoxybenzamidum; Etentsamidi; Etenzamid; Etenzamida;
ies are required to confirm any benefit. gramme. A systematic review of the effectiveness of adalimum-
1. Tobinick E, et al. TNF-alpha modulation for treatment of Alzhe- ab, etanercept and infliximab for the treatment of rheumatoid
Etenzamide; Éthenzamide; Ethenzamidum; Ethoxybenzamide;
imer’s disease: a 6-month pilot study. MedGenMed 2006; 8: 25. arthritis in adults and an economic evaluation of their cost-ef- Ethylsalicylamide; HP-209. 2-Ethoxybenzamide.
Available at: fectiveness (issued November 2006). Available at: http:// Этензамид
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool= www.hta.ac.uk/fullmono/mon1042.pdf (accessed 13/06/08)
pubmed&pubmedid=16926764 (accessed 13/06/08) 15. Weisman MH, et al. A placebo-controlled, randomized, double- C 9 H 11 NO 2 = 165.2.
2. Tobinick EL, Gross H. Rapid cognitive improvement in Alzhe- blinded study evaluating the safety of etanercept in patients with C AS — 938-73-8.
imer’s disease following perispinal etanercept administration. J rheumatoid arthritis and concomitant comorbid diseases. Rheu-
matology (Oxford) 2007; 46: 1122–5. ATC — N02BA07.
Neuroinflammation 2008; 5: 2.
Available at: http://www.jneuroinflammation.com/content/pdf/ 16. Dhillon S, et al. Etanercept: a review of its use in the manage- ATC Vet — QN02BA07.
1742-2094-5-2.pdf (accessed 13/06/08) ment of rheumatoid arthritis. Drugs 2007; 67: 1211–41. Correc-
tion. ibid.; 1849.
Psoriasis. Etanercept is effective in patients with moderate to 17. van der Heijde D, et al. Etanercept Study 400 Investigators. The
O
severe plaque psoriasis (p.1583).1-9 It has also been successfully safety and efficacy of adding etanercept to methotrexate or
tried in the treatment of erythrodermic psoriasis,10 and of plaque methotrexate to etanercept in moderately active rheumatoid ar-
thritis patients previously treated with monotherapy. Ann
psoriasis in children and adolescents.11 Rheum Dis 2008; 67: 182–8. NH2
Efficacy may be dose-related; in one study,1 25% of patients in 18. van der Heijde D, et al. Disease remission and sustained halting
the low-dose (25 mg once weekly) group showed at least a 75% of radiographic progression with combination etanercept and
methotrexate in patients with rheumatoid arthritis. Arthritis O CH3
improvement compared with 44% in the medium-dose group Rheum 2007; 56: 3928–39.
(25 mg twice weekly) and 59% in the high-dose group (50 mg 19. NICE. Adalimumab, etanercept and infliximab for the treatment Pharmacopoeias. In Jpn.
twice weekly) after 24 weeks of etanercept treatment. However, of rheumatoid arthritis: Technology Appraisal Guidance 130
a later multicentre study2 in patients with chronic plaque psoria- (issued October 2007). Available at: http://www.nice.org.uk/ Profile
nicemedia/pdf/TA130guidance.pdf (accessed 13/06/08)
sis found that the therapeutic effect of etanercept was maintained 20. Gartlehner G, et al. Biologics for the treatment of juvenile idio-
Ethenzamide is a salicylic acid derivative (see Aspirin, p.20) giv-
when the dose was reduced after 12 weeks from 50 mg twice pathic arthritis: a systematic review and critical analysis of the en by mouth in painful and inflammatory conditions and to re-
weekly to 25 mg twice weekly. An open-label extension8 of evidence. Clin Rheumatol 2008; 27: 67–76. duce fever.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
52 Analgesics Anti-inflammatory Drugs and Antipyretics
Preparations Preparations Pharmacopoeias. In Eur. (see p.vii), Jpn, and US.
Proprietary Preparations (details are given in Part 3) Proprietary Preparations (details are given in Part 3) Ph. Eur. 6.2 (Etodolac). A white or almost white crystalline
powder. Practically insoluble in water; freely soluble in dehy-
Multi-ingredient: Austria: Coldadolin; Dolmix; Helopyrin; Nisicur; Multi-ingredient: Austral.: Deep Heat; Radian-B†; Belg.: Rado-Salil; Is- drated alcohol and in acetone.
Seltoc; Cz.: Cephyl†; Ger.: Glutisal†; Kolton grippale N†; Indon.: Farapon; rael: Deep Heat Spray; Ital.: Remy; Pol.: Deep Heat; S.Afr.: Deep Heat
Neo Novapon Plus; Jpn: Sin Colgen Kowa Kaze; Pol.: Erka; Etomar; Etopi- Spray; Singapore: Deep Heating Spray†; Switz.: Alginex†; UK: Deep USP 31 (Etodolac). Store in airtight containers.
ryna; Port.: Cephyl; Rus.: Nextrim Aktiv (Некстрим Актив); Switz.: Heat Spray; Dubam; Numark Muscle Spray; Ralgex.
Nicaphlogyl†; Seranex sans codeine†. Adverse Effects, Treatment, and Precau-
tions
Ethylmorphine Hydrochloride (BANM) As for NSAIDs in general, p.96.
Ethoheptazine Citrate (BANM, rINNM) The presence of phenolic metabolites of etodolac in the
Aethylmorphinae Hydrochloridum; Aethylmorphini Hydrochlo-
Citrato de etoheptacina; Éthoheptazine, Citrate d’; Ethoheptazini ridum; Chlorhydrate de Codéthyline; Ethylmorfin-hydrochlorid urine may give rise to a false-positive reaction for bi-
Citras; Wy-401. Ethyl 1-methyl-4-phenylperhydroazepine-4-car- dihydrát; Éthylmorphine, chlorhydrate d’; Ethylmorphini hydro- lirubin.
boxylate dihydrogen citrate. chloridum; Ethylmorphini Hydrochloridum Dihydricum; Ethyl- Effects on the blood. Agranulocytosis has been reported in a
Этогептазина Цитрат morphinium Chloride; Etilmorfina, hidrocloruro de; Etilmorfin- patient receiving etodolac.1 Coombs-positive haemolytic anae-
C 16 H 23 NO 2,C 6 H 8 O 7 = 453.5. hidroklorid; Etilmorfino hidrochloridas; Etylmorfinhydroklorid; mia due to sensitivity to etodolac metabolites has also been re-
C AS — 77-15-6 (ethoheptazine); 6700-56-7 (ethohep- Etylomorfiny chlorowodorek; Etyylimorfiinihydrokloridi. 3-O- ported.2
tazine citrate); 2085-42-9 (( ± )-ethoheptazine citrate). Ethylmorphine hydrochloride dihydrate; 7,8-Didehydro-4,5- 1. Cramer RL, et al. Agranulocytosis associated with etodolac. Ann
epoxy-3-ethoxy-17-methylmorphinan-6-ol hydrochloride dihy- Pharmacother 1994; 28: 458–60.
2. Cunha PD, et al. Immune hemolytic anemia caused by sensitivi-
drate. ty to a metabolite of etodolac, a nonsteroidal anti-inflammatory
CH3 C 19 H 23NO 3 ,HCl,2H 2 O = 385.9. drug. Transfusion 2000; 40: 663–8.
C AS — 76-58-4 (ethylmorphine); 125-30-4 (ethylmor- Effects on the gastrointestinal tract. Etodolac is reported to
N phine hydrochloride). be a preferential inhibitor of cyclo-oxygenase 2 (COX-2) and
ATC — R05DA01; S01XA06. consequently it may produce less gastric toxicity than the non-
ATC Vet — QR05DA01; QS01XA06. selective NSAIDs such as naproxen.1-3
O CH3 1. Taha AS, et al. Effect of repeated therapeutic doses of naproxen
and etodolac on gastric and duodenal mucosal prostaglandins
H 3C O (PGs) in rheumatoid arthritis (RA). Gut 1989; 30: A751.
O 2. Bianchi Porro G, et al. A double-blind gastroscopic evaluation of
the effects of etodolac and naproxen on the gastrointestinal mu-
cosa of rheumatic patients. J Intern Med 1991; 229: 5–8.
(ethoheptazine) 3. Weideman RA, et al. Risks of clinically significant upper gas-
O trointestinal events with etodolac and naproxen: a historical co-
hort analysis. Gastroenterology 2004; 127: 1322–8.
Profile
Ethoheptazine citrate is an opioid analgesic (p.101) structurally NCH3
related to pethidine (p.113). It has been used as an analgesic in
Interactions
the short-term treatment of mild to moderate pain, usually with HO For interactions associated with NSAIDs, see p.99.
other drugs such as aspirin and meprobamate.
Preparations
(ethylmorphine) Pharmacokinetics
Etodolac is a chiral compound given as the racemate.
Proprietary Preparations (details are given in Part 3) Pharmacopoeias. In Chin., Eur. (see p.vii), and Jpn. Peak plasma concentrations of the active (S)-enanti-
Multi-ingredient: India: Equagesic; S.Afr.: Equagesic. Ph. Eur. 6.2 (Ethylmorphine Hydrochloride). A white or almost omer and of the inactive (R)-enantiomer are usually
white crystalline powder. Soluble in water and in alcohol. A 2% obtained within about 2 hours of a dose by mouth but
solution in water has a pH of 4.3 to 5.7. Protect from light. plasma concentrations of the (R)-enantiomer have
Ethyl Nicotinate Profile been reported to greatly exceed those of the (S)-enanti-
Nicotinato de etilo. Ethylmorphine hydrochloride is an opioid analgesic (p.101) and omer. Both enantiomers are highly bound to plasma
has properties similar to those of codeine (p.37). It is used mainly proteins. Both are also distributed to the synovial fluid,
C 8 H 9 NO 2 = 151.2. as a cough suppressant. It has also been used for its analgesic and
C AS — 614-18-6.
although the difference in their concentrations may not
antidiarrhoeal properties. It was formerly given in eye drops as a be as marked as the difference in plasma concentra-
lymphagogue.
tions. The plasma half-life of total etodolac has been
Ethylmorphine free base and the camphorate and camsilate have reported to be about 7 hours; excretion is mainly in the
N also been used.
urine as hydroxylated metabolites and glucuronide
◊ References. conjugates; some may be excreted in the bile.
O CH3
1. Aasmundstad TA, et al. Biotransformation and pharmacokinet- ◊ References.
ics of ethylmorphine after a single oral dose. Br J Clin Pharma-
col 1995; 39: 611–20. 1. Brocks DR, et al. Stereoselective disposition of etodolac enanti-
O omers in synovial fluid. J Clin Pharmacol 1991; 31: 741–6.
2. Jonasson B, et al. Fatal poisonings where ethylmorphine from
2. Brocks DR, et al. The stereoselective pharmacokinetics of
antitussive medications contributed to death. Int J Legal Med
Profile etodolac in young and elderly subjects, and after cholecystecto-
1999; 112: 299–302.
my. J Clin Pharmacol 1992; 32: 982–9.
Ethyl nicotinate is used in concentrations of up to 2% in topical 3. Brocks DR, Jamali F. Etodolac clinical pharmacokinetics. Clin
rubefacient preparations for the relief of pain in musculoskeletal, Preparations
Pharmacokinet 1994; 26: 259–74.
joint, and soft-tissue disorders. It has also been used as supposi- Proprietary Preparations (details are given in Part 3) 4. Boni J, et al. Pharmacokinetic and pharmacodynamic action of
tories in anorectal disorders. Arg.: Dionina; Belg.: Codethyline; Cz.: Diolan; Fin.: Cocillana; Fr.: Dithiol†; etodolac in patients after oral surgery. J Clin Pharmacol 1999;
UK: Collins Elixir. 39: 729–37.
Preparations Multi-ingredient: Austria: Modiscop; Belg.: Longbalsem; Saintbois; 5. Boni JP, et al. Pharmacokinetics of etodolac in patients with sta-
Proprietary Preparations (details are given in Part 3) Tux†; Chile: Codelasa; Fin.: Indalgin; Fr.: Ephydion; Humex†; Tussipax; ble juvenile rheumatoid arthritis. Clin Ther 1999; 21: 1715–24.
Austria: Mucotherm. Vegetoserum; Hung.: Dolor; India: Bell Diono Resolvent; Bell Resolvent;
Ital.: Mindol-Merck†; Norw.: Cosylan; Solvipect comp; Port.: Bronquias- Uses and Administration
Multi-ingredient: Austria: Percucor†; Thermal; Belg.: Transvane; mol†; Calmarum†; Xarope Antigripal†; Spain: Demusin; Sedalmerck†;
Hung.: Nicoflex; Irl.: Transvasin; Norw.: Thermal†; Switz.: Baume Esco Swed.: Cocillana-Etyfin; Lepheton; Switz.: Ipeca†; Phol-Tux; Saintbois; Sano Etodolac, a pyrano-indoleacetic acid derivative, is an
Forte; Frixo-Dragon Vert†; Knobel Huile N; Thermocutan†; Ziegella; UK: Tuss; Turk.: Fenokodin; Venez.: Novacodin. NSAID (p.99) reported to be a preferential inhibitor of
PR Heat Spray; Transvasin Heat Rub.
cyclo-oxygenase 2 (COX-2). It is used for rheumatoid
arthritis, including juvenile idiopathic arthritis, and os-
teoarthritis and for the treatment of acute pain.
Ethyl Salicylate Etodolac (BAN, USAN, rINN) For the treatment of rheumatoid arthritis and osteoar-
Salicilato de etilo. Ethyl 2-hydroxybenzoate. AY-24236; Etodolaakki; Étodolac; Etodolaco; Etodolacum; thritis, the recommended oral dose is initially 600 to
Этилсалицилат Etodolák; Etodolak; Etodolakas; Etodolic Acid. 1,8-Diethyl- 1000 mg daily in divided doses adjusted according to
C 9 H 10 O 3 = 166.2. 1,3,4,9-tetrahydropyrano[3,4-b]indol-1-ylacetic acid. response; single daily doses of up to 600 mg may also
C AS — 118-61-6. Этодолак be given. Modified-release preparations are available
C 17 H 21NO 3 = 287.4. for once-daily use in these conditions. For doses in
C AS — 41340-25-4. children, see below.
ATC — M01AB08. For the treatment of acute pain, the recommended dose
ATC Vet — QM01AB08.
is 200 to 400 mg every 6 to 8 hours to a maximum of
O CH3 1 g daily.
Administration in children. In the USA modified-release
OH O COOH preparations of etodolac may be given for the oral treatment of
H 3C juvenile idiopathic arthritis in children aged 6 to 16 years. Doses
H
N CH3 are given once daily according to body-weight as follows:
Profile
Ethyl salicylate is a salicylic acid derivative that is used similarly • 20 to 30 kg: 400 mg
to methyl salicylate (p.85) in concentrations of up to 5% in topi- O • 31 to 45 kg: 600 mg
cal rubefacient preparations for the relief of pain in musculoskel- • 46 to 60 kg: 800 mg
etal, joint, and soft-tissue disorders. • over 60 kg: 1 g
 Ethoheptazine Citrate/Etoricoxib 53
Preparations with severe hepatic impairment (Child-Pugh score of of developing, such events. In addition, etoricoxib should not be
BP 2008: Etodolac Capsules; Etodolac Tablets; 10 or more). Therapy should be stopped if persistently used in patients with active gastrointestinal ulceration or bleed-
USP 31: Etodolac Capsules; Etodolac Extended-Release Tablets; Etodolac ing.
Tablets.
abnormal liver enzyme values are seen.
Results from controlled studies have suggested that NSAIDs se-
Proprietary Preparations (details are given in Part 3) Etoricoxib should not be used in patients with ischae- lective for COX-2 were associated with a lower incidence of se-
Austria: Lodine†; Braz.: Flancox; Canad.: Ultradol†; Denm.: Todolac; mic heart disease, peripheral arterial disease, or cere- rious gastrointestinal effects. In a study1 of the pooled data from
Fin.: Lodine; Fr.: Lodine; Gr.: Ecridoxan†; Lonine; Hong Kong: Lodine;
Indon.: Lonene; Israel: Etopan; Ital.: Lodine†; Jpn: Hypen; Mex.: Lod- brovascular disease. It should be used with caution in 3 randomised clinical studies, etoricoxib (in doses of 60 or 90 mg
ine†; Port.: Acudor; Articulan; Dualgan; Lodine†; Lodot†; Metazin†; Sodol- patients with significant risk factors for cardiovascular daily) was associated with significantly less frequent upper gas-
ac; Switz.: Lodine; Thai.: Etonox; Turk.: Edolar; Etodin; Etol; Lodine; trointestinal clinical events than diclofenac (150 mg daily). The
Tadolak; UK: Eccoxolac; Etopan; Lodine; USA: Lodine†; Venez.: Lodine†. disease such as hypertension, hyperlipidaemia, and di- result was attributed to the lower rate of uncomplicated ulcers
abetes mellitus. Etoricoxib, particularly at high doses, with etoricoxib compared with diclofenac; there was no differ-
may be associated with more frequent and severe hy- ence in the rate of complicated gastrointestinal events between
Etofenamate (BAN, USAN, rINN) pertension compared with other NSAIDs and selective the 2 drugs. The lower rate of uncomplicated events with etori-
COX-2 inhibitors; blood pressure monitoring during coxib compared with diclofenac was not affected by treatment
B-577; Bay-d-1107; Etofenamaatti; Etofenamát; Etofenamat; with low-dose aspirin or proton pump inhibitors. An analysis2 by
Etofenamatas; Étofénamate; Etofenamato; Etofenamatum; TV- etoricoxib treatment is recommended. Etoricoxib the manufacturer, of pooled data from 10 randomised clinical
485; TVX-485; WHR-5020. 2-(2-Hydroxyethoxy)ethyl N-(ααα- should not be used in patients with hypertension whose studies, found that etoricoxib (in daily doses of 60, 90, or
trifluoro-m-tolyl)anthranilate. blood pressure is not controlled (see also Effects on the 120 mg) was associated with a lower combined risk of upper
Этофенамат Cardiovascular System, below). gastrointestinal perforations and bleeding, and symptomatic gas-
C 18 H 18F 3 NO 4 = 369.3. troduodenal ulcers when compared with non-selective NSAIDs
C AS — 30544-47-9.
Etoricoxib is also contra-indicated in patients with in- (diclofenac 150 mg daily, ibuprofen 2.4 g daily, or naproxen 1 g
ATC — M02AA06. flammatory bowel disease, moderate to severe heart daily) as a group. This reduced risk was seen even in patients
ATC Vet — QM02AA06. failure (NYHA class II to IV), and renal impairment with known risk factors for such complications such as the elder-
associated with a creatinine clearance of less than ly and those with a history of gastrointestinal reactions.
1. Laine L, et al. Assessment of upper gastrointestinal safety of
O O OH
30 mL/minute. Caution is recommended when using etoricoxib and diclofenac in patients with osteoarthritis and
O etoricoxib in dehydrated patients; it may be advisable rheumatoid arthritis in the Multinational Etoricoxib and Di-
H to rehydrate patients before giving etoricoxib. clofenac Arthritis Long-term (MEDAL) programme: a ran-
N CF3 domised comparison. Lancet 2007; 369: 465–73.
Effects on the cardiovascular system. There have been 2. Ramey DR, et al. The incidence of upper gastrointestinal adverse
concerns about the adverse cardiovascular effects of selective cy- events in clinical trials of etoricoxib vs. non-selective NSAIDs:
clo-oxygenase-2 (COX-2) inhibitors after the worldwide with- an updated combined analysis. Curr Med Res Opin 2005; 21:
715–22.
drawal of rofecoxib (see p.121). The cardiovascular safety of
Pharmacopoeias. In Eur. (see p.vii). etoricoxib has been assessed in the MEDAL programme1 which Effects on the kidneys. Limited evidence of the renal toxicity
Ph. Eur. 6.2 (Etofenamate). A yellowish viscous liquid. Practi- pooled data from 3 studies involving over 30 000 patients with of the selective cyclo-oxygenase-2 (COX-2) inhibitors such as
cally insoluble in water; miscible with alcohol and with ethyl either osteoarthritis or rheumatoid arthritis. Patients with osteoar- etoricoxib suggests that such NSAIDs appear to have effects on
acetate. thritis were given etoricoxib 60 or 90 mg daily; those with rheu- renal function similar to those of the non-selective NSAIDs (see
Profile matoid arthritis received 90 mg daily. In all studies, diclofenac p.98).
Etofenamate is an NSAID (p.96) that has been applied topically 150 mg daily was given as the comparator; low-dose aspirin
in a concentration of 5 or 10% for the relief of pain and inflam- (100 mg daily or less) was also allowed where indicated. After Interactions
mation associated with musculoskeletal, joint, and soft-tissue an average treatment duration of 18 months, the rates of throm-
botic events such as myocardial infarction, stroke, and sudden or The metabolism of etoricoxib is mediated by the cyto-
disorders. It has also been given by deep intramuscular injection chrome P450 isoenzyme CYP3A4. Use with other
in single doses of 1 g. unexplained death with etoricoxib were similar to those for di-
clofenac. (It has been suggested that diclofenac itself may in- drugs that inhibit or induce this isoenzyme may result
Preparations crease the risk of some thrombotic events; for further details, see in changes in plasma concentration of etoricoxib. In
Proprietary Preparations (details are given in Part 3) p.97.) The programme also found that the rate of some other non-
Arg.: Bayrogel†; Contour†; Flogol; Austria: Rheumon; Traumon; Belg.: thrombotic cardiovascular events was increased with etoricoxib:
addition, in vitro studies suggest that several other
Flexium; Braz.: Bayro; Chile: Bayagel; Bayro†; Flogojet; Master-Gel†; Val- one of the 3 studies showed that there was a non-significant in- isoenzymes may also mediate the main metabolic
orel; Cz.: Etogel†; Rheuma Denk†; Rheumon; Traumon; Ger.: Algesalona pathway of etoricoxib. Rifampicin, a potent inducer of
E†; Rheuma-Gel; Rheumon; Traumon; Gr.: Cimal†; Etofenol; Fenam†; crease in the rate of heart failure with etoricoxib 90 mg daily
Melferut; Pazergicel†; Radermin; Reumina; Roiplon; Hong Kong: Flogopro- compared to diclofenac; withdrawals due to oedema were also CYP isoenzymes, has produced decreased plasma con-
fen; Hung.: Activon Extra; Rheumon; Traumon†; Ital.: Bayro; Mex.: Bayro; more frequent with high-dose etoricoxib than with diclofenac or centrations of etoricoxib.
Pol.: Rheumon; Traumon; Port.: Fenogel; Reumon; Spain: Aspitopic; Fl- etoricoxib 60 mg daily. In addition, the number of patients stop-
ogoprofen; Zenavan; Switz.: Activon†; Etofen†; Rheumon; Traumalix; ping treatment because of hypertension was higher with both Etoricoxib is an inhibitor of human sulfotransferase ac-
Turk.: Doline; Flexo; Painex; Rheumon; Venez.: Traflan.
doses of etoricoxib than with diclofenac. Similar results were tivity and has been shown to increase the plasma con-
Multi-ingredient: Arg.: Bayagel; Austria: Thermo-Rheumon; Chile:
Bayro-Therm†; Cz.: Thermo-Rheumon†; Ger.: Thermo-Rheumon†; Gr.: seen in the other 2 studies. centration of ethinylestradiol. Interactions with other
Thermo-Roiplon; Hung.: Thermo-Rheumon†; Mex.: Bayro Termo; Pol.: In another study2 that pooled pre-licensing data, the risk of drugs, such as oral salbutamol and minoxidil, also
Thermo-Rheumon; Turk.: Thermo-Doline; Thermo-Rheumon; Ther- thrombotic events with etoricoxib, given at a dose of at least
moflex; Venez.: Reugel.
60 mg daily, was also found to be similar to that for placebo treat- metabolised by this enzyme may be a possibility and
ment, ibuprofen (2.4 g daily), diclofenac (150 mg daily), and licensed product information advises care with such
naproxen (1 g daily), although there was a trend towards more combinations.
events with etoricoxib than with naproxen. For details on the rel-
Etoricoxib (BAN, USAN, rINN) ative risk of thrombotic events associated with non-selective For interactions associated with NSAIDs in general,
Étoricoxib; Etoricoxibum; Etorikoksib; Etorikoksibi; Etorikoxib; L- NSAIDs, see p.97. see p.99.
791456; MK-0663; MK-663. 5-Chloro-6′-methyl-3-[p-(methyl- The EMEA’s Committee for Medicinal Products for Human Use
sulfonyl)phenyl]-2,3′-bipyridine. (CHMP)3 has recommended the inclusion of a warning in the Pharmacokinetics
Эторикоксиб labelling of etoricoxib that it must not be given to patients whose Etoricoxib is well absorbed from the gastrointestinal
C 18 H 15ClN 2 O 2 S = 358.8. blood pressure is persistently above 140/90 mmHg and inade- tract after oral doses. Peak plasma concentrations are
quately controlled; in addition, high blood pressure should be
C AS — 202409-33-4. controlled before starting treatment and monitored for 2 weeks reached in about 1 hour in fasted adults; food delays
ATC — M01AH05. afterwards then regularly thereafter. absorption by about 2 hours, although it has no effect
ATC Vet — QM01AH05. For discussion and advice on the use of selective COX-2 inhibi- on the extent of absorption. Plasma protein binding is
tors in patients with cardiovascular or cerebrovascular disease, about 92%. At steady state the half-life of etoricoxib is
see under Celecoxib, p.34. about 22 hours. Etoricoxib is extensively metabolised
H3C 1. Cannon CP, et al. Cardiovascular outcomes with etoricoxib and
diclofenac in patients with osteoarthritis and rheumatoid arthritis
with less than 2% of a dose recovered in the urine as the
in the Multinational Etoricoxib and Diclofenac Arthritis Long- parent drug. The major route of metabolism is via cy-
N term (MEDAL) programme: a randomised comparison. Lancet tochrome P450 isoenzymes including CYP3A4 to
2006; 368: 1771–81.
2. Curtis SP, et al. Pooled analysis of thrombotic cardiovascular form the 6′-hydroxymethyl derivative of etoricoxib,
O N
events in clinical trials of the COX-2 selective inhibitor etoricox- which is then oxidised to the 6′-carboxylic acid deriv-
ib. Curr Med Res Opin 2006; 22: 2365–74. ative, the major metabolite. Both are inactive or only
H3C S 3. EMEA. EMEA recommends strengthening warnings and con-
traindications for etoricoxib-containing medicines used in the weak cyclo-oxygenase-2 (COX-2) inhibitors. Excre-
O treatment of rheumatoid arthritis and ankylosing spondylitis (is- tion is mainly via the urine (70%) with only 20% of a
sued 26th June, 2008). Available at: http://www.emea.europa.eu/
Cl pdfs/human/press/pr/33363608en.pdf (accessed 16/07/08) dose appearing in the faeces. Studies in animals sug-
gest that etoricoxib may cross the placenta and that
Effects on the gastrointestinal tract. It is generally accept-
ed that the inhibition of cyclo-oxygenase-1 (COX-1) plays a role some is distributed into breast milk.
Adverse Effects, Treatment, and Precau- in the adverse gastrointestinal effects of the NSAIDs, and that the
tions ◊ References.
selective inhibition of the other isoform, COX-2, by NSAIDs
As for NSAIDs in general, p.96. 1. Agrawal NGB, et al. Single- and multiple-dose pharmacokinet-
such as etoricoxib may cause less gastrotoxicity than that seen ics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in
Hypersensitivity reactions including anaphylaxis and with the non-selective inhibition of the traditional NSAIDs. man. J Clin Pharmacol 2003; 43: 268–76.
However, licensed product information states that upper gas- 2. Agrawal NGB, et al. Pharmacokinetics of etoricoxib in patients
angioedema have occurred in patients receiving etori- trointestinal perforation, ulceration, and bleeds, in some cases with hepatic impairment. J Clin Pharmacol 2003; 43: 1136–48.
coxib; it should be stopped at the first signs of hyper- fatal, have occurred with etoricoxib treatment; consequently, it 3. Agrawal NGB, et al. Pharmacokinetics of etoricoxib in patients
sensitivity. Etoricoxib should be avoided in patients should be used with caution in patients with a history of, or at risk with renal impairment. J Clin Pharmacol 2004; 44: 48–58.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
54 Analgesics Anti-inflammatory Drugs and Antipyretics
Uses and Administration Felbinac (BAN, USAN, rINN)
Etoricoxib is an NSAID (p.96) reported to be a selec- HO CL-83544; Felbinaakki; Felbinaco; Felbinacum; Felbinak; LJC-
tive inhibitor of cyclo-oxygenase-2 (COX-2). It is used 10141. Biphenyl-4-ylacetic acid.
in the symptomatic relief of rheumatoid arthritis, oste- Фелбинак
oarthritis, and acute gouty arthritis. C 14 H 12O 2 = 212.2.
O C AS — 5728-52-9.
In osteoarthritis, etoricoxib is given orally in a usual ATC — M02AA08.
dose of 30 mg once daily, increased to 60 mg once dai- NCH3 ATC Vet — QM02AA08.
ly if necessary. The recommended dose in rheumatoid
arthritis is 90 mg once daily; higher doses of 120 mg H3CO
OH
once daily are used in gouty arthritis although such
doses should only be used for the acute symptomatic H3C CH3 O
period and for a maximum of 8 days. For dosage rec- HO
ommendations in patients with hepatic impairment, see (etorphine)
below.
Pharmacopoeias. In BP(Vet). Pharmacopoeias. In Eur. (see p.vii).
◊ References. BP(Vet) 2008 (Etorphine Hydrochloride). A white or almost Ph. Eur. 6.2 ( Felbinac). A white or almost white, crystalline
1. Patrignani P, et al. Clinical pharmacology of etoricoxib: a novel white microcrystalline powder. Sparingly soluble in water and in powder. Practically insoluble in water; sparingly soluble in alco-
selective COX2 inhibitor. Expert Opin Pharmacother 2003; 4: alcohol; very slightly soluble in chloroform; practically insoluble hol; soluble in methyl alcohol.
265–84. in ether. A 2% solution in water has a pH of 4.0 to 5.5. Protect Adverse Effects and Precautions
2. Dallob A, et al. Characterization of etoricoxib, a novel, selective from light. Mild local reactions such as erythema, dermatitis, and pruritus
COX-2 inhibitor. J Clin Pharmacol 2003 43: 573–85. have occurred in patients using felbinac topically. More serious
3. Martina SD, et al. Etoricoxib: a highly selective COX-2 inhibi- Dependence and Withdrawal
As for Opioid Analgesics, p.101. adverse effects including bullous dermatoses such as epidermal
tor. Ann Pharmacother 2005; 39: 854–62. necrolysis and erythema multiforme, photosensitivity, anaphy-
Administration in hepatic impairment. The maximum Adverse Effects and Treatment laxis, and bronchospasm or wheeziness have also been reported.
oral dose of etoricoxib in patients with mild hepatic impairment As for Opioid Analgesics in general, p.102. Etorphine is not used Gastrointestinal disturbances may occur.
(Child-Pugh score of 5 to 6), regardless of indication, is 60 mg therapeutically in humans. Felbinac preparations should be avoided in patients with a histo-
once daily; those with moderate impairment (Child-Pugh 7 to 9) Etorphine hydrochloride is highly potent and rapid acting; ry of hypersensitivity reactions to aspirin or other NSAIDs.
should be given a maximum of 60 mg every other day or 30 mg minute amounts can exert serious effects leading to coma. It may
Incidence of adverse effects. The UK CSM had received 49
once daily. Etoricoxib should not be given to patients with severe be absorbed through skin and mucous membranes. It is thus ad-
reports of adverse reactions associated with felbinac by October
hepatic impairment (Child-Pugh 10 or more). visable to inject an antagonist immediately after contamination of
1989, about 11 months after it was released on the UK market.1
skin or mucous membranes with preparations containing etor-
Musculoskeletal and joint disorders. The selective cyclo- phine hydrochloride and to wash the affected areas copiously. Bronchospasm or wheeziness was reported in 8 patients using
oxygenase-2 (COX-2) inhibitor etoricoxib is used in the treat- Accidental injection or needle scratch injuries should also be felbinac gel. Four of these patients had a history of asthma of
whom 3 were reported to have had a similar reaction to aspirin or
ment of the musculoskeletal disorders osteoarthritis and rheuma- treated immediately by injecting an antagonist. Naloxone is pre-
toid arthritis (see p.11 and p.11, respectively). However, in the ferred as the antagonist in medical treatment. However, veteri- other NSAIDs. Other reported reactions included skin rashes (17
UK, it is recommended that the use of selective COX-2 inhibi- nary preparations of etorphine are supplied with a preparation cases), local application site reactions (7), and dyspepsia (6).
tors is limited to those patients considered to be at high risk of (Revivon) containing diprenorphine hydrochloride (p.1445) and 1. CSM. Felbinac (Traxam) and bronchospasm. Current Problems
27 1989. Also available at: http://www.mhra.gov.uk/home/
developing serious gastrointestinal problems if given a non-se- this should be used for immediate first-aid antagonism if idcplg?IdcService=GET_FILE&dDocName=CON2024444&
lective NSAID (see p.97). naloxone is not available. RevisionSelectionMethod=LatestReleased (accessed 01/11/07)
Etoricoxib is also used in gouty arthritis (p.552) and has been Uses and Administration Uses and Administration
tried in the treatment of ankylosing spondylitis (see Spondyloar- Etorphine hydrochloride is a highly potent opioid analgesic Felbinac, an active metabolite of fenbufen (below), is an NSAID
thropathies, p.13). (p.104) used for reversible neuroleptanalgesia (see Anaesthetic (p.99). It is used topically in the symptomatic treatment of mus-
References. Techniques, p.1780) in veterinary medicine. It is given with culoskeletal pain including that due to soft-tissue injuries. It is
acepromazine maleate or levomepromazine (Immobilon) to applied as a 3% gel or a 3.17% foam to unbroken skin over af-
1. Cochrane DJ, et al. Etoricoxib. Drugs 2002; 62: 2637–51. restrain animals and before minor veterinary surgery. The dura- fected areas 2 to 4 times daily. The total daily dose of gel or foam
2. Schumacher HR, et al. Randomised double blind trial of etori- tion of action of etorphine is up to about 45 to 90 minutes de- should not exceed 25 g regardless of the size or number of affect-
coxib and indometacin in treatment of acute gouty arthritis. BMJ pending on the species but it may be longer in man, especially if ed areas. Therapy should be reviewed after 14 days.
2002; 324: 1488–92. the large animal preparation is involved. Diisopropanolamine felbinac has been used similarly.
3. Gottesdiener K, et al. Results of a randomized, dose-ranging trial
of etoricoxib in patients with osteoarthritis. Rheumatology (Ox- ◊ References.
ford) 2002; 41: 1052–61. 1. Hosie GAC. The topical NSAID, felbinac, versus oral ibuprofen:
4. Wiesenhutter CW, et al. Evaluation of the comparative efficacy Famprofazone (BAN, rINN) ⊗ a comparison of efficacy in the treatment of acute lower back
of etoricoxib and ibuprofen for treatment of patients with oste- injury. Br J Clin Res 1993; 4: 5–17.
oarthritis: a randomized, double-blind, placebo-controlled trial. Famprofazona; Famprofazonum. 4-Isopropyl-2-methyl-3-[me-
Mayo Clin Proc 2005; 80: 470–9. thyl(α-methylphenethyl)aminomethyl]-1-phenyl-3-pyrazolin-5- Preparations
one. BP 2008: Felbinac Cutaneous Foam; Felbinac Gel.
5. van der Heijde D, et al. Evaluation of the efficacy of etoricoxib
in ankylosing spondylitis: results of a fifty-two-week, rand- Фампрофазон Proprietary Preparations (details are given in Part 3)
omized, controlled study. Arthritis Rheum 2005; 52: 1205–15. Austria: Target†; Belg.: Flexfree; Ger.: Spalt Schmerz-Gel†; Irl.: Traxam;
C 24 H 31N 3 O = 377.5. Ital.: Dolinac; Traxam; Jpn: Seltouch; Switz.: Dolo Target†; UK: Traxam.
6. Curtis SP, et al. Etoricoxib in the treatment of osteoarthritis over C AS — 22881-35-2.
52-weeks: a double-blind, active-comparator controlled trial
[NCT00242489]. BMC Musculoskelet Disord 2005; 6: 58. Avail-
a bl e a t : h t t p : / / w w w. bi o m e d c e nt r a l . c o m / c on t e nt / p d f/
1471-2474-6-58.pdf (accessed 01/11/07) Fenbufen (BAN, USAN, rINN)
7. Bingham CO, et al. Efficacy and safety of etoricoxib 30 mg and
celecoxib 200 mg in the treatment of osteoarthritis in two identi- CL-82204; Fenbufeeni; Fenbufén; Fenbufenas; Fenbufène; Fen-
cally designed, randomized, placebo-controlled, non-inferiority H 3C bufenum. 4-(Biphenyl-4-yl)-4-oxobutyric acid.
studies. Rheumatology (Oxford) 2007; 46: 496–507. CH3 N N Фенбуфен
Preparations C 16 H 14O 3 = 254.3.
N
O C AS — 36330-85-5.
Proprietary Preparations (details are given in Part 3) ATC — M01AE05.
Arg.: Arcoxia; Austria: Arcoxia; Auxib; Belg.: Arcoxia; Braz.: Arcoxia; CH3 ATC Vet — QM01AE05.
Cz.: Arcoxia; Denm.: Arcoxia; Fin.: Arcoxia; Fr.: Arcoxia; Ger.: Arcoxia; H 3C CH3
Gr.: Arcoxia; Hong Kong: Arcoxia; India: Ebov; Ecoxib†; Etoxib; Etozox;
Kretos†; Nucoxia; Indon.: Arcoxia; Irl.: Arcoxia; Israel: Arcoxia; Ital.: Al-
gix; Arcoxia; Tauxib; Malaysia: Arcoxia; Mex.: Arcoxia; Neth.: Arcoxia; Profile O
Auxib; Norw.: Arcoxia; NZ: Arcoxia; Philipp.: Arcoxia; Port.: Arcoxia; Famprofazone has analgesic and antipyretic properties and has
Exxiv; Turox; Singapore: Arcoxia; Spain: Arcoxia; Swed.: Arcoxia; Thai.:
Arcoxia; UK: Arcoxia; Venez.: Arcoxia. been given orally, usually with other analgesics.
COOH
Pharmacokinetics. On ingestion, metabolic products of fam-
profazone include amfetamine and metamfetamine enantiom-
ers,1,2 which has led to false positive results on drug testing.3 For
Etorphine Hydrochloride (BANM, rINNM) sporting competition famprofazone was classified by the World
Étorphine, Chlorhydrate d’; Etorphini Hydrochloridum; Hidro- Anti-Doping Agency as a stimulant.4
1. Greenhill B, et al. Metabolic profile of amphetamine and meth-
cloruro de etorfina; M-99; 19-Propylorvinol Hydrochloride. amphetamine following administration of the drug fampro- Pharmacopoeias. In Chin., Eur. (see p.vii), and Jpn.
(6R,7R,14R)-7,8-Dihydro-7-[(1R)-1-hydroxy-1-methylbutyl]-6-O- fazone. J Anal Toxicol 2003; 27: 479–84. Ph. Eur. 6.2 (Fenbufen). A white or almost white, fine crystal-
methyl-6,14α-ethenomorphine hydrochloride; (2R)-2-[(−)-(5R,- 2. Rodriguez AT, et al. Metabolic profile of famprofazone follow- line powder. Very slightly soluble in water; slightly soluble in al-
6R,7R,14R)-4,5-Epoxy-3-hydroxy-6-methoxy-9a-methyl-6,14- ing multidose administration. J Anal Toxicol 2004; 28: 432–8.
3. Musshoff F, Kraemer T. Identification of famprofazone inges- cohol, in acetone, and in dichloromethane.
ethenomorphinan-7-yl]pentan-2-ol hydrochloride. tion. Int J Legal Med 1998; 111: 305–8.
Эторфина Гидрохлорид 4. World Anti-Doping Agency. The world anti-doping code: the Adverse Effects, Treatment, and Precau-
2008 prohibited list international standard. Available at: http://
C 25 H 33 NO 4,HCl = 448.0. www.wada-ama.org/rtecontent/document/2008_List_En.pdf tions
C AS — 14521-96-1 (etorphine); 13764-49-3 (etorphine (accessed 24/07/08) As for NSAIDs in general, p.96, although the com-
hydrochloride). monest adverse effects of fenbufen are skin rashes,
 Etorphine Hydrochloride/Fentanyl 55
usually occurring within the first 2 weeks of therapy, Fenoprofen Calcium (BANM, USAN, rINNM) suggests that dosage adjustment of fenoprofen may be required
when given with phenobarbital.
and particularly in women and in patients with sero-
Calcii Fenoprofenum; Fénoprofène Calcique; Fenoprofeno cálci- 1. Helleberg L, et al. A pharmacokinetic interaction in man be-
negative rheumatoid arthritis or psoriatic arthritis. Dis- co; Lilly-69323; Lilly-53858 (fenoprofen); Lilly-61169 (fenoprofen tween phenobarbitone and fenoprofen, a new anti-inflammatory
orders such as epidermal necrolysis, erythema multi- sodium). Calcium (±)-2-(3-phenoxyphenyl)propionate dihy- agent. Br J Clin Pharmacol 1974; 1: 371–4.
forme, and Stevens-Johnson syndrome have also been drate.
reported. A small number of patients who develop rash Кальций Фенопрофен Pharmacokinetics
may go on to develop a severe illness characterised by (C 15 H 13 O 3 ) 2 Ca,2H 2 O = 558.6. Fenoprofen is readily absorbed from the gastrointesti-
pulmonary eosinophilia or allergic alveolitis. Treat- C AS — 31879-05-7 (fenoprofen); 34597-40-5 (anhydrous nal tract; bioavailability is about 85% but food and
ment with fenbufen should be stopped immediately if fenoprofen calcium); 53746-45-5 (fenoprofen calcium di- milk may reduce the rate and extent of absorption.
a rash appears. hydrate). Peak plasma concentrations occur 1 to 2 hours after a
Breast feeding. UK licensed product information advises that ATC — M01AE04. dose. The plasma half-life is about 3 hours. Fenoprofen
fenbufen should be avoided in breast-feeding mothers, because ATC Vet — QM01AE04. is 99% bound to plasma proteins. About 90% of a dose
of the presence of its metabolites in breast milk. is excreted in the urine in 24 hours, chiefly as the glu-
Effects on the blood. Haemolytic anaemia1 and aplastic curonide and the glucuronide of hydroxylated fenopro-
CH3
anaemia2 have been reported in patients receiving fenbufen. fen. Fenoprofen is distributed into breast milk.
1. Martland T, Stone WD. Haemolytic anaemia associated with fen- O
bufen. BMJ 1988; 297: 921. COOH Uses and Administration
2. Andrews R, Russell N. Aplastic anaemia associated with a non- Fenoprofen, a propionic acid derivative, is an NSAID
steroidal anti-inflammatory drug: relapse after exposure to an-
other such drug. BMJ 1990; 301: 38. (p.99) used in the management of mild to moderate
Effects on the lungs. In January 1989 the UK CSM reported
(fenoprofen) pain and for the relief of pain and inflammation associ-
that it had received 7 reports of a suspected association between ated with disorders such as osteoarthritis, rheumatoid
rash and an allergic interstitial lung disorder in patients receiving Pharmacopoeias. In Br., Chin., and US. arthritis, and ankylosing spondylitis. It is given as the
fenbufen.1 In 5 patients, the lung disorder was diagnosed as pul- BP 2008 (Fenoprofen Calcium). A white or almost white odour- calcium salt although doses are expressed in terms of
monary eosinophilia; in the 2 other patients the pulmonary com- less or almost odourless crystalline powder. Slightly soluble in the base; fenoprofen calcium (dihydrate) 1.2 g is
ponent of the reaction was described as allergic alveolitis. Sever- water and in chloroform; soluble in alcohol.
al of these reactions have been reported in the literature.2,3 USP 31 (Fenoprofen Calcium). A white crystalline powder.
equivalent to about 1 g of fenoprofen. A usual oral
1. CSM. Fenbufen, rash and pulmonary eosinophilia. Current Slightly soluble in water, in methyl alcohol, and in n-hexanol; dose is the equivalent of 300 to 600 mg of fenoprofen
Problems 24 1989. Also available at: http://www.mhra.gov.uk/ practically insoluble in chloroform. Store in airtight containers. three or four times daily, adjusted thereafter according
home/idcplg?IdcService=GET_FILE&dDocName= to response. In the USA, lower doses of 200 mg every
CON2024431&RevisionSelectionMethod=LatestReleased (ac-
cessed 01/11/07) Adverse Effects, Treatment, and Precau- 4 to 6 hours are recommended for mild to moderate
2. Swinburn CR. Alveolitis and haemolytic anaemia induced by az- tions pain. It has been recommended that the total daily dose
apropazone. BMJ 1987; 294: 375. As for NSAIDs in general, p.96. should not exceed 3 g (UK) or 3.2 g (USA).
3. Burton GH. Rash and pulmonary eosinophilia associated with
fenbufen. BMJ 1990; 300: 82–3. Dysuria, cystitis, haematuria, interstitial nephritis, and Preparations
acute renal insufficiency have been reported with feno-
Effects on the skin. In September 1988 the UK CSM reported1 BP 2008: Fenoprofen Tablets;
that it was still receiving large numbers of reports of adverse re- profen. Nephrotic syndrome, which may be preceded USP 31: Fenoprofen Calcium Capsules; Fenoprofen Calcium Tablets.
actions to fenbufen when such reports were expected to have de- by fever, rash, arthralgia, oliguria, azotaemia, and anu- Proprietary Preparations (details are given in Part 3)
clined. Fenbufen was the most commonly reported suspect drug ria, has also occurred. Upper respiratory-tract infection Braz.: Trandor†; Canad.: Nalfon†; Denm.: Nalfon†; Fr.: Nalgesic; Gr.:
in 1986 and 1987. At the time of the report more than 6000 such and nasopharyngitis have been reported. There have Expron†; Mex.: Nalfon†; S.Afr.: Fenopron†; UK: Fenopron; USA: Nalfon;
reports had been received, 80% concerning mucocutaneous reac- Venez.: Fenopron†.
tions and most involving a generalised florid erythematous rash,
been reports of severe hepatic reactions, including
often with pruritus. There were 178 reports of erythema multi- jaundice and fatal hepatitis.
forme, 30 of Stevens-Johnson syndrome, and 2 fatalities.
Fentanyl (BAN, rINN) ⊗
Breast feeding. Fenoprofen is distributed into breast milk al-
1. CSM. Fenbufen and mucocutaneous reactions. Current Prob- though the amount is considered by the BNF to be too small to
lems 23 1988. Also available at: http://www.mhra.gov.uk/home/ be harmful to a breast-fed infant. In contrast, licensed product
idcplg?IdcService=GET_FILE&dDocName=CON2024430& information does not recommend its use since safety has not Fentanil; Fentanilis; Fentanilo; Fentanylum; Fentanyyli. N-(1-
RevisionSelectionMethod=LatestReleased (accessed 01/11/07) Phenethyl-4-piperidyl) propionanilide.
been established.
Hypersensitivity. See under Effects on the Lungs (above). Effects on the blood. Haematological adverse effects includ- Фентанил
ing agranulocytosis, 1 aplastic anaemia, 2 and throm- C 22 H 28 N 2 O = 336.5.
Interactions bocytopenia3,4 have been reported in patients taking fenoprofen; C AS — 437-38-7.
For interactions associated with NSAIDs, see p.99. licensed product information also reports haemolytic anaemia.
ATC — N01AH01; N02AB03.
1. Simon SD, Kosmin M. Fenoprofen and agranulocytosis. N Engl
Use of fenbufen with aspirin may result in decreased J Med 1978; 299: 490. ATC Vet — QN01AH01; QN02AB03.
serum concentrations of fenbufen and its metabolites. 2. Ashraf M, et al. Aplastic anaemia associated with fenoprofen.
BMJ 1982; 284: 1301–2.
3. Simpson RE, et al. Acute thrombocytopenia associated with
Pharmacokinetics fenoprofen. N Engl J Med 1978; 298: 629–30.
Fenbufen is absorbed from the gastrointestinal tract af- 4. Katz ME, Wang P. Fenoprofen-associated thrombocytopenia.
Ann Intern Med 1980; 92: 262.
ter oral use and peak plasma concentrations are O N
reached in about 70 minutes. Fenbufen is over 99% Effects on the liver. Cholestatic jaundice and hepatitis devel-
oped in a 68-year-old woman after receiving fenoprofen 600 mg H 3C
bound to plasma proteins. It is metabolised in the liver four times daily for 7 weeks. Subsequent use of naproxen and N
to the active metabolites, biphenylacetic acid and 4-hy- indometacin did not result in hepatotoxicity.1 However, there has
droxy-biphenylbutyric acid. Fenbufen and its metabo- been a report of cross-hepatotoxicity between fenoprofen and
lites are reported to have plasma half-lives of about 10 naproxen.2
to 17 hours and are mainly eliminated as conjugates in 1. Stennett DJ, et al. Fenoprofen-induced hepatotoxicity. Am J
Hosp Pharm 1978; 35: 901.
the urine. Metabolites of fenbufen have been detected 2. Andrejak M, et al. Cross hepatotoxicity between non-steroidal
in breast milk in small amounts. anti-inflammatory drugs. BMJ 1987; 295: 180–1. NOTE. The following terms have been used as ‘street names’ (see
Effects on the skin. Toxic epidermal necrolysis was associated p.vi) or slang names for various forms of fentanyl:
with fenoprofen in 2 patients.1 Apache; China girl; China town; China white; Dance fever; Fen-
Uses and Administration tanest; Friend; Goodfellas; Great bear; He-man; Jackpot; King
Fenbufen, a propionic acid derivative, is an NSAID 1. Stotts JS, et al. Fenoprofen-induced toxic epidermal necrolysis. ivory; Murder 8; Poison; Tango & Cash; TNT; T.N.T.
J Am Acad Dermatol 1988; 18: 755–7.
(p.99). It is given for the relief of pain and inflamma- Pharmacopoeias. In Eur. (see p.vii).
tion associated with musculoskeletal and joint disor- Overdosage. A report of coma, respiratory depression, hypo-
Ph. Eur. 6.2 (Fentanyl). A white or almost white polymorphic
tension, and metabolic acidosis in a patient who had ingested be-
ders such as rheumatoid arthritis, osteoarthritis, and powder. Practically insoluble in water; freely soluble in alcohol
tween 24 and 36 g of fenoprofen.1 The patient responded to gas-
ankylosing spondylitis in oral doses of 900 mg daily; and in methyl alcohol. Protect from light.
tric lavage and activated charcoal and intensive supportive care.
the dose may be either 450 mg in the morning and 1. Kolodzik JM, et al. Nonsteroidal anti-inflammatory drugs and
evening or 300 mg in the morning with 600 mg in the coma: a case report of fenoprofen overdose. Ann Emerg Med Fentanyl Citrate (BANM, USAN, rINNM) ⊗
1990; 19: 378–81.
evening. Citrato de fentanilo; Fentanil-citrát; Fentanilio citratas; Fentanyl,
citrate de; Fentanylcitrat; Fentanyl-citrát; Fentanyli citras; Fentan-
Preparations Interactions ylu cytrynian; Fentanyylisitraatti; McN-JR-4263-49; Phentanyl Cit-
BP 2008: Fenbufen Capsules; Fenbufen Tablets.
For interactions associated with NSAIDs, see p.99. rate; R-4263. N-(1-Phenethyl-4-piperidyl)propionanilide dihy-
Proprietary Preparations (details are given in Part 3)
Aspirin is reported to reduce plasma concentrations of drogen citrate.
Austria: Lederfen†; Indon.: Cybufen; Irl.: Lederfen; Port.: Basifen; Reu- fenoprofen. Фентанила Цитрат
gast†; Thai.: Cepal; Cinopal†; Turk.: Cinopal; UK: Lederfen. C 22 H 28 N 2 O,C 6 H 8 O 7 = 528.6.
Antiepileptics. Phenobarbital might increase the rate of
metabolism of fenoprofen.1 US licensed product information C AS — 990-73-8.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
56 Analgesics Anti-inflammatory Drugs and Antipyretics
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. Dependence and Withdrawal Rigidity of the respiratory muscles (chest wall rigidity) may oc-
Ph. Eur. 6.2 (Fentanyl Citrate). White or almost white powder. As for Opioid Analgesics, p.101. cur during fentanyl anaesthesia. The effects can be minimised by
Soluble in water; sparingly soluble in alcohol; freely soluble in using a slow intravenous injection but a neuromuscular blocker
methyl alcohol. Protect from light. Fentanyl and illicitly manufactured analogues are sub- may be required to allow artificial ventilation; rigidity has been
USP 31 (Fentanyl Citrate). A white crystalline powder or white ject to abuse (see under Precautions, below). reversed postoperatively by naloxone. Similar muscle rigidity in-
glistening crystals. Sparingly soluble in water; slightly soluble in ◊ Plasma concentrations required to produce satisfactory seda- duced by alfentanil could be attenuated by pretreatment with a
chloroform; soluble in methyl alcohol. Store at a temperature of tion have been reported to increase steadily in neonates receiving benzodiazepine whereas small doses of neuromuscular blockers
25°, excursions permitted between 15° and 30°. Protect from continuous infusions, suggesting the development of tolerance appeared to be ineffective.3
light. to the sedating effects of fentanyl.1 Coughing has been associated4 with intravenous fentanyl; inci-
Movement disorders, extreme irritability, and symptoms charac- dence was decreased with a longer injection time,5 in light ciga-
Fentanyl Hydrochloride (BANM, rINNM) ⊗ teristic of opioid abstinence syndrome have been reported in chil- rette smokers,5,6 and in older patients.6 For the use of beclometa-
dren after withdrawal of prolonged fentanyl infusions.2,3 Similar- sone and lidocaine to prevent cough associated with intravenous
Fentanyl, Chlorhydrate de; Fentanyli Hydrochloridum; Hidro- ly, withdrawal symptoms and, in one case, myoclonus have fentanyl in anaesthesia, see p.1518 and p.1852, respectively.
cloruro de fentanilo. occurred in adults when fentanyl transdermal patches have been The risk of respiratory depression associated with epidural doses
Фентанила Гидрохлорид stopped.4,5 Acute opioid withdrawal syndrome has also been of fentanyl, a highly lipid-soluble opioid, has been considered
seen in cancer patients switched from modified-release oral mor- relatively small and only slight ventilatory depression was noted7
C 22 H 28 N 2 O,HCl = 372.9. phine to transdermal fentanyl despite adequate analgesia being after a dose of 50 micrograms. However, profound delayed res-
C AS — 1443-54-5. maintained.6 piratory depression has been reported in 2 women 100 minutes8
1. Arnold JH, et al. Changes in the pharmacodynamic response to and 80 minutes,9 respectively after fentanyl 100 micrograms had
Incompatibility. Fentanyl citrate is incompatible with thiopen- fentanyl in neonates during continuous infusion. J Pediatr 1991; been given epidurally for caesarean section. No adverse effects
tal sodium and methohexital sodium. 119: 639–43. on neonatal respiration or neurobehaviour were detected in a
A thick white precipitate formed in the intravenous tubing when 2. Lane JC, et al. Movement disorder after withdrawal of fentanyl study10 of neonates of mothers given epidural infusions of bupi-
infusion. J Pediatr 1991; 119: 649–51.
fentanyl citrate with droperidol was given shortly after nafcillin 3. Dominguez KD, et al. Opioid withdrawal in critically ill ne-
vacaine and fentanyl during labour. However, a later report11 de-
sodium. There was no precipitate when fentanyl citrate alone onates. Ann Pharmacother 2003 37: 473–7. scribed 2 neonates who developed respiratory depression after
was mixed with nafcillin sodium.1 4. Han PKJ, et al. Myoclonus secondary to withdrawal from their mothers were given epidural fentanyl during labour; the ef-
Fentanyl citrate underwent rapid and extensive loss when ad- transdermal fentanyl: case report and literature review. J Pain fect was reversed by intramuscular naloxone 400 micrograms.
Symptom Manage 2002; 23: 66–72. The authors noted that the doses of fentanyl used were higher
mixed with fluorouracil in PVC containers.2 The loss was due to 5. Ishihara C, et al. Withdrawal symptom after discontinuation of
sorption of fentanyl to the PVC as a result of the alkaline pH of than those in the previous study.
transdermal fentanyl at a daily dose of 0.6 mg. Pharm World Sci
the admixture, and presumably could occur from admixture of 2005; 27: 13–15. Respiratory depression is also a risk with topically applied fenta-
fentanyl citrate with any sufficiently alkaline drug. 6. Anonymous. Opiate withdrawal with transdermal fentanyl. nyl preparations. Severe hypoventilation with some fatalities has
Pharm J 1995; 255: 680. occurred in patients given fentanyl as a transdermal patch for mi-
See also Stability, below. nor painful conditions.12 More recently, Health Canada had re-
1. Jeglum EL, et al. Nafcillin sodium incompatibility with acidic Adverse Effects and Treatment ceived 2 reports of fatal respiratory depression associated with
solutions. Am J Hosp Pharm 1981; 38: 462, 464. the use of transdermal fentanyl patches in adolescents for rela-
As for Opioid Analgesics in general, p.102.
2. Xu QA, et al. Rapid loss of fentanyl citrate admixed with fluor- tively minor conditions (chronic headache and throat pain);13 in
ouracil in polyvinyl chloride containers. Ann Pharmacother Respiratory depression, which occurs especially with both cases the respiratory depression developed within 24 hours
1997; 31: 297–302. high doses of fentanyl, responds to naloxone (see also of applying the first and only patch. See also Administration,
Stability. In a 48-hour study fentanyl citrate in glucose 5% or Effects on the Respiratory System, below). Atropine Transdermal Route, under Precautions below.
sodium chloride 0.9% was stable when stored at room tempera- may be used to block the vagal effects of fentanyl such 1. Bennett MRD, Adams AP. Postoperative respiratory complica-
ture under usual light conditions in glass or PVC containers;1 the tions of opiates. Clin Anaesthesiol 1983; 1: 41–56.
as bradycardia. Unlike morphine, fentanyl is reported 2. Yaster M, et al. Midazolam-fentanyl intravenous sedation in
concentration of fentanyl delivered by a patient-controlled sys- not to cause significant histamine release. Transient children: case report of respiratory arrest. Pediatrics 1990; 86:
tem was relatively constant throughout a 30-hour study period. 463–7.
Fentanyl citrate injection diluted to 20 micrograms/mL with so- hypotension may follow intravenous dosage. Muscle 3. Sanford TJ, et al. Pretreatment with sedative-hypnotics, but not
dium chloride 0.9% was stable for 30 days at 3° or 23° in PVC rigidity can occur and may require neuromuscular with nondepolarizing muscle relaxants, attenuates alfentanil-in-
reservoirs for portable infusion pumps.2 In another study3 fenta- blockers. duced muscle rigidity. J Clin Anesth 1994; 6: 473–80.
nyl citrate diluted to 50 micrograms/mL with sodium chloride 4. Tweed WA, Dakin D. Explosive coughing after bolus fentanyl
0.9% remained stable for at least 14 days when stored at room
Local reactions such as rash, erythema, and itching injection. Anesth Analg 2001; 92: 1442–3.
have been reported with transdermal use. Gum bleed- 5. Lin J-A, et al. Prolonged injection time and light smoking de-
temperature in PVC reservoirs for portable patient-controlled crease the incidence of fentanyl-induced cough. Anesth Analg
systems. ing and irritation, and taste perversion have been re- 2005; 101: 670–4.
ported with transmucosal use. 6. Oshima T, et al. Identification of independent risk factors for
An admixture of fentanyl citrate and bupivacaine in sodium fentanyl-induced cough. Can J Anesth 2006; 53: 753–8.
chloride 0.9% appeared4 compatible and stable when stored for Effects on the cardiovascular system. For a reference to the 7. Morisot P, et al. Ventilatory response to carbon dioxide during
up to 30 days at 3° or 23° in a portable infusion pump. In another effects of fentanyl on histamine release compared with some oth- extradural anaesthesia with lignocaine and fentanyl. Br J
study5 the stability of solutions containing fentanyl, bupivacaine, Anaesth 1989; 63: 97–102.
er opioids, see under Pethidine, p.114.
and adrenaline, alone and in combination was studied over a pe- 8. Brockway MS, et al. Profound respiratory depression after ex-
Effects on mental function. Fentanyl had some dose-related tradural fentanyl. Br J Anaesth 1990; 64: 243–5.
riod of 56 days when stored at various temperatures in the light 9. Wang CY. Respiratory depression after extradural fentanyl. Br J
or in the dark in PVC bags. Both fentanyl and bupivacaine were effects on mental function and motor activity in healthy sub-
Anaesth 1992; 69: 544.
adsorbed from solution onto the PVC for the first 3 days but jects,1 but immediate and delayed recall were not affected. See
10. Porter J, et al. Effect of epidural fentanyl on neonatal respira-
thereafter concentrations of these drugs remained relatively sta- also under Alfentanil (p.16). tion. Anesthesiology 1998; 89: 79–85.
ble; freezing appeared to slow the concentration change for bupi- Acute toxic delirium has been reported after treatment with 11. Kumar M, Paes B. Epidural opioid analgesia and neonatal res-
vacaine but not for fentanyl. Solutions containing adrenaline be- transdermal fentanyl.2 piratory depression. J Perinatol 2003; 23: 425–7.
1. Scamman FL, et al. Ventilatory and mental effects of alfentanil 12. FDC Reports Pink Sheet 1994; January 24: 12.
came more acidic during the study as the adrenaline 13. Health Canada. Transdermal fentanyl (Duragesic): respiratory
progressively deteriorated but this was greatly reduced by freez- and fentanyl. Acta Anaesthesiol Scand 1984; 28: 63–7.
2. Kuzma PJ, et al. Acute toxic delirium: a uncommon reaction to arrest in adolescents. Can Adverse React News 2004; 14 (4):
ing. Autoclaving produced a further reduction in the concentra- transdermal fentanyl. Anesthesiology 1995; 83: 869–71. 1–2. Also available at: http://www.hc-sc.gc.ca/dhp-mps/
tion of all drugs. There was no sign of precipitation from any of alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v14n4-eng.pdf
the solutions studied. Effects on the nervous system. There have been reports of (accessed 26/06/08)
seizures with low and high doses of fentanyl or sufentanil.1 There Effects on the skin. A patient developed a macular rash cover-
An admixture of fentanyl citrate, ketamine hydrochloride, and was, however, no EEG evidence of cortical seizure activity in a
droperidol in sodium chloride 0.9% was stable6 for at least 30 ing the whole body, except for the face and scalp, while using
patient who had seizure-like muscle movements during a fenta- transdermal fentanyl patches.1
days when stored in glass bottles at 25°; the minor decrease in the nyl infusion;2 the muscle movements might have been due to
concentrations of all 3 drugs was attributed to either hydrolytic 1. Stoukides CA, Stegman M. Diffuse rash associated with
myoclonus produced by depression of higher CNS inhibitory transdermal fentanyl. Clin Pharm 1992; 11: 222.
degradation or adsorption. This admixture also appeared com- centres or to a pronounced form of opioid-induced muscle rigid-
patible when stored in PVC bags at 4° and 25°; the small increase ity. Effects on the urinary tract. Urinary retention developed in
in drug concentrations over 30 days may be a result of water per- For a report of encephalopathy associated with prolonged use of 2 premature infants after sedation with fentanyl infusion at a dose
meation and evaporation through the bags. fentanyl and midazolam in infants in intensive care, see Enceph- of 3 micrograms/kg per hour.1 In both cases catheterisation re-
Fentanyl is potentially unstable in PVC containers when ad- alopathy under Adverse Effects of Diazepam, p.988. lieved symptoms.
mixed with alkaline drugs (see Incompatibility, above). 1. Zaccara G, et al. Clinical features, pathogenesis and management 1. Das UG, Sasidharan P. Bladder retention of urine as a result of
of drug-induced seizures. Drug Safety 1990; 5: 109–51. continuous intravenous infusion of fentanyl: 2 case reports.
1. Kowalski SR, Gourlay GK. Stability of fentanyl citrate in glass Pediatrics 2001; 108: 1012–1015.
2. Scott JC, Sarnquist FH. Seizure-like movements during a fenta-
and plastic containers and in a patient-controlled delivery sys-
nyl infusion with absence of seizure activity in a simultaneous
tem. Am J Hosp Pharm 1990; 47: 1584–7.
2. Allen LV, et al. Stability of fentanyl citrate in 0.9% sodium chlo-
EEG recording. Anesthesiology 1985; 62: 812–14. Precautions
ride solution in portable infusion pumps. Am J Hosp Pharm Effects on the respiratory system. Fentanyl, like other opi- As for Opioid Analgesics in general, p.103.
1990; 47: 1572–4. oid agonists, causes dose-related respiratory depression; it is sig-
nificant with intravenous fentanyl doses of more than Caution is advised in patients with myasthenia gravis;
3. Chapalain-Pargade S, et al. Microbiological and physicochemi-
cal stability of fentanyl and sufentanil solutions for patient-con- 200 micrograms and may be more prolonged than analgesia. An- the effects of muscular rigidity on respiration may be
trolled delivery systems. J Pain Symptom Manage 2006; 32: aesthesia with fentanyl may result in either prolonged or delayed particularly pronounced in these patients.
90–7. respiratory depression postoperatively.1 Consequently, patients
4. Tu Y-H, et al. Stability of fentanyl citrate and bupivacaine hydro-
US licensed product information contra-indicates the
should continue to be monitored postoperatively until spontane-
chloride in portable pump reservoirs. Am J Hosp Pharm 1990; ous breathing has been re-established. Severe respiratory depres- use of standard transdermal fentanyl patches in opioid-
47: 2037–40. naive patients because of the risk of fatal respiratory
sion in a 14-month-old child after intravenous sedation with fen-
5. Dawson PJ, et al. Stability of fentanyl, bupivacaine and adrena- tanyl and midazolam has also highlighted the necessity for depression (see Effects on the Respiratory System,
line solutions for extradural infusion. Br J Anaesth 1992; 68:
414–17. careful monitoring when giving with other respiratory depres- above and Administration, Transdermal Route, be-
sants.2 If present at the end of operation respiratory depression
6. Lee DKT, et al. Compatibility of fentanyl citrate, ketamine hy-
may be reversed by an opioid antagonist such as naloxone; alter-
low). Similar contra-indications apply to fentanyl buc-
drochloride, and droperidol in 0.9% sodium chloride injection cal tablets (see Administration, Transmucosal Route,
stored in polyvinyl chloride bags. Am J Health-Syst Pharm 2005; natively, a respiratory stimulant such as doxapram that does not
62: 1190–2. reverse analgesia has been given. below).
 Fentanyl 57
Absorption of fentanyl from standard transdermal • use with any inhibitors of the cytochrome P450 isoenzyme tration-time curve increased, when given with ritonavir in a study
patches may be increased as the temperature rises and CYP3A4 may result in an increase in plasma-fentanyl con- in healthy subjects.1
centrations, which may cause potentially fatal respiratory de- 1. Olkkola KT, et al. Ritonavir’s role in reducing fentanyl clearance
patients should therefore avoid exposing the patch to pression; patients who are taking CYP3A4 inhibitors and and prolonging its half-life. Anesthesiology 1999; 91: 681–5.
external heat; similarly, patients with fever may require using fentanyl patches for an extended period of time should
Benzodiazepines. For the effects of opioids such as fentanyl
monitoring because of increased absorption. It may be monitored and the dose of fentanyl adjusted if necessary
with benzodiazepines, see Analgesics under Interactions of Di-
take 17 hours or longer for plasma concentrations of 1. FDA. Information for healthcare professionals: fentanyl azepam, p.989.
fentanyl to decrease by 50% after removal of a transdermal system (marketed as Duragesic and generics) (is-
sued 21st December, 2007). Available at: http://www.fda.gov/ Propofol. For reference to the effect that fentanyl has on blood
transdermal patch; patients who have had adverse ef- cder/drug/InfoSheets/HCP/fentanyl_2007HCP.htm (accessed concentrations of propofol, see p.1792.
fects should be monitored for up to 24 hours and those 23/07/08)
2. Health Canada. Fentanyl transdermal patch and fatal adverse re-
requiring replacement opioid therapy should initially actions. Can Adverse React News 2008; 18 (3): 1–2. Also availa- Pharmacokinetics
receive low doses increased gradually thereafter. Sim- ble at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/ After parenteral doses fentanyl citrate has a rapid onset
ilar advice is also given for patients receiving fentanyl pdf/medeff/carn-bcei_v18n3-eng.pdf (accessed 23/07/08)
and short duration of action. After transmucosal deliv-
via an iontophoretic drug delivery system; the mean TRANSMUCOSAL ROUTE. The FDA1 has received reports of se- ery, up to 50% of the dose is rapidly absorbed from the
half-life of fentanyl in this system is 11 hours. rious adverse effects, including fatalities, in patients who
have taken the fentanyl buccal tablets, Fentora (Cephalon, buccal mucosa; the remainder is swallowed and slowly
The bioavailability of different transmucosal fentanyl USA), resulting from inappropriate use in patients who were absorbed from the gastrointestinal tract. Some first-
preparations is not equivalent and consequently they not opioid tolerant, misunderstanding of dosing instructions, pass metabolism occurs via this route. The absolute bio-
or inappropriate substitution for other fentanyl-containing availability of transmucosal delivery is about half that
should not be substituted on a dose-per-dose basis. formulations. The FDA reiterated that Fentora:
for intravenous fentanyl but varies between formula-
Abuse. Several synthetic analogues of fentanyl, so-called ‘de- • should only be used for breakthrough pain in opioid-tolerant tions. Absorption is slow after transdermal application.
signer drugs’, have been manufactured illicitly for recreational cancer patients
Fentanyl is metabolised in the liver by N-dealkylation
use, particularly in the USA. They are highly potent, and respira- • should not be used in those who only need an opioid on an
tory depression and death may occur very rapidly.1 The ‘fentan- intermittent, or as required, basis and who are not on around- and hydroxylation via the cytochrome P450 isoen-
yls’ have been smoked or snorted as well as injected intravenous- the-clock opioids zyme CYP3A4. Metabolites and some unchanged
ly. • should not be used for the management of acute or postopera- drug are excreted mainly in the urine. The short dura-
Fentanyl analogues identified by WHO2,3 as being subject to tive pain including headaches, migraines, and pain due to in- tion of action is probably due to rapid redistribution
street abuse or likely to be abused include: alpha-methylfentanyl jury into the tissues rather than metabolism and excretion.
(also known as ‘China white’ or ‘synthetic heroin’), 3-methyl- • should not be directly substituted for other fentanyl-contain- The relatively longer elimination half-life reflects
fentanyl, acetyl-alpha-methylfentanyl, alpha-methylthiofenta- ing formulations slower release from tissue depots. About 80% has been
nyl, para-fluorofentanyl, beta-hydroxyfentanyl, beta-hydroxy-3- 1. FDA. Information for healthcare professionals: fentanyl buccal
methylfentanyl, thiofentanyl, and 3-methylthiofentanyl. tablets (marketed as Fentora) (issued 26th September, 2007).
reported to be bound to plasma proteins. Fentanyl ap-
Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/ pears in the CSF. It crosses the placenta and has been
Fentanyl itself is also subject to illicit use. It is chemically unre- fentanyl_buccal.htm (accessed 24/07/08)
lated to morphine and does not react in screening tests for mor-
detected in breast milk.
phine-related opioids. It has therefore been recommended4 that Breast feeding. The American Academy of Pediatrics1 states ◊ Marked differences in results of pharmacokinetic studies of
fentanyl should be tested for specifically in cases with suspected that there have been no reports of any clinical effect in infants of fentanyl have been attributed1 to differences in assay methods.
opioid misuse. breast-feeding mothers given fentanyl, and that therefore it may The need for sensitive assay methods has been emphasised be-
be considered to be usually compatible with breast feeding. The cause the potency of fentanyl means that small doses are used.
Used fentanyl transdermal systems may contain significant BNF also considers that the amount of fentanyl distributed into
amounts of fentanyl and have been subject to abuse. In some cas- However, there are differences in pharmacokinetics between bo-
breast milk is too small to be harmful to a breast-fed infant. How- lus doses and prolonged infusion with highly lipophilic drugs
es the contents of the patches have been injected intravenously; ever, licensed product information states that, since fentanyl is
such abuse has resulted in death.5,6 Licensed product information such as fentanyl.2 Terminal half-lives ranging from 2 to 7 hours
distributed into breast milk, it should be avoided in nursing have been reported in healthy subjects and surgical patients.
advises that used patches and iontophoretic transdermal systems mothers because of the possibility of sedation or respiratory de-
should be folded firmly in half, adhesive side inwards to conceal However, the duration of action of fentanyl after a single intrave-
pression in breast-fed infants. nous dose of up to 100 micrograms may be only 30 to 60 minutes
the release membrane, and disposed of safely. A study2 using fentanyl 100 micrograms intravenously for in- as a result of rapid redistribution into the tissues. US licensed
1. Buchanan JF, Brown CR. ‘Designer drugs’: a problem in clinical duction of anaesthesia in 5 mothers concluded that the amount of product information has given values for a three-compartment
toxicology. Med Toxicol 1988; 3: 1–17. fentanyl excreted into breast milk within 24 hours of induction pharmacokinetic model with a distribution time of 1.7 minutes, a
2. WHO. WHO expert committee on drug dependence: twenty- was less than 0.1% of the maternal dose, and hence unlikely to redistribution time of 13 minutes, and a terminal elimination
fourth report. WHO Tech Rep Ser 761 1988. affect a healthy full-term breast-feeding infant. half-life of 219 minutes. Giving repeated or large doses, or con-
3. WHO. WHO expert committee on drug dependence: twenty- 1. American Academy of Pediatrics. The transfer of drugs and oth- tinuous infusions, may result in accumulation and a more pro-
sixth report. WHO Tech Rep Ser 787 1989. er chemicals into human milk. Pediatrics 2001; 108: 776–89. longed action.
Correction. ibid.; 1029. Also available at:
4. Berens AIL, et al. Illicit fentanyl in Europe. Lancet 1996; 347: h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l / The clinical significance of secondary peak plasma-fentanyl
1334–5. pediatrics%3b108/3/776 (accessed 26/06/08) concentrations and the possible role of entero-systemic
5. Reeves MD, Ginifer CJ. Fatal intravenous misuse of transdermal 2. Nitsun M, et al. Pharmacokinetics of midazolam, propofol, and recirculation3 has been controversial, but some4 considered that
fentanyl. Med J Aust 2002; 177: 552–3. fentanyl transfer to human breast milk. Clin Pharmacol Ther irregular decay curves were not unlikely for lipophilic com-
2006; 79: 549–57. pounds such as fentanyl, especially in patients undergoing oper-
6. Tharp AM, et al. Fatal intravenous fentanyl abuse: four cases
involving extraction of fentanyl from transdermal patches. Am J Children. The BNFC states that the half-life of fentanyl is pro- ations and subject to large changes in blood flow. Unexpectedly
Forensic Med Pathol 2004; 25: 178–81. longed in neonates and accumulation is likely with prolonged high plasma-fentanyl concentrations in a patient following epi-
use; muscle rigidity may occur and the use of muscle relaxants dural use were thought to be a result of aortic clamping and might
Administration. INTRAVENOUS ROUTE. Fentanyl is much reflect the effect of changes in blood flow.5
more lipid-soluble than morphine and after standard single in- may be required. See also under Pharmacokinetics, below.
The main metabolites of fentanyl, which are excreted in the
travenous doses has a rapid onset and short duration of action. Exercise. Opioid toxicity requiring naloxone treatment oc- urine, have been identified as 4-N-(N-propionylanilino) piperid-
However, fentanyl is rapidly redistributed in the body and has curred in a patient who wore a fentanyl patch while engaging in ine and 4-N-(N-hydroxypropionylanilino) piperidine; 1-(2-
a longer elimination half-life than morphine (see under Phar- vigorous outdoor exercise.1 Physicians should be aware that phenethyl)-4-N-(N-hydroxypropionylanilino) piperidine is a
macokinetics, below). Hence, with high or repeated doses, along with fever and external heat sources, physical activity may minor metabolite.6 Fentanyl has no active or toxic metabolites.4
fentanyl becomes a relatively long-acting drug; to avoid accu- cause increased absorption of transdermal fentanyl.
mulation patients should be monitored and doses adjusted ac- 1. Mather LE. Clinical pharmacokinetics of fentanyl and its newer
1. Carter KA. Heat-associated increase in transdermal fentanyl ab- derivatives. Clin Pharmacokinet 1983; 8: 422–46.
cordingly. sorption. Am J Health-Syst Pharm 2003; 60: 191–2. 2. Scholz J, et al. Clinical pharmacokinetics of alfentanil, fentanyl
Repeated intra-operative doses of fentanyl should be given with Handling. Avoid contact with skin and the inhalation of fenta- and sufentanil: an update. Clin Pharmacokinet 1996; 31:
care, since not only may the respiratory depression persist into 275–92.
nyl citrate particles.
the postoperative period but it may become apparent for the first 3. Bennett MRD, Adams AP. Postoperative respiratory complica-
tions of opiates. Clin Anaesthesiol 1983; 1: 41–56.
time postoperatively when the patient is away from immediate
nursing attention.
Interactions 4. Moore RA, et al. Opiate metabolism and excretion. Baillieres
Clin Anaesthesiol 1987; 1: 829–58.
For interactions associated with opioid analgesics, see
5. Bullingham RES, et al. Unexpectedly high plasma fentanyl lev-
TRANSDERMAL ROUTE. Fatalities have been associated with the p.103. Use of fentanyl with non-vagolytic neuromus- els after epidural use. Lancet 1980; i: 1361–2.
use of standard fentanyl transdermal patches (see Effects on cular blockers may produce bradycardia and possibly 6. Goromaru T, et al. Identification and quantitative determination
the Respiratory System, above). Incorrect or inappropriate of fentanyl metabolites in patients by gas chromatography-mass
use resulting in serious adverse effects and fatalities had
asystole. spectrometry. Anesthesiology 1984; 61: 73–7.
prompted regulatory authorities to issue warnings and recom- Fentanyl is metabolised via the cytochrome P450 Administration. Some references to the pharmacokinetics of
mendations for changes to product labelling; in particular isoenzyme CYP3A4; use with potent inhibitors of this fentanyl after constant rate intravenous infusion,1 transdermal
transdermal fentanyl patches are not appropriate for the treat- isoenzyme, such as ritonavir and other HIV-protease application,2-5 use of the oral sublingual6 and transmucosal7-11
ment of acute or postoperative pain. Nonetheless, reports of routes, intranasal dosage,12 subcutaneous infusion,13 and epidur-
fatalities and life-threatening adverse reactions have contin- inhibitors, may increase fentanyl plasma concentra-
al use.14-16
ued to be received1,2 and, in December 2007, the FDA1 reiter- tions.
ated that: 1. Duthie DJR, et al. Pharmacokinetics of fentanyl during constant
Antidepressants. For reference to a possible case of serotonin rate iv infusion for the relief of pain after surgery. Br J Anaesth
• fentanyl patches are indicated for the management of persist- syndrome associated with use of fentanyl and SSRIs, see Opioid 1986; 58: 950–6.
ent, moderate to severe chronic pain in opioid-tolerant patients Analgesics under Interactions of Fluoxetine, p.397. 2. Grond S, et al. Clinical pharmacokinetics of transdermal opio-
ids: focus on transdermal fentanyl. Clin Pharmacokinet 2000;
• licensed product information must be consulted when deter- Antivirals. Ritonavir, an inhibitor of the cytochrome P450 38: 59–89.
mining the initial dose as overestimating when converting pa- isoenzyme CYP3A4, might prolong fentanyl-induced respirato- 3. Solassol I, et al. Inter- and intraindividual variabilities in phar-
macokinetics of fentanyl after repeated 72-hour transdermal ap-
tients from another opioid analgesic can result in fatal over- ry depression. The plasma clearance of fentanyl was decreased, plications in cancer pain patients. Ther Drug Monit 2005; 27:
dose with the first dose and the elimination half-life and area under the plasma concen- 491–8.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
58 Analgesics Anti-inflammatory Drugs and Antipyretics
4. Marier J-F, et al. Pharmacokinetics, tolerability, and perform- had no active or toxic metabolites and had not been associated For the treatment of intractable chronic pain in adults
ance of a novel matrix transdermal delivery system of fentanyl with clinical problems when given to patients with renal dys-
relative to the commercially available reservoir formulation in when opioid analgesia is indicated transdermal patch-
healthy subjects. J Clin Pharmacol 2006; 46: 642–53. function.
es delivering amounts of fentanyl ranging from 12 to
5. Marier J-F, et al. Comparative bioequivalence study between a 1. Corall IM, et al. Plasma concentrations of fentanyl in normal
novel matrix transdermal delivery system of fentanyl and a surgical patients and those with severe renal and hepatic disease. 100 micrograms/hour are available. In the UK, fenta-
commercially available reservoir formulation. Br J Clin Phar- Br J Anaesth 1980; 52: 101P. nyl patches may be used in strong opioid-naive pa-
macol 2007; 63: 121–4. 2. Moore RA, et al. Opiate metabolism and excretion. Baillieres
6. Lennernäs B, et al. Pharmacokinetics and tolerability of differ- Clin Anaesthesiol 1987; 1: 829–58.
tients; however, in the USA, use is restricted to patients
ent doses of fentanyl following sublingual administration of a who are already tolerant to opioid therapy of compara-
rapidly dissolving tablet to cancer patients: a new approach to ble potency.
treatment of incident pain. Br J Clin Pharmacol 2005; 59: Uses and Administration
249–53. Fentanyl, a phenylpiperidine derivative, is a potent opi- • Doses should be individually titrated for each patient
7. Streisand JB, et al. Absorption and bioavailability of oral trans- according to previous opioid usage. Initial dosages
mucosal fentanyl citrate. Anesthesiology 1991; 75: 223–9. oid analgesic (p.104) chemically related to pethidine
8. Darwish M, et al. Pharmacokinetics and dose proportionality of (p.113) and is primarily a μ-opioid agonist. should not exceed 25 micrograms/hour in opioid-
fentanyl effervescent buccal tablets in healthy volunteers. Clin
Fentanyl is used as an analgesic, as an adjunct to gen- naive patients; in addition, it is recommended that
Pharmacokinet 2005; 44: 1279–86.
9. Darwish M, et al. Comparison of equivalent doses of fentanyl eral anaesthetics, and as an anaesthetic for induction these patients are initially titrated with low doses of
buccal tablets and arteriovenous differences in fentanyl pharma-
and maintenance. It is also used as a respiratory depres- short-acting opioids before transferring to fentanyl
cokinetics. Clin Pharmacokinet 2006; 45: 843–50.
sant in the management of mechanically ventilated pa- patches
10. Darwish M, et al. Single-dose and steady-state pharmacokinet-
ics of fentanyl buccal tablet in healthy volunteers. J Clin Phar- tients under intensive care. When used with an antipsy- • For patients who have been receiving a strong opioid
macol 2007; 47: 56–63.
11. Darwish M, et al. Absolute and relative bioavailability of fenta- chotic such as droperidol it can induce a state of analgesic the initial dose of the fentanyl patch
nyl buccal tablet and oral transmucosal fentanyl citrate. J Clin neuroleptanalgesia in which the patient is calm and in- should be based on the previous 24-hour opioid re-
Pharmacol 2007; 47: 343–50. quirement. Use of a patch providing 25 micrograms
12. Walter SH, et al. Pharmacokinetics of intranasal fentanyl. Br J
different to his surroundings and is able to cooperate
Anaesth 1993; 70 (suppl 1): 108. with the surgeon. of fentanyl per hour is equivalent to about 60 to
13. Miller RS, et al. Plasma concentrations of fentanyl with subcu-
Fentanyl is usually given parenterally or by the trans- 90 mg daily of oral morphine sulfate. During trans-
taneous infusion in palliative care patients. Br J Clin Pharmacol
1995; 40: 553–6. mucosal route as the citrate, in transdermal patches as fer to treatment with fentanyl patches previous opio-
14. Gourlay GK, et al. Pharmacokinetics of fentanyl in lumbar and the base, or by iontophoretic transdermal delivery as id analgesic therapy should be phased out gradually
cervical CSF following lumbar epidural and intravenous admin- in order to allow for the gradual increase in plasma-
istration. Pain 1989; 38: 253–9. the hydrochloride. Fentanyl citrate 157 micrograms
15. Bader AM, et al. Maternal and neonatal fentanyl and bupi- and fentanyl hydrochloride 111 micrograms are each fentanyl concentrations
vacaine concentrations after epidural infusion during labor. An- • More than one patch may be applied if doses greater
esth Analg 1995; 81: 829–32. equivalent to about 100 micrograms of fentanyl. Doses
16. Moises EC, et al. Pharmacokinetics and transplacental distribu- are expressed in terms of the base. than 100 micrograms/hour are required (applied at
tion of fentanyl in epidural anesthesia for normal pregnant
It is more lipid soluble than morphine and after an in- the same time to avoid confusion); additional or al-
women. Eur J Clin Pharmacol 2005; 61: 517–22.
travenous injection of 100 micrograms the effects of ternative analgesic therapy should be considered if
Cardiopulmonary bypass. In general, studies1,2 indicate that doses greater than 300 micrograms/hour are re-
serum concentrations of fentanyl during cardiopulmonary by- fentanyl begin almost immediately, although maxi-
pass decrease initially and then remain stable. The fall in concen- mum analgesia and respiratory depression may not oc- quired. Patches should be replaced every 72 hours
trations has been attributed to haemodilution although adsorption cur for several minutes; the duration of action of fenta- with the new patch being applied to a different site;
to the bypass apparatus has also been found. nyl depends on the dose and the intensity of the pain use of the same area of the skin should be avoided
1. Buylaert WA, et al. Cardiopulmonary bypass and the pharma-
involved, and may vary from 10 minutes to several for several days
cokinetics of drugs: an update. Clin Pharmacokinet 1989; 17:
10–26. hours. • Elderly or debilitated patients should be observed
2. Gedney JA, Ghosh S. Pharmacokinetics of analgesics, sedatives
For premedication the equivalent of 50 to carefully for signs of toxicity and the dose reduced if
and anaesthetic agents during cardiopulmonary bypass. Br J necessary
Anaesth 1995; 75: 344–51. 100 micrograms of fentanyl may be given intramuscu-
Children. The disposition of intravenous fentanyl 10 to larly 30 to 60 minutes before the induction of anaesthe- Fentanyl patches are not appropriate for acute or post-
50 micrograms/kg in 14 neonates undergoing various major sur- sia. operative pain.
gical procedures was highly variable.1 The mean elimination As an adjunct to general anaesthesia, fentanyl is usu- A patient-activated iontophoretic transdermal fentanyl
half-life of 317 minutes and other pharmacokinetic parameters delivery system, IONSYS (Janssen-Cilag, UK; Ortho-
including volume of distribution and total body clearance were ally given by intravenous injection. Dosage recom-
greater than reported in adults, but both pharmacodynamic and mendations show a wide range depending on the tech- McNeil, USA), is available for the management of
pharmacokinetic mechanisms appeared responsible for the very nique. acute moderate to severe postoperative pain in hospi-
prolonged respiratory depression that can occur in neonates after
• Patients with spontaneous respiration may be given talised patients. Patients should be titrated to an accept-
fentanyl anaesthesia. In 9 premature neonates given fentanyl able level of analgesia before starting therapy. IONSYS
30 micrograms/kg intravenously for induction of anaesthesia2 50 to 200 micrograms as an initial dose with supple-
the elimination half-life ranged from 6 to 32 hours, but cautious ments of 50 micrograms. In the USA it is recom- contains fentanyl hydrochloride and each system de-
interpretation was advised because of the method of calculation. mended that doses above 2 micrograms/kg be ac- livers an equivalent of 40 micrograms of fentanyl per
1. Koehntop DE, et al. Pharmacokinetics of fentanyl in neonates. companied by assisted ventilation. Significant dose over 10 minutes, to a maximum of 6 doses per
Anesth Analg 1986; 65: 227–32.
respiratory depression follows doses of more than hour, for 24 hours after the first dose or for 80 doses
2. Collins C, et al. Fentanyl pharmacokinetics and hemodynamic (maximum of 3.2 mg), whichever is reached first. The
effects in preterm infants during ligation of patent ductus arteri- 200 micrograms
osus. Anesth Analg 1985; 64: 1078–80. maximum duration of treatment is 72 hours, or 3 con-
• Patients whose ventilation is assisted may be given secutive systems applied sequentially, with the new
The elderly. In one study the elimination half-life of intrave- 3 0 0 m i c r o g r a m s t o 3 .5 m g ( u p t o
nous fentanyl increased from 265 minutes in patients with a system being applied to a different site; only one sys-
mean age of 36 years to 945 minutes in those with a mean age of 50 micrograms/kg) as an initial dose, with supple- tem should be worn at a time. It should be applied to
67 years.1 The authors of another study were critical of the rela- ments of 100 to 200 micrograms depending on the intact, non-irritated, and non-irradiated skin on the
tively short sampling time used and in contrast found that major patient’s response. High doses have been reported to chest or upper outer arm.
fentanyl pharmacokinetic parameters did not correlate with age.2 moderate or attenuate the response to surgical stress
However, elderly patients had increased brain sensitivity to intra- A lozenge-on-a-stick dosage form of fentanyl citrate
venous fentanyl, as shown by EEG changes2 and lower doses
(see Anaesthesia, below)
for transmucosal delivery is used as an analgesic in the
might be indicated in older patients for pharmacodynamic rather Fentanyl may also be given by intravenous infusion. In management of breakthrough cancer pain in those
than pharmacokinetic reasons. ventilated patients a loading dose of about already receiving and tolerant to opioid treatment. Loz-
1. Bentley JB, et al. Age and fentanyl pharmacokinetics. Anesth 1 microgram/kg per minute is given for the first 10
Analg 1982; 61: 968–71. enges containing the equivalent of 200 micrograms to
2. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose re-
minutes followed by an infusion of about up to 1.6 mg of fentanyl are available. An initial unit
quirements with age: a simultaneous pharmacokinetic and phar- 100 nanograms/kg per minute; alternatively, the load- dose of 200 micrograms may be taken over 15 minutes
macodynamic evaluation. J Pharmacol Exp Ther 1987; 240: ing dose may be given as a bolus. The infusion rate
159–66. for an episode of breakthrough pain and repeated once
should be titrated according to response and rates of up if necessary after a further 15 minutes. Doses are sub-
Hepatic impairment. The pharmacokinetics of fentanyl were to 3 micrograms/kg per minute have been used in car-
not affected significantly in surgical patients with cirrhosis of the sequently titrated according to response, up to a unit
liver.1 A 1987 review2 considered that fentanyl had not been as- diac surgery. Infusions should be stopped about 40 dose of 1.6 mg if necessary. Once the patient has been
sociated with clinical problems when given to patients with liver minutes before the end of surgery unless artificial ven- stabilised on an effective dose, no more than 4 unit dos-
dysfunction. tilation is to be continued postoperatively. In patients es should be taken daily.
1. Haberer JP, et al. Fentanyl pharmacokinetics in anaesthetized pa- with spontaneous respiration, lower infusion rates of
tients with cirrhosis. Br J Anaesth 1982; 54: 1267–70. In the USA, a buccal tablet containing fentanyl citrate
50 to 80 nanograms/kg per minute are used.
2. Moore RA, et al. Opiate metabolism and excretion. Baillieres for transmucosal delivery is also available and licensed
Clin Anaesthesiol 1987; 1: 829–58. Reduced doses are used in the elderly or debilitated pa- for the same indication as the lozenge. Tablets contain-
Renal impairment. Clearance of fentanyl from plasma was re- tients ing the equivalent of 100 micrograms to up to
ported to be enhanced in surgical patients with end-stage renal Similar doses to those used for premedication may also 800 micrograms of fentanyl are available. An initial
disease,1 although clearance was reduced and elimination half-
life increased in patients with renal failure undergoing transplan-
be given by intramuscular injection postoperatively, dose of 100 micrograms may be taken for an episode
tation,2 possibly because of the influence of uraemia on metabo- and by intramuscular or slow intravenous injection as of breakthrough pain and repeated once if necessary af-
lism in the liver. Nevertheless, a 1987 review2 noted that fentanyl an adjunct to regional anaesthesia. ter 30 minutes; thereafter, patients must wait at least 4
 Fentanyl 59
hours before treating another episode. Doses are subse- potentially lethal respiratory depression can occur (see also 2. Robinson S, Gregory GA. Fentanyl-air-oxygen anesthesia for li-
under Precautions, above). Dosage guidelines have been sug- gation of patent ductus arteriosus in preterm infants. Anesth An-
quently titrated according to response. The dose of the alg 1981; 60: 331–4.
gested.7
maintenance opioid used for persistent pain should be 3. Friesen RH, Henry DB. Cardiovascular changes in preterm ne-
1. Macaluso AD, et al. Oral transmucosal fentanyl citrate for pre- onates receiving isoflurane, halothane, fentanyl, and ketamine.
re-evaluated if the patient has more than 4 episodes of medication in adults. Anesth Analg 1996; 82: 158–61. Anesthesiology 1986; 64: 238–42.
breakthrough pain a day. 2. Nelson PS, et al. Comparison of oral transmucosal fentanyl cit- 4. Anand KJS, et al. Randomised trial of fentanyl anaesthesia in
preterm babies undergoing surgery: effects on the stress re-
Caution must be exercised when switching between rate and an oral solution of meperidine, diazepam, and atropine
sponse. Lancet 1987; i: 243–8.
for premedication in children. Anesthesiology 1989; 70: 616–21.
the lozenge and buccal tablet as the extent of absorp- 5. Yaster M. The dose response of fentanyl in neonatal anesthesia.
3. Schechter NL, et al. The use of oral transmucosal fentanyl citrate Anesthesiology 1987; 66: 433–5.
tion may be substantially different. for painful procedures in children. Pediatrics 1995; 95: 335–9.
For details of doses in children, see below. 4. Blick SKA, Wagstaff AJ. Fentanyl buccal tablet: in breakthrough PHAEOCHROMOCYTOMA. Unlike morphine and some other
pain in opioid-tolerant patients with cancer. Drugs 2006; 66: opioids, fentanyl and alfentanil do not release histamine and
Administration. INHALATION ROUTE. In a study1 inhaled fen- 2387–93. may be used safely in the anaesthetic management of patients
tanyl provided plasma concentrations similar to those after in- 5. Zeppetella G, Ribeiro MDC. Opioids for the management of with phaeochromocytoma.1
travenous doses; use as patient-controlled analgesia was sug- breakthrough (episodic) pain in cancer patients. Available in the 1. Hull CJ. Phaeochromocytoma: diagnosis, preoperative prepara-
gested. Inhaled formulations of fentanyl are under Cochrane Database of Systematic Reviews; Issue 1. Chichester: tion and anaesthetic management. Br J Anaesth 1986; 58:
investigation for the treatment of breakthrough cancer pain John Wiley; 2006 (accessed 26/06/08). 1453–68.
and acute pain. 6. Anonymous. Oral transmucosal fentanyl citrate. Med Lett Drugs POSTOPERATIVE SHIVERING. As pethidine appears to be effec-
1. Mather LE, et al. Pulmonary administration of aerosolised fenta- Ther 1994; 36: 24–5.
tive in the treatment of postoperative shivering a number of
nyl: pharmacokinetic analysis of systemic delivery. Br J Clin 7. Aronoff GM, et al. Evidence-based oral transmucosal fentanyl
Pharmacol 1998; 46: 37–43. citrate (OTFC) dosing guidelines. Pain Med 2005; 6: 305–14.
other opioids including fentanyl have also been tried. Not all
opioids are necessarily effective but fentanyl has been report-
INTRANASAL ROUTE. Studies1-3 have shown that intranasal fen- ed to be so,1 although information is scanty.2
Administration in children. Indications for fentanyl therapy
tanyl is as effective as the intravenous route for postoperative in children are similar to those in adults (see above). 1. Alfonsi P, et al. Fentanyl, as pethidine, inhibits post anaesthesia
pain management and that it can be used in a patient-control- shivering. Br J Anaesth 1993; 70 (suppl 1): 38.
led analgesia system. Intranasal fentanyl has also been Fentanyl is usually given by intravenous injection as an adjunct 2. Kranke P, et al. Pharmacological treatment of postoperative
studied4-6 for the management of acute pain in children. Intra- to general anaesthesia. In the UK recommended initial doses shivering: a quantitative systematic review of randomized con-
nasal spray formulations of fentanyl are under investigation range from 2 to 3 micrograms/kg in children aged 2 to 12 years trolled trials. Anesth Analg 2002; 94: 453–60.
for the treatment of breakthrough cancer pain. with spontaneous respiration; supplements of 1 microgram/kg Intensive care. Despite the short duration of action of fentanyl
1. Striebel HW, et al. Intranasal fentanyl titration for postoperative may be given. (The BNFC suggests initial doses of 1 to after single doses, rapid redistribution in the body results in an
pain management in an unselected population. Anaesthesia 5 micrograms/kg for neonates and children up to 12 years elimination half-life longer than that of morphine. Consequently
1993; 48: 753–7. of age.) When ventilation is assisted, the initial recommended
2. Striebel HW, et al. Patient-controlled intranasal analgesia: a fentanyl is not a short-acting drug when used for analgesia in in-
dose is also 2 to 3 micrograms/kg, with supplements of tensive care, and may offer little advantage over morphine.1
method for noninvasive postoperative pain management. Anesth
Analg 1996; 83: 548–51.
1 microgram/kg. (The BNFC suggests an initial dose of 5 to 1. Aitkenhead AR. Analgesia and sedation in intensive care. Br J
3. Toussaint S, et al. Patient-controlled intranasal analgesia: effec- 10 micrograms/kg for neonates and children up to 12 years of Anaesth 1989; 63: 196–206.
tive alternative to intravenous PCA for postoperative pain relief. age, with supplements of 1 to 3 micrograms/kg.) In the USA dos-
Can J Anesth 2000; 47: 299–302. es are similar to those licensed in the UK. Pain. CANCER PAIN. Transdermal fentanyl is used in the man-
4. Manjushree R, et al. Intranasal fentanyl provides adequate post- agement of chronic intractable cancer pain; for references see
operative analgesia in pediatric patients. Can J Anesth 2002; 49: Children may also be given fentanyl by intravenous infusion: li- Administration, Transdermal Route, above. For references to
190–3. censed product information implies that doses are similar to the use of transmucosal fentanyl in the management of break-
5. Borland ML, et al. Intranasal fentanyl is an equivalent analgesic those used in adults (see above) although the BNFC recommends through cancer pain, see Administration, Transmucosal
to oral morphine in paediatric burns patients for dressing chang- that the infusion rate in ventilated patients is 1.5 micrograms/kg
es: a randomised double blind crossover study. Burns 2005; 31: Route, above.
per hour in neonates and is 1 to 6 micrograms/kg per hour in old-
831–7. LABOUR PAIN. Fentanyl has been reported to be an effective
6. Borland M, et al. A randomized controlled trial comparing intra- er children.
nasal fentanyl to intravenous morphine for managing acute pain
intravenous analgesic during active labour. Epidural fentanyl
Transdermal patches delivering amounts of fentanyl ranging is unreliable when used alone,1,2 although it does enhance the
in children in the emergency department. Ann Emerg Med 2007;
49: 335–40.
from 12 to 100 micrograms/hour may be used for the treatment epidural analgesia achieved with the local anaesthetic bupi-
of intractable chronic pain in children aged 2 years and older vacaine. The reduction in the minimum local analgesic con-
INTRASPINAL ROUTE. For a discussion on the intraspinal use of who are already tolerant to opioid therapy of comparable poten- centration of epidural bupivacaine for labour pain increased
fentanyl, see Postoperative Pain, below. cy. The initial dose should be based on the previous 24-hour opi- with increasing dose of fentanyl added to bupivacaine.3 How-
TRANSDERMAL ROUTE. Transdermal fentanyl is used for chron- oid requirement. Use of a patch providing 12 micrograms of fen- ever, the incidence of pruritus increased significantly with
ic intractable cancer pain in adults and children.1-5 tanyl per hour is equivalent to about 30 to 44 mg daily of oral fentanyl in a dose of 4 micrograms/mL and therefore the op-
Transdermal fentanyl is also used in the treatment of chronic morphine sulfate. See Uses and Administration, above for fur- timum dose of fentanyl may be 3 micrograms/mL for bupi-
non-cancer pain;4-6 however transdermal use is contra-indicated ther details. Patches should be applied to the upper backs of vacaine-sparing epidural analgesia during labour. Respiratory
in the management of acute or postoperative pain because the young children to minimise the potential for removal. depression has also been reported with the combination.4
problems of dose titration in the short term increase the possibil- Although the transmucosal lozenge-on-a-stick formulation is 1. Reynolds F. Extradural opioids in labour. Br J Anaesth 1989; 63:
ity of development of significant respiratory depression4 (see not licensed for use in children, the BNFC suggests a single dose 251–3.
also under Adverse Effects and under Precautions, above). of 15 to 20 micrograms/kg (maximum of 400 micrograms) for 2. Lindow SW, et al. A randomised double-blind comparison of
epidural fentanyl versus fentanyl and bupivicaine [sic] for pain
Although the licensed dosage interval for transdermal patches of the management of breakthrough pain and as premedication relief in the second stage of labour. Br J Obstet Gynaecol 2004;
fentanyl is 72 hours studies have suggested that up to about 25% in those aged 2 years and older, and who weigh more than 10 kg. 111: 1075–80.
of cancer patients may require more frequent application with 3. Lyons G, et al. Extradural pain relief in labour: bupivacaine spar-
some patients requiring fresh patches every 48 hours.7,8 Equally, Anaesthesia. Fentanyl and its congeners alfentanil and sufen- ing by extradural fentanyl is dose dependent. Br J Anaesth 1997;
in an attempt to supply lower doses than are allowed for by ex- tanil are shorter-acting than morphine and appear to produce 78: 493–7.
isting transdermal dosage forms, patches have sometimes been fewer circulatory changes; they are preferred for use as supple- 4. McClure JH, Jones G. Comparison of bupivacaine and bupi-
ments during anaesthesia with inhalational or intravenous drugs. vacaine with fentanyl in continuous extradural analgesia during
cut, folded, or partially masked with non-porous dressings; the labour. Br J Anaesth 1989; 63: 637–40.
manufacturers do not recommend such practices as they consider Fentanyl is widely used as the analgesic component of balanced
the dose supplied will be unreliable, and there is potential for anaesthesia. It has been used to attenuate cardiovascular stress POSTOPERATIVE PAIN. Small intravenous bolus doses of an opi-
overdosage. responses to intubation (see Anaesthesia, p.1900), and may be oid analgesic may be injected immediately after surgery for
An iontophoretic drug delivery system containing fentanyl hy- used in higher doses in an attempt to reduce the cardiovascular, postoperative analgesia and faster acting opioids such as fen-
drochloride is also available for the management of acute mod- endocrine, and metabolic changes that may accompany surgery. tanyl may be preferable to morphine.1 Fentanyl has also been
erate to severe postoperative pain in a hospital setting (see Post- When attenuation of surgical stress is especially important, for given by epidural injection in doses of 100 or 200 micrograms
operative Pain, below for some references). example in cardiac surgery, intravenous fentanyl 50 to or by continuous epidural infusion in doses of 20 to
1. Jeal W, Benfield P. Transdermal fentanyl: a review of its pharma-
100 micrograms/kg in conjunction with oxygen and a neuromus- 80 micrograms/hour; patient-controlled systems have been
cological properties and therapeutic efficacy in pain control. cular blocker, and sometimes up to 150 micrograms/kg, may be used.2
Drugs 1997; 53: 109–38. used for general anaesthesia. Total intravenous anaesthesia with Epidural fentanyl or sufentanil provided effective postoperative
2. Muijsers RBR, Wagstaff AJ. Transdermal fentanyl: an updated fentanyl and propofol has been successful.1 analgesia after caesarean section with comparable adverse effect
review of its pharmacological properties and therapeutic efficacy profiles. 3 The suggested optimal dose of fentanyl was
in chronic cancer pain control. Drugs 2001; 61: 2289–2307. Satisfactory anaesthesia has been reported2 with high-dose fen-
3. Gourlay GK. Treatment of cancer pain with transdermal fenta- tanyl citrate (30 to 50 micrograms/kg) in premature infants when 100 micrograms. For references comparing epidural fentanyl
nyl. Lancet Oncol 2001; 2: 165–72. used as sole anaesthetic, in conjunction with pancuronium, for with alfentanil, see Postoperative Analgesia under Uses and Ad-
4. Kornick CA, et al. Benefit-risk assessment of transdermal fenta- ligation of patent ductus arteriosus; cardiovascular stability was ministration of Alfentanil, p.18. In a review4 of perioperative
nyl for the treatment of chronic pain. Drug Safety 2003; 26: maintained throughout the procedure. However, others3 found pain management epidural opioids were considered to provide
951–73. effective analgesia at lower doses than systemic opioids. Fenta-
5. Zernikow B, et al. Transdermal fentanyl in childhood and ado- significant hypotension in preterm infants given either fentanyl
lescence: a comprehensive literature review. J Pain 2007; 8: 20 micrograms/kg, isoflurane, halothane, or ketamine; systolic nyl may be given through a lumbar epidural catheter that is often
187–207. arterial pressure was best maintained with the ketamine tech- inserted immediately postoperatively. After an initial loading
6. Allan L, et al. Randomised crossover trial of transdermal fenta- nique. The surgical stress response in preterm babies was abol- dose of 1 to 1.5 micrograms/kg of fentanyl, infusion at the rate of
nyl and sustained release oral morphine for treating chronic non- ished by the addition of fentanyl 10 micrograms/kg intravenous- 0.7 to 2 micrograms/kg per hour is begun and continued for
cancer pain. BMJ 2001; 322: 1154–8. about 48 hours on average. Some prefer to use intermittent injec-
7. Radbruch L, et al. Transdermal fentanyl for the management of ly to an anaesthetic regimen of nitrous oxide and tubocurarine.4
cancer pain: a survey of 1005 patients. Palliat Med 2001; 15: Dose responses of fentanyl in neonatal anaesthesia have been tion. A small study5 comparing 2 patient-controlled routes of ad-
309–21. discussed.5 ministration found that cervical epidural fentanyl provided better
8. Donner B, et al. Long-term treatment of cancer pain with postoperative pain relief at rest than intravenous fentanyl; how-
transdermal fentanyl. J Pain Symptom Manage 1998; 15: For details of doses in neonates and children, see above. ever, there was no decrease in the total dose required and the
168–75. Neuroleptanalgesia. An injection of short-acting fentanyl authors considered that the benefits of epidural fentanyl did not
TRANSMUCOSAL ROUTE. Transmucosal fentanyl has been tried 50 micrograms/mL with the longer-acting antipsychotic droperi- outweigh its potential complications.
for sedation and analgesia before anaesthesia or painful pro- dol 2.5 mg/mL has been used for neuroleptanalgesia, premedica- Combined opioid and local anaesthetic epidural infusions have
cedures in adults1 and children2,3 and is used for breakthrough tion, and as an adjunct to anaesthesia. However, the use of such also proved effective, for example fentanyl 1 microgram/mL
cancer pain in opioid-tolerant patients.4,5 It has been noted6 a fixed-ratio combination cannot be recommended. with bupivacaine 0.1%; both could be infused at lower rates than
that this dosage method can cause all the adverse effects of 1. Jenstrup M, et al. Total iv anaesthesia with propofol-alfentanil or either drug alone. Although a study6 comparing bupivacaine-
parenteral opioids; nausea and vomiting are common and propofol-fentanyl. Br J Anaesth 1990; 64: 717–22. fentanyl combinations with each drug alone for epidural analge-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
60 Analgesics Anti-inflammatory Drugs and Antipyretics
sia after caesarean section confirmed an additive analgesic effect Fepradinol (rINN) Floctafenine (BAN, USAN, rINN)
for the combination, there was no demonstrable clinical benefit
Fépradinol; Fepradinolum. (±)-α-{[(2-Hydroxy-1,1-dimethyle- Floctafenina; Floctafénine; Floctafeninum; R-4318; RU-15750.
compared with fentanyl alone in this patient group who expect
thyl)amino]methyl}benzyl alcohol. 2,3-Dihydroxypropyl N-(8-trifluoromethyl-4-quinolyl)anthrani-
early mobilisation. However, the combination may be of greater
benefit in patients for whom early ambulation is not routine. Фепрадинол late.
Fentanyl has also been given by epidural injection to children for C 12 H 19NO 2 = 209.3. Флоктафенин
postoperative analgesia.7 C AS — 63075-47-8. C 20 H 17F 3 N 2 O 4 = 406.4.
Fentanyl has been tried by intrathecal injection for postoperative C AS — 23779-99-9.
pain.8 ATC — N02BG04.
As mentioned in Administration, Transdermal Route, above, an OH ATC Vet — QN02BG04.
iontophoretic transdermal system for postoperative pain is also
available.9-11 CH3
OH
1. Mitchell RWD, Smith G. The control of acute postoperative
pain. Br J Anaesth 1989; 63: 147–58. N
2. Morgan M. The rational use of intrathecal and extradural opio- H CH3 HO O O
ids. Br J Anaesth 1989; 63: 165–88. OH H
3. Grass JA, et al. A randomized, double-blind, dose-response
comparison of epidural fentanyl versus sufentanil analgesia af- N
ter cesarean section. Anesth Analg 1997; 85: 365–71. Profile CF3
4. Swarm RA, et al. Pain treatment in the perioperative period. Fepradinol is an NSAID (p.96) that has been used topically in a
Curr Probl Surg 2001; 38: 835–920. N
concentration of 6% for the relief of pain and inflammation. The
5. Roussier M, et al. Patient-controlled cervical epidural fentanyl hydrochloride has been used similarly.
compared with patient-controlled i.v. fentanyl for pain after
pharyngolaryngeal surgery. Br J Anaesth 2006; 96: 492–6. Preparations Adverse Effects, Treatment, and Precautions
6. Cooper DW, et al. Patient-controlled extradural analgesia with As for NSAIDs in general, p.96.
bupivacaine, fentanyl, or a mixture of both, after caesarean sec- Proprietary Preparations (details are given in Part 3) Anaphylactic shock has been reported, and may be preceded by
tion. Br J Anaesth 1996; 76: 611–15. Chile: Sinalgia†; Mex.: Sinalgia; Spain: Dalgen; Flexidol†.
7. Lejus C, et al. Postoperative extradural analgesia in children: minor allergic manifestations; floctafenine should be stopped in
comparison of morphine with fentanyl. Br J Anaesth 1994; 72: any patient who develops signs suggestive of allergy (such as
156–9. pruritus or urticaria). Reactions may also involve the liver.
8. Sudarshan G, et al. Intrathecal fentanyl for post-thoracotomy Floctafenine may cross-react with glafenine (p.62) and should
pain. Br J Anaesth 1995; 75: 19–22. Feprazone (BAN, rINN)
not be given to patients who have had glafenine-associated reac-
9. Chelly JE. An iontophoretic, fentanyl HCl patient-controlled DA-2370; Feprazona; Féprazone; Feprazonum; Phenylprena-
transdermal system for acute postoperative pain management. tions.
Expert Opin Pharmacother 2005; 6: 1205–14. zone; Prenazone. 4-(3-Methylbut-2-enyl)-1,2-diphenylpyrazolid-
ine-3,5-dione. Porphyria. Floctafenine is considered to be unsafe in patients
10. Koo PJ. Postoperative pain management with a patient-control-
led transdermal delivery system for fentanyl. Am J Health-Syst with porphyria because it has been shown to be porphyrinogenic
Pharm 2005; 62: 1171–6. Фепразон in in-vitro systems.
11. Mayes S, Ferrone M. Fentanyl HCl patient-controlled ionto- C 20 H 20N 2 O 2 = 320.4.
phoretic transdermal system for the management of acute post- Interactions
C AS — 30748-29-9 (feprazone); 57148-60-4 (feprazone For interactions associated with NSAIDs, see p.99.
operative pain. Ann Pharmacother 2006; 40: 2178–86. piperazine salt 1:1).
Preparations ATC — M01AX18; M02AA16. Pharmacokinetics
BP 2008: Fentanyl Injection; ATC Vet — QM01AX18; QM02AA16. Floctafenine is absorbed from the gastrointestinal tract; peak
USP 31: Fentanyl Citrate Injection. plasma concentrations are obtained 1 to 2 hours after ingestion.
Proprietary Preparations (details are given in Part 3) Its plasma half-life is about 8 hours. It is metabolised in the liver
Arg.: Durogesic; Fentax; Gray-F; Nafluvent; Sublimaze; Talnur; Austral.: Ac- to floctafenic acid. It is excreted mainly as glucuronide conju-
tiq; Durogesic; Sublimaze; Austria: Durogesic; Belg.: Durogesic; Braz.: gates in the urine and bile.
Durogesic; Fentabbott; Fentanest; Fentatil; Canad.: Duragesic; Chile: Du-
rogesic; Cz.: Durogesic; Fentagesic; Fentahexal; Fentalis; Ionsys; Matrifen; Uses and Administration
Wintanyl; Denm.: Actiq; Durogesic; Haldid; Fin.: Actiq; Durogesic; Fr.: Ac- Floctafenine, an anthranilic acid derivative related to glafenine
tiq; Durogesic; Ionsys; Ger.: Actiq; Durogesic; Fenta-Hameln†; Gr.: Actiq; (p.62), is an NSAID (p.99) used in oral doses of up to 1.2 g daily,
Durogesic; Fentadur; Matrifen; Hong Kong: Durogesic; Hung.: Durogesic; N in divided doses, for the short-term relief of pain.
Matrifen; Sedaton; India: Durogesic; Trofentyl; Indon.: Durogesic; Irl.: Ac- O N
tiq; Durogesic; Fental; Sublimaze; Israel: Durogesic; Tanyl; Ital.: Actiq; Du- Preparations
rogesic; Fentanest; Jpn: Durotep; Malaysia: Durogesic; Talgesil; Mex.: Du- H 3C
rogesic; Fenodid; Fentanest; Neth.: Actiq; Durogesic; Norw.: Actiq; Proprietary Preparations (details are given in Part 3)
Durogesic; Leptanal; NZ: Durogesic; Sublimaze; Philipp.: Durogesic; Sub- O Canad.: Idarac†; Fr.: Idarac; Irl.: Idarac†; Thai.: Idarac.
limaze; Pol.: Durogesic; Fentahexal; Port.: Durogesic; Fentanest; Ionsys; CH3
Nilfene; Rus.: Durogesic (Дюрогезик); S.Afr.: Durogesic; Sublimaze; Tanyl;
Singapore: Durogesic; Spain: Actiq; Durogesic; Fentanest; Swed.: Actiq;
Durogesic; Leptanal; Matrifen; Switz.: Actiq; Durogesic; Sintenyl; Thai.: Profile Flufenamic Acid (BAN, USAN, rINN)
Durogesic; Turk.: Durogesic; UK: Actiq; Durogesic; Fentalis; Ionsys; Feprazone, a phenylbutazone (p.117) derivative, is an NSAID
Matrifen; Osmach; Sublimaze; Tilofyl; USA: Actiq; Duragesic; Fentora; Ion- Acide Flufénamique; Ácido flufenámico; Acidum Flufenamicum;
sys; Sublimaze; Venez.: Durogesic. (p.96). It has been given orally in the treatment of mild to mod-
erate pain, fever, and inflammation associated with musculoskel- CI-440; CN-27554; Flufenaamihappo; Flufenamsyra; INF-1837;
Multi-ingredient: Arg.: Disifelit; Austral.: Marcain with Fentanyl; Naro-
etal and joint disorders. Feprazone has also been given rectally Kwas flufenamowy; NSC-82699. N-(ααα-Trifluoro-m-tolyl)an-
pin with Fentanyl; Braz.: Nilperidol; Ital.: Leptofen; NZ: Bupafen; Marcain
with Fentanyl; Naropin with Fentanyl. and used topically as a 5% cream. thranilic acid.
Pinazone, the piperazine salt of feprazone, has been used similar- Флуфенамовая Кислота
ly. C 14 H 10F 3 NO 2 = 281.2.
Fentiazac (BAN, USAN, rINN) C AS — 530-78-9 (flufenamic acid); 61891-34-7 (flufena-
Preparations mate aluminium); 16449-54-0 (flufenamate aluminium).
BR-700; Fentiazaco; Fentiazacum; Wy-21894. [4-(4-Chlorophe- Proprietary Preparations (details are given in Part 3) ATC — M01AG03.
nyl)-2-phenylthiazol-5-yl]acetic acid. Ital.: Zepelin; Spain: Brotazona; Venez.: Vapesin. ATC Vet — QM01AG03.
Фентиазак
C 17 H 12 ClNO 2 S = 329.8.
C AS — 18046-21-4. COOH
Firocoxib (USAN, rINN) H
ATC — M01AB10; M02AA14.
ATC Vet — QM01AB10; QM02AA14. Firocoxibum; ML-1785713. 3-(Cyclopropylmethoxy)-5,5-dime- N CF3
thyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one.
Фирококсиб
O C 17 H 20O 5 S = 336.4.
OH C AS — 189954-96-9. Adverse Effects, Treatment, and Precautions
ATC Vet — QM01AH90. As for NSAIDs in general, p.96.
Breast feeding. No adverse effects have been seen in breast-
S fed infants whose mothers were receiving flufenamic acid, and
the American Academy of Pediatrics considers1 that it is there-
O O fore usually compatible with breast feeding.
Cl N
S An early study2 found that only very small amounts of flufenam-
O CH3 ic acid were excreted into breast milk after oral doses.
1. American Academy of Pediatrics. The transfer of drugs and oth-
Profile er chemicals into human milk. Pediatrics 2001; 108: 776–89.
Fentiazac is an NSAID (p.96) that has been used for the relief of O Correction. ibid.; 1029. Also available at:
h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
pain and inflammation associated with musculoskeletal, joint, O CH3 pediatrics%3b108/3/776 (accessed 01/11/07)
peri-articular, and soft-tissue disorders. It has also been used in 2. Buchanan RA, et al. The breast milk excretion of flufenamic ac-
the treatment of fever. Fentiazac has been given in usual oral dos- CH3 id. Curr Ther Res 1969; 11: 533–8.
es of 200 mg once or twice daily. Fentiazac has also been applied Effects on the gastrointestinal tract. Acute proctocolitis as-
topically and has been given rectally as the calcium salt. Profile sociated with oral flufenamic acid in a patient.1
Preparations Firocoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor, is 1. Ravi S, et al. Colitis caused by non-steroidal anti-inflammatory
Proprietary Preparations (details are given in Part 3)
an NSAID used in veterinary medicine for the treatment of in- drugs. Postgrad Med J 1986; 62: 773–6.
Ital.: O-Flam; Port.: Donorest†; IDR†; Norvedan†. flammation and pain associated with osteoarthritis in dogs.
Porphyria. Flufenamic acid has been associated with acute at-
tacks of porphyria and is considered unsafe in porphyric patients.
 Fentiazac/Flurbiprofen 61
Uses and Administration There has been some interest in the potential of flupirtine to treat 2. Kaufhold J, et al. Flurbiprofen-associated tubulointerstitial ne-
Flufenamic acid, an anthranilic acid derivative related to prion diseases such as Creutzfeldt-Jakob disease (see below). phritis. Am J Nephrol 1991; 11: 144–6.
mefenamic acid (p.80), is an NSAID (p.99). Flufenamic acid is 3. McIntire SC, et al. Acute flank pain and reversible renal dys-
◊ References. function associated with nonsteroidal anti-inflammatory drug
mainly used topically in a concentration of 3 or 3.5% for the re- use. Pediatrics 1993; 92: 459–60.
1. Friedel HA, Fitton A. Flupirtine: a review of its pharmacological
lief of pain and inflammation associated with musculoskeletal, properties, and therapeutic efficacy in pain states. Drugs 1993; 4. MacKay K. Membranous nephropathy associated with the use of
joint, and soft-tissue disorders. Flufenamic acid and its alumini- 45: 548–69. flurbiprofen. Clin Nephrol 1997; 47: 279–80.
um salt have also been given orally. Effects on the liver. A case of cholestatic jaundice probably
Creutzfeldt-Jakob disease. A double-blind placebo-control-
Preparations led study1 in 28 patients with Creutzfeldt-Jakob disease (CJD) due to flurbiprofen has been reported.1
Proprietary Preparations (details are given in Part 3) found flupirtine to have beneficial effects on cognitive function. 1. Kotowski KE, Grayson MF. Side effects of non-steroidal anti-
However, further studies are needed to establish any place in inflammatory drugs. BMJ 1982; 285: 377.
Ger.: Dignodolin†; Jpn: Opyrin.
Multi-ingredient: Austria: Mobilisin; Mobilisin plus; Rheugesal; Belg.:
therapy. Effects on the skin. Cutaneous vasculitis apparently due to
Mobilisin; Braz.: Mobilisin Composto; Ger.: Algesalona†; Hung.: Mobili- 1. Otto M, et al. Efficacy of flupirtine on cognitive function in pa- flurbiprofen occurred in a 59-year-old woman with long-stand-
sin†; Ital.: Mobilisin; Port.: Latesil; Mobilisin; Spain: Movilisin; Switz.: Alge- tients with CJD: a double-blind study. Neurology 2004; 62: ing rheumatoid arthritis.1 Contact dermatitis has also been seen
salona†; Assan; Assan thermo; Mobilisin. 714–18.
in a 22-year-old woman who applied a poultice containing flur-
Preparations biprofen to her wrist.2
Proprietary Preparations (details are given in Part 3) 1. Wei N. Flurbiprofen and cutaneous vasculitis. Ann Intern Med
Braz.: Katadolon; Ger.: Katadolon; Trancopal Dolo; Port.: Metanor; No- 1990; 112: 550–1.
Flunixin Meglumine (BANM, USAN, rINNM) vocebrin; Rus.: Katadolon (Катадолон). 2. Kawada A, et al. Contact dermatitis due to flurbiprofen. Contact
Fluniksiinimeglumiini; Flunixin megluminová sůl; Flunixine méglu- Dermatitis 2000; 42: 167–8.
mine; Flunixini megluminum; Flunixinmeglumin; Flunixino meglu- Hypersensitivity. A diffuse, pruritic, maculopapular rash de-
mina; Flunixinum Megluminicum; Meglumini Flunixinum; Sch- veloped in a patient 48 hours after taking a second dose of flur-
14714 (flunixin). 2-{[2-Methyl-3-(trifluoromethyl)phenyl]amino}- Flurbiprofen (BAN, USAN, rINN) biprofen.1 Two days later, the rash had become urticarial, and
3-pyridinecarboxylic acid compounded with 1-deoxy-1-(methyl- BTS-18322; Flurbiprofeeni; Flurbiprofén; Flurbiprofenas; Flurbi- angioedema and hypotension were also noted. Patch testing with
amino)-D-glucitol (1:1); 2-(α3,α3,α3-Trifluoro-2,3,-xylidino)nico- profène; Flurbiprofeno; Flurbiprofenum; U-27182. 2-(2-Fluorobi- flurbiprofen powder was positive.
tinic acid compounded with 1-deoxy-1-(methylamino)-D-glucitol phenyl-4-yl)propionic acid. See also Effects on the Skin, above.
(1:1). 1. Romano A, Pietrantonio F. Delayed hypersensitivity to flurbi-
Флурбипрофен profen. J Intern Med 1997; 241: 81–3.
Меглумина Флуниксин C 15 H 13 FO 2 = 244.3.
C 14 H 11F 3 N 2 O 2 ,C 7 H 17 NO 5 = 491.5. C AS — 5104-49-4. Precautions
C AS — 38677-85-9 (flunixin); 42461-84-7 (flunixin meg- ATC — M01AE09; M02AA19; S01BC04.
lumine). As for NSAIDs in general, p.98.
ATC Vet — QM01AE09; QM02AA19; QS01BC04.
Breast feeding. Flurbiprofen is distributed into breast milk;
however, the BNF and licensed product information consider the
CH3 COOH amount to be too small to be harmful to a breast-fed infant.
H
N N CF3 Herpes simplex keratitis. Whether flurbiprofen can exacer-
bate infection when used to treat ocular herpes simplex is unclear
CH3 from animal studies,1,2 but licensed product information for flur-
F biprofen sodium eye drops recommends that they should not be
COOH used in patients with active epithelial herpes simplex keratitis.
(flunixin) Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. Patients with a history of herpes simplex keratitis should also be
Ph. Eur. 6.2 (Flurbiprofen). A white or almost white crystalline monitored closely when undergoing treatment with these eye
powder. Practically insoluble in water; freely soluble in alcohol drops.
Pharmacopoeias. In Eur. (see p.vii) and US for veterinary use 1. Trousdale MD, et al. Effect of flurbiprofen on herpes simplex
only. and in dichloromethane; dissolves in aqueous solutions of alkali
keratitis in rabbits. Invest Ophthalmol Vis Sci 1980; 19: 267–70.
Ph. Eur. 6.2 (Flunixin Meglumine for Veterinary Use; Flunixin hydroxides and carbonates. 2. Hendricks RL, et al. The effect of flurbiprofen on herpes simplex
Meglumine BP(Vet) 2008). A white to almost white crystalline USP 31 (Flurbiprofen). A white crystalline powder. Practically virus type 1 stromal keratitis in mice. Invest Ophthalmol Vis Sci
powder. Freely soluble in water and in methyl alcohol; practical- insoluble in water; freely soluble in dehydrated alcohol, in ace- 1990; 31: 1503–11.
ly insoluble in acetone. A 5% solution in water has a pH of 7.0 to tone, in ether, and in methyl alcohol; soluble in acetonitrile. Store
9.0. in airtight containers. Interactions
USP 31 (Flunixin Meglumine). A white to off-white crystalline For interactions associated with NSAIDs, see p.99.
powder. Soluble in water, in alcohol, and in methyl alcohol; prac- Flurbiprofen Sodium (BANM, rINNM)
Parasympathomimetics. Licensed product information for
tically insoluble in ethyl acetate. pH of a 5% solution in water is Flurbiprofène Sodique; Flurbiprofeno sódico; Natrii Flurbiprofe- acetylcholine chloride ophthalmic preparations and for flurbi-
between 7.0 and 9.0. Store at a temperature of 25°, excursions num. Sodium (±)-2-(2-fluoro-4-biphenylyl)propionate dihydrate. profen sodium eye drops states that there have been reports that
permitted between 15° and 30°. Натрий Флурбипрофен acetylcholine and carbachol have been ineffective when used in
Profile C 15 H 12 FNaO 2 ,2H 2 O = 302.3. patients treated with topical (ophthalmic) NSAIDs.
Flunixin meglumine is an NSAID (p.96) used in veterinary med- C AS — 56767-76-1.
icine for the relief of pain and inflammation in acute and chronic Pharmacopoeias. In Br. and US. Pharmacokinetics
disorders and as adjunctive therapy in the treatment of endotoxic BP 2008 (Flurbiprofen Sodium). A white to creamy-white, crys- Flurbiprofen is readily absorbed from the gastrointesti-
or septic shock and mastitis. talline powder. Sparingly soluble in water; soluble in alcohol; nal tract after oral doses with peak plasma concentra-
practically insoluble in dichloromethane.
tions occurring about 1 to 2 hours after ingestion. Ab-
Adverse Effects and Treatment sorption after rectal doses may be more rapid. It is
Flupirtine Maleate (BANM, USAN, rINNM) about 99% bound to plasma proteins and has a plasma
As for NSAIDs in general, p.96.
D-9998; Flupirtine, Maléate de; Flupirtini Maleas; Maleato de flu- half-life of about 3 to 6 hours. It is metabolised mainly
pirtina; W-2964M. Ethyl 2-amino-6-(4-fluorobenzylamino)-3-py- Minor symptoms of ocular irritation including tran-
by hydroxylation (via the cytochrome P450 isoenzyme
ridylcarbamate maleate. sient burning and stinging have been reported on instil-
CYP2C9) and conjugation in the liver and excreted in
Флупиртина Малеат lation of flurbiprofen sodium eye drops; there may be
urine. Flurbiprofen is distributed into breast milk.
C 15 H 17FN 4 O 2 ,C 4H 4 O 4 = 420.4. increased bleeding from ocular surgery and wound
healing may be delayed. Local irritation has also fol- Flurbiprofen is a chiral compound given as the rac-
C AS — 56995-20-1 (flupirtine); 75507-68-5 (flupirtine
maleate). lowed rectal use, and local effects including a sensation emate and the above pharmacokinetic characteristics
ATC — N02BG07. of warming or burning in the mouth may be seen after refer to the racemic mixture. Allowance may have to
ATC Vet — QN02BG07. using flurbiprofen lozenges. be made for the different activities of the enantiomers.
Incidence of adverse effects. Reports from the manufactur- ◊ References.
ers on the range and incidence of the adverse effects of flurbipro- 1. Aarons L, et al. Plasma and synovial fluid kinetics of flurbipro-
F fen in rheumatoid arthritis. Br J Clin Pharmacol 1986; 21:
fen.1,2 155–63.
H 1. Sheldrake FE, et al. A long-term assessment of flurbiprofen. 2. Smith IJ, et al. Flurbiprofen in post-partum women: plasma and
N N NH2
Curr Med Res Opin 1977; 5: 106–16. breast milk disposition. J Clin Pharmacol 1989; 29: 174–84.
O 2. Brooks CD, et al. Clinical safety of flurbiprofen. J Clin Pharma- 3. Kean WF, et al. The pharmacokinetics of flurbiprofen in younger
col 1990; 30: 342–51. and elderly patients with rheumatoid arthritis. J Clin Pharmacol
CH3 Effects on the CNS. A severe symmetrical parkinsonian syn- 1992; 32: 41–8.
N O
H 4. Davies NM. Clinical pharmacokinetics of flurbiprofen and its
drome developed in a 52-year-old man who had taken flurbipro- enantiomers. Clin Pharmacokinet 1995; 28: 100–14.
fen for 7 days.1
(flupirtine) 1. Enevoldson TP, et al. Acute parkinsonism associated with flur-
biprofen. BMJ 1990; 300: 540–1. Uses and Administration
Profile Effects on the kidneys. Renal papillary necrosis has been de-
Flurbiprofen, a propionic acid derivative, is an NSAID
Flupirtine maleate is an analgesic that has been given for the re- scribed in a patient who had used flurbiprofen for many years.1 (p.99). It is used in musculoskeletal and joint disorders
lief of pain (see Choice of Analgesic, p.2) in usual doses of Acute flank pain and reversible renal dysfunction has been such as ankylosing spondylitis, osteoarthritis, and
100 mg three or four times daily by mouth, or 150 mg three or reported in 2 patients treated with flurbiprofen.2,3 Membranous rheumatoid arthritis, in soft-tissue disorders such as
four times daily as a rectal suppository; daily doses of up to nephropathy also developed in a patient who took flurbiprofen
600 mg by mouth or 900 mg rectally have been used where nec-
sprains and strains, for postoperative pain, and in mild
daily for 12 to 18 months.4
essary. Flupirtine has also been given by intramuscular injection 1. Nafría EC, et al. Renal papillary necrosis induced by flurbipro-
to moderate pain including dysmenorrhoea and mi-
as the gluconate in the management of acute pain. fen. DICP Ann Pharmacother 1991; 25: 870–1. graine. Flurbiprofen is also used as lozenges in the
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
62 Analgesics Anti-inflammatory Drugs and Antipyretics
symptomatic relief of sore throat. Flurbiprofen sodium Furprofen Glycol Salicylate
is used in eye drops to inhibit intra-operative miosis Furprofeno. 4-(2-Furanylcarbonyl)-α-methylbenzeneacetic acid. Ethylene Glycol Monosalicylate; Glycoli Salicylas; Glykolisalisylaat-
and to control postoperative inflammation of the ante- Фурпрофен ti; Glykolsalicylat; Hidroksietilo salicilatas; Hidroxietil-szalicilát; Hy-
rior segment of the eye. C 14 H 12O 4 = 244.2. droksietyylisalisylaatti; Hydroxietylsalicylat; Hydroxyaethyli Salicy-
C AS — 66318-17-0. las; Hydroxyéthyle, salicylate d’; Hydroxyethylis salicylas; Hydroxy-
For pain and inflammation, flurbiprofen is given in ethyl-salicylát; Salicilato de glicol. 2-Hydroxyethyl salicylate.
usual oral doses of 150 to 200 mg daily in divided dos-
es, increased to 300 mg daily in acute or severe condi- Гликоль Салицилат
O C 9 H 10 O 4 = 182.2.
tions if necessary. A modified-release preparation for
once-daily use is also available. Patients with dysmen- O C AS — 87-28-5.
O
orrhoea may be given an initial dose of 100 mg fol-
lowed by 50 to 100 mg every four to six hours to a
OH
maximum total daily dose of 300 mg. Doses given rec-
tally as suppositories are similar to those given by oral- CH3 O
ly. OH
For the relief of sore throat, a lozenge containing Profile OH O
Furprofen, a propionic acid derivative, is an NSAID (p.96) that
8.75 mg of flurbiprofen may be sucked or allowed to has been given by mouth for the relief of pain.
dissolve slowly in the mouth every 3 to 6 hours to a Pharmacopoeias. In Eur. (see p.vii).
maximum daily dose of 5 lozenges. It is recommended Preparations Ph. Eur. 6.2 (Hydroxyethyl Salicylate). An oily, colourless or al-
Proprietary Preparations (details are given in Part 3) most colourless liquid or colourless crystals. M.p. about 21°.
that treatment should be limited to a maximum of 3 Sparingly soluble in water; freely soluble in alcohol; very soluble
Ital.: Dolex†.
days. in acetone and in dichloromethane. Protect from light.
To inhibit intra-operative miosis during ocular sur- Profile
gery one drop of flurbiprofen sodium 0.03% is in- Glafenine (rINN) Glycol salicylate is a salicylic acid derivative used similarly to
stilled into the eye every 30 minutes beginning 2 hours methyl salicylate (p.85) in topical rubefacient preparations in
Glafenina; Glafénine; Glafeninum; Glaphenine. 2,3-Dihydroxy- usual concentrations of 5 to 15% for the relief of muscular and
before surgery and ending not less than 30 minutes be- propyl N-(7-chloro-4-quinolyl)anthranilate. rheumatic pain. Dipropylene glycol salicylate has been used in
fore surgery. To control postoperative inflammation Глафенин similar preparations.
the same dosage regimen is used before ocular surgery C 19 H 17ClN 2 O 4 = 372.8.
followed 24 hours after surgery by the instillation of Preparations
C AS — 3820-67-5.
one drop 4 times daily for 1 to 3 weeks. Flurbiprofen ATC — N02BG03. Proprietary Preparations (details are given in Part 3)
Cz.: Lumbinon†; Ger.: Auroanalin N†; Dolo-Arthrosenex N; Dolo-Ar-
sodium eye drops have also been used in the topical ATC Vet — QN02BG03. throsenex NH; Dolo-Rubriment H†; Etrat Spor tgel HES; Kytta†;
treatment of cystoid macular oedema. Lumbinon†; Mobilat Akut HES; Phardol mono; Phlogont Rheuma†;
Phlogont†; Rheubalmin N†; Salhumin Gel; Traumasenex; zuk Schmerzgel,
Flurbiprofen axetil has been given in some countries OH zuk Schmerzsalbe†.
by intravenous injection for severe pain. Multi-ingredient: Arg.: Infrarub†; Venostasin; Austral.: Deep Heat;
HO O O Cl Goanna Analgesic Ice†; Austria: Ambenat; Etrat; Igitur-Rheumafluid; Men-
The R-enantiomer, tarenflurbil, is under investigation thoneurin; Mobilisin; Moviflex; Rheumex; Rubizon-Rheumagel; Rubriment;
H Sportino Akut†; Venostasin compositum; Belg.: Algipan; Emerxil; Mobilisin;
in the management of Alzheimer’s disease. N Percutalgine; Rado-Salil; Rado-Spray†; Stilene; Braz.: Etrat†; Mobilisin Com-
Preparations posto; Venostasin†; Canad.: Midalgan†; Cz.: Arnidol; Dolo-Rubriment†;
Rheuma-Salbe†; Rubriment-N†; Fin.: Moviflex†; Fr.: Algipan; Cortisal; Le
BP 2008: Flurbiprofen Eye Drops; Flurbiprofen Suppositories; Flurbiprofen N Thermogene†; Lumbalgine; Percutalgine; Ger.: ABC Warme-Salbe†; Am-
Tablets; bene N; Arthrodestal N†; Auroanalin Thermo; Caye Rheuma-Balsam; Dolo
USP 31: Flurbiprofen Sodium Ophthalmic Solution; Flurbiprofen Tablets. Mobilat†; Doloneuro†; DoloVisano Salbe†; Essaven Sport†; Etrat Sport-
Profile gel†; Heparin Plus†; Hot Thermo; Infrotto Ultra†; Lumbinon Thermo†;
Proprietary Preparations (details are given in Part 3) Menthoneurin-Salbe; mikanil†; Ostochont†; Phardol Rheuma†; Phardol
Arg.: Clinadol; Flurbic; Flurbid†; Luarprofeno; Tolerane; Austral.: Ocufen;
Glafenine, an anthranilic acid derivative, is an NSAID (p.96) that Warme-Balsam†; Phlogont-Thermal; Rheubalmin Thermo†; Rheuma Bad;
Strepfen; Austria: Froben; Ocuflur†; Belg.: Froben; Ocuflur; Braz.: was used for the relief of all types of pain. However, its high in- Rheuma-Salbe N; Rheuma-Salbe†; Rubriment-N†; Sportino Akut; Tetesept
Ocufen; Targus; Canad.: Ansaid; Froben; Novo-Flurprofen; Ocufen; Chile: cidence of anaphylactic reactions has led to its withdrawal from Badekonzentrat Rheuma Bad†; Thermo-Menthoneurin†; Thermo-Rheu-
Ansaid; Distex; Ocufen; Cz.: Ansaid†; Flugalin†; Ocuflur†; Strepfen; Trans- the market in most countries. Glafenine hydrochloride was also mon N†; Thermosenex; Togal Mobil-Gel†; Trauma-Puren†; Venoplant
ActLAT†; Denm.: Flurofen; Fr.: Cebutid; Ocufen; Strefen; Ger.: Dobendan AHS†; Vertebralon N†; Warme-Gel†; zuk thermo†; Gr.: Bayolin; Hong
used. Kong: New Patecs A; Prelloran†; Salomethyl; Hung.: Bayolin†; Mobilisin†;
Direkt; Dobrofen†; Ocuflur; Gr.: Bedice†; Bonatol-R; Fladolef-B†; Flurofen;
Fluroptic; Inflaflur; Ocuflur; Hong Kong: Ocufen†; Hung.: Flugalin; Ocu- Nicoflex; India: Algipan; Irl.: Algipan; Israel: Deep Heat Spray; Ital.: Bal-
Adverse effects and precautions. Glafenine is a common samo Sifcamina; Disalgil†; Mobilisin; Salonpas; Sloan; Malaysia: Salonpas;
flur†; Strepfen; India: Arflur†; Cadiflur; Froben; Ocuflur; Irl.: Froben; cause of anaphylaxis. There may be hepatotoxicity (sometimes
Ocufen†; Strepsils Intensive; Ital.: Benactiv; Froben; Ocufen; Tantum Activ Neth.: Cremor capsici comp; Cremor Capsici compositus; Kruidvat Spier-
Gola; Transact Lat; Jpn: Ropion; Malaysia: Acustop Cataplasma; Mex.: fatal), nephrotoxicity, and gastrointestinal disturbances. It should balsem; Pol.: Deep Heat; Lumbolin; Port.: DM Creme; DM Gel; Midal-
Ansaid; Ocufen; Neth.: Froben; NZ: Froben†; Ocufen†; Strepfen; Pol.: Flu- be stopped at the first sign of any allergic reaction. Crystallisation gan†; S.Afr.: Deep Heat Spray; Infrarub; Singapore: Deep Heating Spray†;
galin; Strepsils Intensive; Port.: Edolfene; Froben; Ocuflur†; Reupax†; Strep- of glafenine in the urinary tract has also occurred. Cross-reactiv- Saak†; Spain: Movilisin; Switz.: Assan; Assan thermo; Demotherm Pom-
fen; Transact Lat; Rus.: Strepfen (Стрепфен); S.Afr.: Froben; Ocufen; made contre le rhumatisme†; Dolo Demotherm; Dolo-Arthrosenex;
TransAct; Singapore: Acustop Cataplasma†; Ocufen†; Spain: Froben;
ity with floctafenine has been reported. Dolo-Arthrosenex sine Heparino†; Dolo-Veniten†; Histalgane; Histalgane
Neo Artrol†; Ocuflur; Switz.: Froben; Ocuflur; Thai.: Flurozin; Turk.: Ma- mite; Midalgan; Mobilisin; Phlebostasin compositum†; Prelloran†; Radalgin;
jezik; UK: Froben; Ocufen; Strefen; USA: Ansaid; Ocufen; Venez.: Flurben†; Remexal; Sportusal; Sportusal Spray sine heparino; Venoplant comp; Ve-
Ocufen†. nucreme; Venugel; Thai.: Percutalgine†; UK: Cremalgin; Deep Heat Spray;
Glucametacin (rINN) Dubam; Fiery Jack; Ralgex; Ralgex Freeze Spray; Ralgex Heat Spray (low-
odour); Salonair; Salonpas; Transvasin Heat Spray.
Glucametacina; Glucamétacine; Glucametacinum. 2-{2-[1-(4-
Fosfosal (rINN) Chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido}-2-
deoxy-D-glucose.
Fosfosalum; UR-1521. 2-Phosphono-oxybenzoic acid. Gold Keratinate
Глюкаметацин
Фосфосал C 25 H 27ClN 2 O 8 = 518.9. Aurothiopolypeptide; Queratinato de oro.
C 7 H 7 O 6 P = 218.1. C AS — 52443-21-7. C AS — 9078-78-8.
C AS — 6064-83-1. Profile
Gold keratinate is a gold compound with a gold content of about
O CH3 13%; It has similar actions and uses to those of sodium aurothi-
O omalate (p.122). It has been given by intramuscular injection as
O O the calcium salt for the treatment of rheumatoid arthritis.
OH
Preparations
NH
Proprietary Preparations (details are given in Part 3)
O HO H 3C N
O Arg.: Aurochobet.
P OH
HO O
OH HO Cl
OH
Golimumab (USAN, rINN)
Profile CNTO-148; Golimumabum. Immunoglobulin G1, anti-(human
Fosfosal is a salicylic acid derivative (see Aspirin, p.20). It has Profile
been given in usual oral doses of up to 3.6 g daily for the treat- Glucametacin, a derivative of indometacin (p.66), is an NSAID tumor necrosis factor α) (human monoclonal CNTO 148 γ1-
ment of pain. (p.96) that has been given orally in musculoskeletal, joint, peri- chain), disulfide with human monoclonal CNTO 148 κ-chain,
articular, and soft-tissue disorders. dimer.
Preparations Preparations Голимумаб
Proprietary Preparations (details are given in Part 3) Proprietary Preparations (details are given in Part 3) C AS — 476181-74-5.
Spain: Aydolid; Disdolen; Protalgia. Braz.: Teoremin; Mex.: Teoremac.
Multi-ingredient: Spain: Aydolid Codeina; Disdolen Codeina.
Profile
Multi-ingredient: Chile: Fibrorelax. Golimumab is a human monoclonal antibody to tumour necrosis
factor α, a pro-inflammatory mediator (see Infliximab, p.71), that
 Fosfosal/Hydromorphone Hydrochloride 63
is being investigated in the management of rheumatoid arthritis, Profile
psoriatic arthritis, and ankylosing spondylitis. Hydrocodone, a phenanthrene derivative, is an opioid analgesic
◊ References. (p.101) related to codeine (p.37) and has similar actions, but is HO
1. Zhou H, et al. Pharmacokinetics and safety of golimumab, a ful-
more potent on a weight-for-weight basis. Hydromorphone (be-
ly human anti-TNF-α monoclonal antibody, in subjects with low) is one of the metabolites of hydrocodone.
rheumatoid arthritis. J Clin Pharmacol 2007; 47: 383–96. Hydrocodone is used mainly as the tartrate in combination prep-
2. Kay J, et al. Golimumab in patients with active rheumatoid ar- arations for the relief of irritant cough, though it has no particular O
thritis despite treatment with methotrexate: a randomized, dou-
ble-blind, placebo-controlled, dose-ranging study. Arthritis
advantage over codeine. Hydrocodone tannate has been used
similarly. Hydrocodone tartrate is also used for the relief of mod- NCH3
Rheum 2008; 58: 964–75.
erate to moderately severe pain, usually with paracetamol. The
usual oral dose of hydrocodone tartrate in such combination O
preparations is 5 to 10 mg every 4 to 6 hours.
Hexyl Nicotinate For details of doses in children, see below. (hydromorphone)
Heksyylinikotinaatti; Hexylnicotinatum; Hexylnikotinat; Nicoti-
Hydrocodone hydrochloride is given orally and also by injection.
nato de hexilo. n-Hexyl nicotinate. The polistirex derivative (a hydrocodone and sulfonated diethe- NOTE. The following terms have been used as ‘street names’ (see
C 12 H 17NO 2 = 207.3. nylbenzene-ethenylbenzene copolymer complex) is used in p.vi) or slang names for various forms of hydromorphone:
C AS — 23597-82-2. modified-release preparations. Dillies; HillBilly Heroin; Hospital heroin.
Hydrocodone has also been used in the treatment of dyspnoea. Pharmacopoeias. In Eur. (see p.vii) and US.
N Ph. Eur. 6.2 (Hydromorphone Hydrochloride). A white or al-
Abuse. The abuse or overuse of preparations containing hy- most white, crystalline powder. Freely soluble in water; very
drocodone and paracetamol has been associated with sen- slightly soluble in alcohol; practically insoluble in dichlorometh-
O CH3 sorineural hearing loss.1,2 Cochlear implants improved the hear- ane. Protect from light.
ing loss in some of the patients. USP 31 (Hydromorphone Hydrochloride). A fine white, or
A case of palatal perforation associated with intranasal abuse of practically white, odourless, crystalline powder. Soluble 1 in 3 of
O a crushed preparation of hydrocodone and paracetamol has also water; sparingly soluble in alcohol; practically insoluble in ether.
been reported.3 Store in airtight containers at a temperature of 25°, excursions
Profile 1. Friedman RA, et al. Profound hearing loss associated with hy- permitted between 15° and 30°. Protect from light.
Hexyl nicotinate is used in topical preparations as a rubefacient. drocodone/acetaminophen abuse. Am J Otol 2000; 21: 188–91.
Preparations 2. Ho T, et al. Hydrocodone use and sensorineural hearing loss. Incompatibility. Colour change from pale yellow to light green
Pain Physician 2007; 10: 467–72. occurred when solutions of minocycline hydrochloride or tetra-
Proprietary Preparations (details are given in Part 3) cycline hydrochloride were mixed with hydromorphone hydro-
3. Jewers WM, et al. Palatal perforation associated with intranasal
Multi-ingredient: Belg.: Transvane; Irl.: Transvasin; Port.: Hipodor†; prescription narcotic abuse. Oral Surg Oral Med Oral Pathol chloride in 5% glucose injection.1 Mixtures of hydromorphone
UK: Transvasin Heat Rub. Oral Radiol Endod 2005; 99: 594–7. hydrochloride and dexamethasone sodium phosphate exhibited
Administration in children. Hydrocodone tartrate may be concentration-dependent incompatibility.2 White cloudiness,
given as part of a combination preparation for the relief of irritant haziness, or precipitation developed 4 hours after mixing thio-
Hydrocodone Hydrochloride (BANM, rINNM) cough in children aged from 6 to 12 years in usual oral doses of pental sodium and hydromorphone hydrochloride.3
Hidrocloruro de hidrocodona; Hydrocodone, Chlorhydrate d’; 2.5 mg every 4 to 6 hours. Older children may be given the usual Stability of mixtures of fluorouracil and hydromorphone hydro-
Hydrocodoni Hydrochloridum. adult dose (see above). chloride in 0.9% sodium chloride or 5% glucose depended on the
Гидрокодона Гидрохлорид concentration of fluorouracil present.4 Hydromorphone hydro-
Pharmacokinetics. References. chloride 0.5 mg/mL with fluorouracil 1 mg/mL was stable for at
C 18 H 21NO 3 ,HCl,2 ⁄ H 2O = 380.9. 1. Hutchinson MR, et al. CYP2D6 and CYP3A4 involvement in the least 7 days at 32° and for at least 35 days at 23°, 4°, or −20°.
C AS — 25968-91-6 (anhydrous hydrocodone hydrochlo- primary oxidative metabolism of hydrocodone by human liver
ride). When the concentration of fluorouracil was increased to
microsomes. Br J Clin Pharmacol 2004; 57: 287–97. 16 mg/mL, hydromorphone was noted to decompose incurring
ATC — R05DA03.
ATC Vet — QR05DA03. Preparations unacceptable losses after 3 days at 32° or after 7 days at 23°, but
USP 31: Hydrocodone Bitartrate and Acetaminophen Tablets; Hydroco- was stable for at least 35 days at 4° or −20°.
done Bitartrate and Homatropine Methylbromide Tablets; Hydrocodone 1. Nieves-Cordero AL, et al. Compatibility of narcotic analgesic
H3CO Bitartrate Tablets. solutions with various antibiotics during simulated Y-site injec-
tion. Am J Hosp Pharm 1985; 42: 1108–9.
Proprietary Preparations (details are given in Part 3) 2. Walker SE, et al. Compatibility of dexamethasone sodium phos-
Belg.: Biocodone; Canad.: Hycodan; Ger.: Dicodid; Switz.: Dicodid†; Hy- phate with hydromorphone hydrochloride or diphenhydramine
drocodeinon. hydrochloride. Am J Hosp Pharm 1991; 48: 2161–6.
O Multi-ingredient: Arg.: Hidronovag Complex; Canad.: Coristine-DH†; 3. Chiu MF, Schwartz ML. Visual compatibility of injectable drugs
Dalmacol; Dimetane Expectorant DC; Hycomine; Novahistex DH; Nova- used in the intensive care unit. Am J Health-Syst Pharm 1997;
NCH3 histine DH; ratio-Calmydone; ratio-Coristex-DH; Tussionex; Vasofrinic DH; 54: 64–5.
India: Cardiazol-Dicodid†; USA: Alor; Anaplex HD; Anexsia; Atuss EX†; 4. Xu QA, et al. Stability and compatibility of fluorouracil with
Atuss G; Atuss HC; Atuss HD; Atuss HS; Atuss HX; Bancap HC; Ceta Plus; morphine sulfate and hydromorphone hydrochloride. Ann Phar-
O Co-Gesic; Co-Tuss V; Codal-DH; Codiclear DH; Codimal DH; Cophene macother 1996; 30: 756–61.
XP; Cordron-HC; Cyndal HD†; Cytuss HC; Cytuss-HC NR; Damason-P;
De-Chlor G; De-Chlor HC; De-Chlor HD†; De-Chlor MR; De-Chlor NX;
(hydrocodone) Deconamine CX; Dolacet; Donatussin DC; Drocon-CS; Duocet; Duratuss Dependence and Withdrawal
HD; Dytan-HC; ED Tuss HC; ED-TLC; Endagen-HD; Endal-HD; Endal-HD As for Opioid Analgesics, p.101.
Plus; Entex HC; Entuss Expectorant; Entuss-D; Entuss-D Jr; H-Tuss-D†; His-
tex HC; Histinex D; Histinex HC; Histinex PV; Histussin D†; Histussin HC;
Hydrocodone Tartrate (BANM, rINNM) Hy-KXP; Hy-Phen; Hycet; HycoClear Tuss; Hycodan; Hycomine Com- Adverse Effects, Treatment, and Precau-
Dihydrocodeinone Acid Tartrate; Hydrocodone Acid Tartrate; pound; Hycotuss; Hydex PD; Hydro DP; Hydro PC†; Hydro-GP; Hydro- tions
Hydrocodone Bitartrate (USAN); Hydrocodone, Tartrate d’; Hy- Tussin HD; Hydro-Tussin HG; Hydrocet; Hydrocodone CP; Hydrocodone
GF; Hydrocodone HD; Hydrogesic; Hydromet; Hydron CP; Hydron EX; As for Opioid Analgesics in general, p.102.
drocodoni Bitartras; Hydrocodoni Tartras; Hydrocone Hydron KGS; Hydron PSC; Hydropane; Hyphed; HyTan; Ibudone; Iodal;
Bitartrate; Tartrato de dihidrocodeinona; Tartrato de hidrocodo- Iotussin HC; Kwelcof; Levall 5.0; Liquicet; Lorcet 10/650; Lorcet Plus; UK licensed product information contra-indicates the
na. 6-Deoxy-3-O-methyl-6-oxomorphine hydrogen tartrate Lorcet-HD; Lortab; Lortab ASA; Lortuss HC; Marcof; Margesic H; Maxi- use of hydromorphone hydrochloride in patients with
Tuss HCG; Maxi-Tuss HCX; Maxidone; Nalex DH; Nalex Expectorant;
hemipentahydrate; (−)-(5R)-4,5-Epoxy-3-methoxy-9a-methyl- Narcof; Nariz HC; Neo HC; Norco; Notuss PD; Notuss-Forte; Oncet; P- hepatic impairment; however, product information in
morphinan-6-one hydrogen tartrate hemipentahydrate. V-Tussin; Pancof XP; Pancof-HC; Pancof-XL; Para-Hist HD; Pneumotussin; the USA permits its cautious use although doses may
Poly-Tussin; Pro-Red; Protuss-D†; Protuss†; Relacon-HC; Relasin-HCX;
Гидрокодона Тартрат Reprexain; S-T Forte 2; SRC Expectorant; Stagesic; Su-Tuss HD; T-Gesic; need to be reduced. It should also be used with caution
C 18 H 21NO 3 ,C 4 H 6 O 6 ,2 ⁄ H 2 O = 494.5. Tusana-D; Tusdec-HC; Tusnel-HC; Tussafed HC†; Tussafed-HCG; Tussafin and given in reduced doses to those with renal impair-
C AS — 125-29-1 (hydrocodone); 143-71-5 (anhydrous hy- Expectorant; Tussanil DH; Tussend; Tussigon; Tussionex Pennkinetic; Tusso-
drocodone tartrate); 34195-34-1 (hydrocodone tartrate DF; Tusso-HC; Tussplex; Tyrodone; Unituss HC; Vanex Expectorant; Vanex- ment.
hemipentahydrate). HD; Vazotuss HC; Vicodin; Vicodin Tuss; Vicoprofen; Vitussin; Xodol; Z-Cof
HC; Zamicet; Zydone; Zymine HC. Effects on the nervous system. Myoclonus has been
ATC — R05DA03. reported1 in a 55-year-old man given relatively low doses of in-
ATC Vet — QR05DA03. travenous hydromorphone with a total daily dose of 4 mg on day
NOTE. Compounded preparations of hydrocodone tartrate may be 1 and 6 mg on day 2; symptoms resolved when the drug was
represented by the following names: stopped on day 3. A chart review2 for neuroexcitatory symptoms
Hydromorphone Hydrochloride in 48 patients with terminal illnesses on hydromorphone found
• Co-hycodAPAP (PEN)—hydrocodone tartrate and paraceta-
mol. ⊗
(BANM, rINNM) 13 cases of agitation, 9 of myoclonus, and 4 of seizures; maximal
The following terms have been used as ‘street names’ (see dose and treatment duration were noted to increase the risk of
Dihydromorphinone Hydrochloride; Hidrocloruro de dihidro- neurotoxicity.
p.vi) or slang names for various forms of hydrocodone tar- morfinona; Hidrocloruro de hidromorfona; Hidromorfono hid-
trate: 1. Patel S, et al. A myoclonic reaction with low-dose hydromor-
Cough Syrup; Vikes. rochloridas; Hydromorfon-hydrochlorid; Hydromorfonhydro- phone. Ann Pharmacother 2006; 40: 2068–70.
klorid; Hydromorfonihydrokloridi; Hydromorphone, chlorhy- 2. Thwaites D, et al. Hydromorphone neuroexcitation. J Palliat
Pharmacopoeias. In Eur. (see p.vii) and US. Med 2004; 7: 545–50.
Ph. Eur. 6.2 (Hydrocodone Hydrogen Tartrate 2.5-Hydrate). drate d’; Hydromorphoni hydrochloridum. 6-Deoxy-7,8-dihy-
White or almost white, hygroscopic, crystalline powder. Freely dro-6-oxomorphine hydrochloride; (−)-(5R)-4,5-Epoxy-3-hy-
droxy-9a-methylmorphinan-6-one hydrochloride.
Interactions
soluble or soluble in water; sparingly soluble in alcohol; practi- For interactions associated with opioid analgesics, see
cally insoluble in cyclohexane. A 2% solution in water has a pH Гидроморфона Гидрохлорид
of 3.2 to 3.8. Store in airtight containers. Protect from light. p.103.
C 17 H 19 NO 3 ,HCl = 321.8.
USP 31 (Hydrocodone Bitartrate). Fine, white crystals or crys- Alcohol. The FDA received data from pharmacokinetic studies
C AS — 466-99-9 (hydromorphone); 71-68-1 (hydromor-
talline powder. Soluble in water; slightly soluble in alcohol; in- in healthy subjects which showed that significantly higher peak
soluble in chloroform and in ether. pH of a 2% solution in water phone hydrochloride). plasma concentrations of hydromorphone were achieved, as a re-
is between 3.2 and 3.8. Store in airtight containers. Protect from ATC — N02AA03. sult of dose-dumping, when alcohol was ingested with once-
light. ATC Vet — QN02AA03. daily hydromorphone modified-release capsules (Palladone;
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
64 Analgesics Anti-inflammatory Drugs and Antipyretics
Purdue Frederick, USA); these increases were considered poten- 4. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Man- topenia or coagulation defects should also not be given
tially lethal, even in opioid-tolerant patients.1 Subsequently, this age 2005; 29 (suppl): S57–S66.
5. Grosset AB, et al. Comparative efficacy of oral extended-release parenteral ibuprofen, and those given it should be mon-
formulation was voluntarily withdrawn by the US manufacturer
in July 2005.
hydromorphone and immediate-release hydromorphone in pa- itored during treatment for signs of bleeding. Renal
tients with persistent moderate to severe pain: two randomized
controlled trials. J Pain Symptom Manage 2005; 29: 584–94. function should be monitored and if anuria or marked
1. Food and Drug Administration. FDA alert for healthcare profes- oliguria is evident at the time of a scheduled second or
6. Du Pen S, et al. Intrathecal hydromorphone for intractable non-
sionals: alcohol-Palladone interaction (issued 13th July, 2005).
malignant pain: a retrospective study. Pain Med 2006; 7: 10–15. third dose, it should be delayed until renal function has
Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/
hydromorphoneHCP.pdf (accessed 26/06/08) 7. Chang AK, et al. Safety and efficacy of hydromorphone as an
analgesic alternative to morphine in acute pain: a randomized returned to normal.
clinical trial. Ann Emerg Med 2006; 48: 164–72. Symptoms of nausea, vomiting, and tinnitus have been
Pharmacokinetics Preparations reported after ibuprofen overdosage. More serious tox-
Hydromorphone hydrochloride is rapidly but incom- USP 31: Hydromorphone Hydrochloride Injection; Hydromorphone Hy- icity is uncommon, but gastric emptying followed by
pletely absorbed from the gastrointestinal tract after drochloride Tablets.
supportive measures is recommended if the quantity
oral doses; peak plasma concentrations occur within Proprietary Preparations (details are given in Part 3)
Arg.: Dolonovag; Austral.: Dilaudid; Austria: Dilaudid; Hydal; Belg.: Palla- ingested within the previous hour exceeds 400 mg/kg.
0.5 to 1 hour. Oral bioavailability is about 50% as it done; Canad.: Dilaudid; Hydromorph; Cz.: Jurnista; Palladone; Denm.: Breast feeding. No adverse effects have been seen in breast-
undergoes extensive first-pass metabolism. Hydromor- Opidol†; Palladon; Fin.: Palladon; Fr.: Sophidone; Ger.: Dilaudid; Palladon;
Hung.: Palladone; Irl.: Palladone; Israel: Palladone; Mex.: Liberaxim; fed infants whose mothers were receiving ibuprofen, and the
phone is about 8 to 19% bound to plasma proteins. A Neth.: Palladon; Norw.: Palladon; NZ: Dilaudid†; Port.: Jurnista; Palladone; American Academy of Pediatrics considers1 that it is therefore
plasma elimination half-life of about 2.5 hours has Swed.: Opidol†; Palladon; Switz.: Palladon; UK: Palladone; USA: Dilaudid; usually compatible with breast feeding. The BNF also considers
Palladone†. the amount of ibuprofen distributed into breast milk to be too
been reported after oral or intravenous doses. Hydro- Multi-ingredient: Swed.: Dilaudid-Atropin; Switz.: Dilaudid-Atropin†; small to be harmful to a breast-fed infant. A study2 estimated that
morphone appears to be widely distributed in the tis- USA: Dilaudid Cough. a breast-fed infant would ingest about 0.0008% of the maternal
sues; it crosses the placenta and is distributed into dose. However, licensed product information for some prepara-
breast milk. It is extensively metabolised by glucuroni- tions, including some topical preparations, recommends that
dation in the liver and excreted in the urine mainly as breast feeding should be avoided during ibuprofen treatment.
Ibuprofen (BAN, USAN, rINN) 1. American Academy of Pediatrics. The transfer of drugs and oth-
conjugated hydromorphone, dihydroisomorphine, and er chemicals into human milk. Pediatrics 2001; 108: 776–89.
Ibuprofeeni; Ibuprofén; Ibuprofenas; Ibuprofène; Ibuprofeno; Ibu-
dihydromorphine. Correction. ibid.; 1029. Also available at:
profenum; RD-13621; U-18573. 2-(4-Isobutylphenyl)propionic h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
◊ References. acid. pediatrics%3b108/3/776 (accessed 07/11/07)
Ибупрофен 2. Walter K, Dilger C. Ibuprofen in human milk. Br J Clin Pharma-
1. Vallner JJ, et al. Pharmacokinetics and bioavailability of hydro- col 1997; 44: 211–12.
C 13 H 18O 2 = 206.3.
morphone following intravenous and oral administration to hu- Children. An analysis1 of the outcome of treatment of 83 915
man subjects. J Clin Pharmacol 1981; 21: 152–6. C AS — 15687-27-1.
ATC — C01EB16; G02CC01; M01AE01; M02AA13. children found that the risk of hospitalisation for gastrointestinal
2. Parab PV, et al. Pharmacokinetics of hydromorphone after intra- bleeding, renal failure, or anaphylaxis was no greater in children
venous, peroral and rectal administration to human subjects. Bi- ATC Vet — QC01EB16; QG02CC01; QM01AE01; given ibuprofen than in those given paracetamol.
opharm Drug Dispos 1988; 9: 187–99. QM02AA13. 1. Lesko SM, Mitchell AA. An assessment of the safety of pediatric
3. Vashi V, et al. Clinical pharmacology and pharmacokinetics of ibuprofen. JAMA 1995; 273: 929–33.
once-daily hydromorphone hydrochloride extended-release cap- Effects on the blood. Blood disorders including agranulocy-
sules. J Clin Pharmacol 2005; 45: 547–54. CH3
tosis, aplastic anaemia, 1 pure white-cell aplasia, 2 and
thrombocytopenia3 have been reported in patients taking ibupro-
Uses and Administration CH3 COOH fen. Fatal haemolytic anaemia occurred in a man taking ibupro-
Hydromorphone hydrochloride, a phenanthrene deriv- fen and oxazepam.4
H 3C 1. Gryfe CI, Rubenzahl S. Agranulocytosis and aplastic anemia
ative, is an opioid analgesic (p.104). It is related to possibly due to ibuprofen. Can Med Assoc J 1976; 114: 877.
morphine (p.89) but with a greater analgesic potency. 2. Mamus SW, et al. Ibuprofen-associated pure white-cell aplasia.
Hydromorphone hydrochloride is used for the relief of Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and N Engl J Med 1986; 314: 624–5.
Viet. 3. Jain S. Ibuprofen-induced thrombocytopenia. Br J Clin Pract
moderate to severe pain and for the relief of non-pro- Ph. Eur. 6.2 (Ibuprofen). A white or almost white, crystalline 1994; 48: 51.
ductive cough. powder or colourless crystals. M.p. 75° to 78°. Practically insol- 4. Guidry JB, et al. Fatal autoimmune hemolytic anemia associated
with ibuprofen. JAMA 1979; 242: 68–9.
uble in water; freely soluble in acetone, in dichloromethane, and
In the treatment of pain, hydromorphone hydrochlo- in methyl alcohol; it dissolves in dilute solutions of alkali hy- Effects on the cardiovascular system. For a discussion of
ride is a useful alternative to morphine for subcutane- droxides and carbonates. the cardiovascular effects of NSAIDs, including ibuprofen, see
ous use since its greater solubility in water allows a USP 31 (Ibuprofen). A white to off-white crystalline powder p.96.
smaller dose volume. After injection onset of action having a slight characteristic odour. Practically insoluble in wa- Effects on the CNS. Aseptic meningitis has occurred in pa-
ter; very soluble in alcohol, in acetone, in chloroform, and in tients taking NSAIDs. A review1 of NSAID-related CNS ad-
usually occurs within 15 minutes and analgesia is re- methyl alcohol; slightly soluble in ethyl acetate. Store in airtight verse effects summarised 23 literature reports of NSAID-associ-
ported to last for more than 5 hours; after oral doses containers. ated aseptic meningitis; 17 reports involved ibuprofen, 4
onset of analgesia is usually within 30 minutes. It is sulindac, 1 naproxen, and 1 tolmetin. Of the 23 reports, 11 were
given by subcutaneous or intramuscular injection in Ibuprofen Lysine (USAN) in patients with a diagnosis of SLE. Typically the reaction is seen
initial doses of 1 to 2 mg every 4 to 6 hours as neces- Ibuprofen Lysinate; Soluphene. Lysine 2-(4-isobutylphenyl)propi- in patients who have just restarted NSAID therapy after a gap in
sary. It may also be given by slow intravenous injection their treatment. Within a few hours of restarting the NSAID the
onate.
patient experiences fever, headache, and a stiff neck; abdominal
or by intravenous or subcutaneous infusion, with doses Ибупрофен Лизин pain may be present. The patient may become lethargic and
adjusted according to individual requirements. Higher C 19 H 32N 2 O 4 = 352.5. eventually comatose. Symptoms resolve if the NSAID is
parenteral doses may be given to opioid-tolerant pa- C AS — 57469-77-9. stopped. It is believed to be a hypersensitivity reaction but there
ATC — C01EB16; G02CC01; M01AE01; M02AA13. does not appear to be cross-reactivity between NSAIDs.
tients using a highly concentrated solution containing ATC Vet — QC01EB16; QG02CC01; QM01AE01;
10 mg/mL that allows smaller dose volumes. In the Similar conclusions have also been reported more recently.2 Af-
QM02AA13. ter experience of 2 cases, a review of the literature identified 71
UK, the initial oral dose is 1.3 mg every 4 hours; there- Stability. Solutions of ibuprofen lysine in Water for Injections episodes of ibuprofen-induced aseptic meningitis in 36 patients;
after the dose may be increased as necessary. In the stored at room temperature were found to be most stable when 22 patients had recurrent episodes after repeated ibuprofen use.
USA, initial oral doses of 2 mg may be given every 4 protected from light.1 An underlying auto-immune connective tissue disorder was
to 6 hours; doses may be increased to 4 mg or more for 1. Volonté MG, et al. Stability of ibuprofen in injection solutions. noted in 22 patients of whom 14 had SLE, 6 had an undifferenti-
Am J Health-Syst Pharm 2005; 62: 630–3. ated or mixed disorder, 1 had rheumatoid arthritis , and 1 had
severe pain. Modified-release preparations are availa-
Sjögren’s syndrome. In most cases, symptoms developed within
ble for less frequent administration, but see Alcohol, Adverse Effects, Treatment, and Precau- 24 hours of starting ibuprofen although 1 patient had been taking
under Interactions, above. By rectum, the usual dose is tions ibuprofen for 2 years before the onset of symptoms. Cross-reac-
3 mg every 6 to 8 hours. As for NSAIDs in general, p.96. Ibuprofen may be bet- tivity was reported in only 1 patient who had also developed
aseptic meningitis with both naproxen and rofecoxib.
For the relief of non-productive cough hydromor- ter tolerated than other NSAIDs. 1. Hoppmann RA, et al. Central nervous system side effects of non-
phone hydrochloride is given, as a syrup, in doses of Adverse effects that may be associated with the use of steroidal anti-inflammatory drugs: aseptic meningitis, psychosis,
and cognitive dysfunction. Arch Intern Med 1991; 151:
1 mg repeated every 3 to 4 hours. ibuprofen injection in premature neonates include in- 1309–13.
traventricular haemorrhage, periventricular leucoma- 2. Rodríguez SC, et al. Characteristics of meningitis caused by ibu-
◊ References. lacia, bronchopulmonary dysplasia, pulmonary haem- profen: report of 2 cases with recurrent episodes and review of
the literature. Medicine 2006; 85: 214–20.
1. Bruera E, et al. A randomized, double-blind, double-dummy, orrhage, necrotising enterocolitis, intestinal
Effects on electrolytes. Hyponatraemia has been described in
crossover trial comparing the safety and efficacy of oral sus- perforation, oliguria, fluid retention, and haematuria; patients receiving ibuprofen;1-3 other risk factors such as pre-ex-
tained-release hydromorphone with immediate-release hydro-
morphone in patients with cancer pain. J Clin Oncol 1996; 14: hypoxaemia and gastrointestinal haemorrhage have isting renal impairment or use with desmopressin were generally
1713–17. also been reported. In addition ibuprofen injection present.
2. Miller MG, et al. Continuous subcutaneous infusion of morphine should not be given to neonates with life-threatening 1. Blum M, Aviram A. Ibuprofen induced hyponatraemia. Rheuma-
vs. hydromorphone: a controlled trial. J Pain Symptom Manage tol Rehabil 1980; 19: 258–9.
infection, with significant renal impairment, or with 2. Rault RM. Case report: hyponatremia associated with nonsteroi-
1999; 18: 9–16.
known or suspected necrotising enterocolitis. Infants dal antiinflammatory drugs. Am J Med Sci 1993; 305: 318–20.
3. Quigley C. Hydromorphone for acute and chronic pain. Availa- who are bleeding (especially gastrointestinal bleeding 3. García EBG, et al. Hyponatraemic coma induced by desmo-
ble in The Cochrane Database of Systematic Reviews; Issue 1. pressin and ibuprofen in a woman with von Willebrand’s disease.
Chichester: John Wiley; 2002 (accessed 26/06/08). or intracranial haemorrhage) or who have thrombocy- Haemophilia 2003; 9: 232–4.
 Ibuprofen 65
Effects on the eyes. Reversible amblyopia has been reported effect is less clear cut, but those who have ingested less than tive pain, dental pain, musculoskeletal and joint
in patients receiving ibuprofen.1,2 For reference to effects on the 100 mg/kg are unlikely to require treatment. disorders such as ankylosing spondylitis, osteoarthritis,
optic nerve associated with ibuprofen, see p.97. Nonetheless, reports illustrate the complexity of major overdos-
1. Collum LMT, Bowen DI. Ocular side-effects of ibuprofen. Br J
and rheumatoid arthritis including juvenile idiopathic
age with ibuprofen. A syndrome of coma, hyperkalaemia with
Ophthalmol 1971; 55: 472–7. cardiac arrhythmias, metabolic acidosis, pyrexia, and respiratory arthritis, peri-articular disorders such as bursitis and
2. Palmer CAL. Toxic amblyopia from ibuprofen. BMJ 1972; 3: and renal failure was reported2 in a 17-year-old man after major tenosynovitis, and soft-tissue disorders such as sprains
765.
overdosage with ibuprofen and minor overdosage with doxepin. and strains. It is also used to reduce fever.
Effects on the gastrointestinal tract. Ibuprofen may be as- Hyperkalaemia was not evident until 14 hours after hospital ad-
sociated with a lower risk of upper gastrointestinal effects than Ibuprofen is also used as an alternative to indometacin
mission and was thought to be due to a combination of potassium
some other NSAIDs, but nonetheless it can cause dyspepsia, replacement for initial hypokalaemia, acidosis, muscle damage, in the treatment of patent ductus arteriosus.
nausea and vomiting, gastrointestinal bleeding, and peptic ulcers and ibuprofen-induced renal failure. A 6-year-old child The usual oral dose for painful conditions is 1.2 to
and perforation. Colitis and its exacerbation have occurred.1,2 developed3 shock, coma, and metabolic acidosis after ingestion 1.8 g daily in divided doses although maintenance dos-
1. Ravi S, et al. Colitis caused by non-steroidal anti-inflammatory of a dose of ibuprofen equivalent to 300 mg/kg. Treatment con-
drugs. Postgrad Med J 1986; 62: 773–6. sisting of intubation, mechanical ventilation, fluid resuscitation,
es of 600 mg to 1.2 g daily may be effective in some
2. Clements D, et al. Colitis associated with ibuprofen. BMJ 1990;
gastric lavage, and activated charcoal proved successful. In an- patients. If necessary the dose may be increased; in the
301: 987.
other report,4 in which a 21-month-old child had ingested the UK the maximum recommended dose is 2.4 g daily
Effects on the kidneys. Reports of adverse renal effects with equivalent of 500 mg/kg of ibuprofen, the presenting symptoms whereas in the USA it is 3.2 g daily. Modified-release
ibuprofen include an increase in serum creatinine concentration,1 were acute renal failure with severe metabolic acidosis. The child
acute renal failure,2-6 and nephrotic syndrome.7 Cystitis, haema- preparations of ibuprofen are available for once- or
developed tonic-clonic seizures 46 hours after ingestion, with
turia, and interstitial nephritis may occur. Acute flank pain and significant hypocalcaemia and hypomagnesaemia, which may twice-daily dosing, although actual dosages vary with
reversible renal dysfunction has been reported in some patients have been exacerbated by use of sodium polystyrene sulfonate different preparations. Patients with rheumatoid arthri-
treated with ibuprofen.8,9 See also Effects on Electrolytes, above. and furosemide. The seizures, which could not be controlled tis generally require higher doses of ibuprofen than
1. Whelton A, et al. Renal effects of ibuprofen, piroxicam, and with diazepam, phenytoin, and phenobarbital, ceased on correc- those with osteoarthritis. The recommended dose for
sulindac in patients with asymptomatic renal failure: a prospec- tion of electrolyte balance.
tive, randomized, crossover comparison. Ann Intern Med 1990; fever reduction is 200 to 400 mg every 4 to 6 hours to
112: 568–76. 1. Perry SJ, et al. Ibuprofen overdose: the first two years of
over–the–counter sales. Hum Toxicol 1987; 6: 173–8. a maximum of 1.2 g daily. For oral doses in children,
2. Brandstetter RD, Mar DD. Reversible oliguric renal failure asso-
ciated with ibuprofen treatment. BMJ 1978; 2: 1194–5. 2. Menzies DG, et al. Fulminant hyperkalaemia and multiple com- see Administration in Children, below.
3. Kimberly RP, et al. Apparent acute renal failure associated with plications following ibuprofen overdose. Med Toxicol Adverse
therapeutic aspirin and ibuprofen administration. Arthritis Drug Exp 1989; 4: 468–71. Ibuprofen may be given parenterally in the treatment
Rheum 1979; 22: 281–5. 3. Zuckerman GB, Uy CC. Shock, metabolic acidosis, and coma of patent ductus arteriosus in preterm infants; for de-
4. Spierto RJ, et al. Acute renal failure associated with the use of following ibuprofen overdose in a child. Ann Pharmacother
1995; 29: 869–71. tails of doses, see below.
over-the-counter ibuprofen. Ann Pharmacother 1992; 26: 714.
5. Fernando AHN, et al. Renal failure after topical use of NSAIDs. 4. Al-Harbi NN, et al. Hypocalcemia and hypomagnesemia after Ibuprofen is applied topically as a 5% cream, foam,
BMJ 1994; 308: 533. ibuprofen overdose. Ann Pharmacother 1997; 31: 432–4.
gel, or spray solution; a 10% gel is also available. It is
6. Moghal NE, et al. Ibuprofen and acute renal failure in a toddler.
Arch Dis Child 2004; 89: 276–7. Interactions also used topically as a dressing containing
7. Justiniani FR. Over-the-counter ibuprofen and nephrotic syn-
For interactions associated with NSAIDs, see p.99. 500 micrograms/cm2 of ibuprofen for the management
drome. Ann Intern Med 1986; 105: 303.
8. McIntire SC, et al. Acute flank pain and reversible renal dys- of ulcers and superficial wounds.
Antineoplastics. For the effect of ibuprofen on the metabolism
function associated with nonsteroidal anti-inflammatory drug Ibuprofen is usually given as the base but derivatives,
use. Pediatrics 1993; 92: 459–60. of pemetrexed, see p.762.
9. Wattad A, et al. A unique complication of nonsteroidal anti-in- Aspirin. It has been suggested that ibuprofen may reduce the
including various salts, esters, and other complexes,
flammatory drug use. Pediatrics 1994; 93: 693. cardioprotective effect of aspirin but see NSAIDS under Interac- have also been used. These include lysine (see Patent
Effects on the liver. Raised liver transaminase values were tions of Aspirin, p.23. Ductus Arteriosus, below) and sodium salts, guaiacol
noted in 3 patients with chronic hepatitis C infection after taking and pyridoxine esters, and mabuprofen (ibuprofen
Lipid regulating drugs. For a report of rhabdomyolysis and
ibuprofen.1 Values returned to normal on stopping the drug; the aminoethanol), isobutanolammonium, and meglumine
renal failure attributed to an interaction between ibuprofen and
effect recurred in one patient who was re-exposed. Other hepatic
ciprofibrate, see p.1233. derivatives.
adverse effects reported with ibuprofen include hepatitis2 and
liver failure.3. Muscle relaxants. Baclofen toxicity may develop after starting Ibuprofen is usually given as a racemic mixture but
See also Effects on the Skin, below. ibuprofen; for further details, see p.1888. preparations containing only the S-(+)-isomer dexibu-
1. Riley TR, Smith JP. Ibuprofen-induced hepatotoxicity in patients profen (p.39) are available in some countries.
with chronic hepatitis C: a case series. Am J Gastroenterol 1998; Pharmacokinetics
93: 1563–5. Administration in children. In the UK, the following oral
2. Borel I, et al. Hépatite aiguë sévère après prise d’ibuprofène. Ibuprofen is absorbed from the gastrointestinal tract
doses of ibuprofen, given according to age, are recommended by
Gastroenterol Clin Biol 2001; 25: 430–2. and peak plasma concentrations occur about 1 to 2 the BNFC for the treatment of pain, inflammation, or fever in
3. Rodríguez-González FJ, et al. Orthotopic liver transplantation hours after ingestion. Ibuprofen is also absorbed on
after subacute liver failure induced by therapeutic doses of ibu- children:
profen. Am J Gastroenterol 2002; 97: 2476–7. rectal use. It is partially absorbed after topical applica- • 1 to 3 months: 5 mg/kg 3 or 4 times daily
Effects on the skin. Skin rashes may occur during hypersensi- tion to the skin; some licensed product information • 3 to 6 months: 50 mg 3 times daily
tivity reactions although serious dermatological effects attributed states that percutaneous absorption from topical gel is • 6 to 12 months: 50 mg 3 or 4 times daily
to ibuprofen are rare. Reports of more serious effects have in- about 5% of that from an oral dose form. Ibuprofen is • 1 to 4 years: 100 mg 3 times daily
cluded Stevens-Johnson syndrome (often associated with hepa- 90 to 99% bound to plasma proteins and has a plasma • 4 to 7 years: 150 mg 3 times daily
totoxicity),1-4 photosensitivity,5 and bullous leukocytoclastic • 7 to 10 years: 200 mg 3 times daily
vasculitis.6 half-life of about 2 hours. It is rapidly excreted in the
1. Sternlieb P, Robinson RM. Stevens-Johnson syndrome plus toxic urine mainly as metabolites and their conjugates. • 10 to 12 years: 300 mg 3 times daily
hepatitis due to ibuprofen. N Y State J Med 1978; 78: 1239–43. About 1% is excreted in urine as unchanged ibuprofen • 12 to 18 years: 200 to 400 mg 3 or 4 times daily increased, if
2. Srivastava M, et al. Drug-associated acute-onset vanishing bile necessary, to a maximum of 2.4 g daily
duct and Stevens-Johnson syndromes in a child. Gastroenterolo- and about 14% as conjugated ibuprofen. There appears
• in severe conditions in children aged between 3 months and 12
gy 1998; 115: 743–6. to be little if any distribution into breast milk. years, a dose of 30 mg/kg daily in 3 or 4 divided doses may be
3. Health Canada. Ibuprofen: Stevens-Johnson syndrome. Can Ad-
verse React News 2005; 15 (3): 3. Also available at: http:// The above figures refer to racemic ibuprofen. Howev- given
www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/ er, ibuprofen’s disposition is stereoselective and there In the USA, suggested doses for children aged 6 months and over
carn-bcei_v15n3-eng.pdf (accessed 29/08/08) are: for fever, 5 to 10 mg/kg (depending on the severity of the
4. Taghian M, et al. Acute vanishing bile duct syndrome after ibu-
is some metabolic conversion of the inactive R-(−)-
enantiomer to the active S-(+)-enantiomer, dexibupro- fever) and for pain, 10 mg/kg; doses may be given every 6 to 8
profen therapy in a child. J Pediatr 2004; 145: 273–6.
5. Bergner T, Przybilla B. Photosensitization caused by ibuprofen. hours up to a maximum daily dose of 40 mg/kg.
J Am Acad Dermatol 1992; 26: 114–16.
fen (p.39). In the treatment of rheumatic disease including juvenile idio-
6. Davidson KA, et al. Ibuprofen-induced bullous leukocytoclastic ◊ References. pathic arthritis, the BNFC recommends a dose of 10 mg/kg 3 or
vasculitis. Cutis 2001; 67: 303–7. 1. Davies NM. Clinical pharmacokinetics of ibuprofen: the first 30 4 times daily (maximum 2.4 g daily) in children aged 3 months
Hypersensitivity. A fatal asthma attack occurred in a 65-year- years. Clin Pharmacokinet 1998; 34: 101–54. and over; if necessary up to 60 mg/kg daily in 4 to 6 divided dos-
old woman, with adult-onset asthma, 30 minutes after ingestion 2. Sharma PK, et al. Pharmacokinetics of oral ibuprofen in prema- es (maximum 2.4 g daily) may be given in systemic juvenile id-
ture infants. J Clin Pharmacol 2003; 43: 968–73.
of ibuprofen 800 mg.1 3. Gregoire N, et al. Population pharmacokinetics of ibuprofen
iopathic arthritis.
For other hypersensitivity reactions or possible reactions see also enantiomers in very premature neonates. J Clin Pharmacol Similar dosage regimens are also suggested by UK licensed
Effects on the CNS and Effects on the Skin, above. 2004; 44: 1114–24. product information; however, ibuprofen use is not generally
1. Ayres JG, et al. Asthma death due to ibuprofen. Lancet 1987; i: 4. Han EE, et al. Pharmacokinetics of ibuprofen in children with recommended in children weighing less than 5 kg and some sug-
1082. cystic fibrosis. Clin Pharmacokinet 2004; 43: 145–56. gest a maximum daily dose of 500 mg in those weighing less
5. Hao H, et al. Enantioselective pharmacokinetics of ibuprofen than 30 kg. A usual daily dose in the USA for juvenile idiopathic
Meningitis. For reports of aseptic meningitis after use of ibu- and involved mechanisms. Drug Metab Rev 2005; 37: 215–-34.
profen, see Effects on the CNS, above. 6. Kyllonen M, et al. Perioperative pharmacokinetics of ibuprofen arthritis is 30 to 40 mg/kg in divided doses.
enantiomers after rectal administration. Paediatr Anaesth 2005; For post-immunisation pyrexia, a dose of 50 mg has been rec-
Overdosage. There was a substantial increase in the number of 15: 566–73. ommended; a second dose may be given after 6 hours. If the py-
cases of ibuprofen overdose reported to the National Poisons In- rexia persists after the second dose, medical advice should be
formation Service of the UK in the 2 years after its introduction Uses and Administration sought. Infants aged 2 to 3 months may also be given a 50-mg
as an ‘over-the-counter’ medication.1 However, no concurrent dose of ibuprofen for post-immunisation pyrexia on the advice of
increase in severity of poisoning was found and in only 1 of 203 Ibuprofen, a propionic acid derivative, is an NSAID
a doctor.
cases was ibuprofen thought to have caused serious problems. It (p.99). Its anti-inflammatory properties may be weaker
Ibuprofen or its lysine salt are also used in the treatment of pat-
was concluded that ibuprofen appeared to be much less toxic in than those of some other NSAIDs. ent ductus arteriosus in preterm infants; dosage details for this
acute overdose than either aspirin or paracetamol. Current advice
is that doses below 100 mg/kg are unlikely to cause toxicity in
Ibuprofen is used in the management of mild to mod- indication are given below.
children, whereas clinical features will occur in children who erate pain and inflammation in conditions such as dys- Cachexia. For reference to the use of ibuprofen with megestrol
have ingested more than 400 mg/kg. In adults the dose-response menorrhoea, headache including migraine, postopera- to treat cancer cachexia, see p.2115.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
66 Analgesics Anti-inflammatory Drugs and Antipyretics
Cystic fibrosis. In patients with cystic fibrosis (see p.166), the rosan; Ibuflam; Ibuflex; Ifentil; Inpained; Maxifen; Medifen; Mejorultra†; Mo- Profile
inflammatory response to chronic pulmonary infection with trin; Natiken†; Novartril†; Offeno†; Pro-XB; Proartinal; Probuxil; Quadrax; Ibuproxam is an NSAID (p.96) that has been used topically as a
Realdrax; Ribufen; Tabalon; Neth.: Advil; Brufen; Femapirin; Ibosure; Ibul-
Pseudomonas organisms contributes to lung destruction. gan†; Nurofen; Pedea; Roco; Sarixell; Spidifen; Zafen; Norw.: Brufen; 5% ointment in musculoskeletal, joint, and soft-tissue disorders.
NSAIDs have been studied in patients with cystic fibrosis as an Ibumetin; Ibuprox; Ibux; NZ: ACT-3; Brufen; Fenapaed; Ibucare; Nurofen; Preparations
alternative to corticosteroids to reduce pulmonary inflammation. Panafen; Philipp.: Advil; Brufen; Dolan; Idyl; Medicol; Midol; Skelan; Pol.:
A systematic review1 found evidence in support of using high- Bolinet; Deep Relief†; Dolgit; Ibufen; Ibum; Ibupar; Ibuprom; Nurofen; Pe- Proprietary Preparations (details are given in Part 3)
dea; Port.: Anadvil; Arfen; Baroc; Brufen; Calbrun; Dolocyl; Dolomate; Do- Ital.: Ibudros†; Spain: Nialen.
dose NSAIDs, most notably ibuprofen, to slow the progression lormin; Faspic; Frenidor; Ibupax†; Junifen; Moment; Motrin†; Norvectan;
of lung damage in patients with cystic fibrosis. However, there Nuprilan†; Nurofen; Ozonol; Pedea; Plusofen; Seclodin; Solufen; Solvium;
are limited data about the long-term safety of high doses1 and Spidifen; Sporfen; Trifene; Zafen; Zip-A-Dol; Rus.: Aldospray
some consider that this may have limited such use of NSAIDs;2 (Альдоспрей); Burana (Бурана); Dolgit (Долгит); Ibufen (Ибуфен); Nuro- Imidazole Salicylate (rINN)
others remain to be convinced that a benefit has been demon- fen (Нурофен); Solpaflex (Солпафлекс); S.Afr.: Advil; Antiflam†; Betagesic;
Betaprofen; Brufen; Brugesic†; Iboflam; Ibugesic; Ibuleve; Ibumax; Ibumed; Imidazole, Salicylate d’; Imidazoli Salicylas; Salicilato de imidazol.
strated.3 The reviewers did consider that there were sufficient Inza; Lenafen†; Norflam T; Nurofen; Painil†; Ranfen; Singapore: Ampifen†; Imidazole compounded with salicylic acid.
data to recommend that NSAIDs be temporarily stopped when Bifen; Ibufen; Ibuloid†; Nurofen; Spain: Advil; Aldospray Analgesico; Algias- Имидазола Салицилат
intravenous aminoglycosides or other nephrotoxic drugs are din; Algidrin; Alogesia; Altior; Babypiril; Bexistar; Calmafher†; Dadosel; Dal-
sy; Diltix; Doctril; Dolbufen; Dolorac; Dorival; Espidifen; Factopan; Femina- C 10 H 10N 2 O 3 = 206.2.
used.1
lin; Fiedosin; Frenatermin; Gelofeno; Ibubex; Ibufen; Ibumac; Ibuprox; C AS — 36364-49-5.
1. Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory Inadol†; Isdibudol†; Isdol†; Junifen; Narfen; Neobrufen; Nodolfen; Nor- ATC — N02BA16.
drug therapy for cystic fibrosis. Available in The Cochrane Da- vectan; Nurofen; Oberdol; Oltyl†; Optajun; Paidofebril; Pedea; Pirexin;
tabase of Systematic Reviews; Issue 4. Chichester: John Wiley; ATC Vet — QN02BA16.
Pocyl†; Ratiodol; Remidol†; Saetil; Solvium; Takigrip†; Tedifebrin; Swed.:
2007 (accessed 07/11/07). Alindrin; Brufen; Ibumetin; Ipren; Switz.: Algifor; Artofen; Brufen; Dismenol;
2. Fennel PB, et al. Use of high-dose ibuprofen in a pediatric cystic Dolo-Dismenol; Dolo-Spedifen; Dolocyl; Ecoprofen; Grefen; Ibufen-L; Ibus-
fibrosis center. J Cyst Fibros 2007; 6: 153–8. ifar; Iproben; Iprogel†; Irfen; Melabon; Nurofen; Optifen; Perskindol Ibupro-
3. Bush A, Davies J. Non! to non-steroidal anti-inflammatory ther- fen acute; Saridon N; Sinedol Ibuprofen; Spedifen; Treupel Dolo Ibuprofen; N
apy for inflammatory lung disease in cystic fibrosis (at least at Thai.: Ambufen; Anbifen; Aprofen; Babefen Sus†; Borafen; Borakid; Brufen;
the moment). J Pediatr 2007; 151: 228–30. Brumed†; Bruprin; Brusil; Bumed; Cefen; Cenbufen; Duran†; Faspic; G-Fen; NH
Gesica; Greatofen; Heidi; Ibrofen; Ibu; Ibufac; Ibugan; Ibulan; Iburen†; Ju-
Pain. Findings from a long-term study1 in 585 patients (mean nifen†; Mano-Bruzone; Nurofen; Ostofen†; P-Fen; Perofen†; Pippen;
age of 64 years) with knee pain suggested that oral and topical Probue; Probufen; Profena†; Profeno; Rheumanox; Rumasian; Rumatifen; HO
ibuprofen had an equivalent analgesic effect although the former Rupan†; Schufen; Skelan IB; Tofen; Trofen; Umafen; Turk.: Advil; Artril; Be-
bol; Biophen; Brufen; Dolgit; Dolven; Gerofen; Ibu-600; Ibufen; Nurofen; HO
was associated with more minor adverse effects; there was no Pedifen; Profen; Repozal; Rofen; Siyafen; Suprafen; Temsofen; Ultrafen; Up-
difference in the rate of major adverse effects. ren; UAE: Profinal; UK: Advil; Anadin Ibuprofen; Anadin Joint Pain; Anadin
1. Underwood M, et al. Topical or oral ibuprofen for chronic knee Ultra; Arthrofen; Biatain-Ibu; Brufen; Calprofen; Cuprofen; Ebufac; Fenbid; O
pain in older people: the TOIB study. Health Technol Assess Fenpaed; Feverfen; Galprofen; Hedex Ibuprofen; Ibrufhalal; Ibufem; Ibugel;
2008; 12: 1–176. Ibuleve; Ibumousse; Ibuspray; Ibutop Cuprofen; Ibutop Ralgex; Librofem;
Mandafen; Manorfen; Mentholatum Ibuprofen; Migrafen; Motrin†; No- Profile
Patent ductus arteriosus. Ibuprofen or its lysine salt may be vaprin; Nurofen; Nurofen Migraine; Obifen; Orbifen; Pacifene; Pedea; Phor Imidazole salicylate is a salicylic acid derivative (see Aspirin,
given parenterally for the treatment of patent ductus arteriosus Pain; Proflex; Radian-B Ibuprofen; Relcofen; Rimafen; USA: Advil; Anadar; p.20) that has been used in the treatment of fever and inflamma-
(p.68) in preterm infants of less than 34 weeks’ gestation; doses Genpril†; Haltran†; Ibu; Ibu-Tab; Ibu-4, -6, -8; Ibutab; Menadol; Midol Cramp
& Body Aches; Motrin; NeoProfen; Nuprin†; Saleto-200; Venez.: Advil; tory respiratory-tract and otorhinolaryngeal disorders. Imidazole
are expressed in terms of ibuprofen. Three intravenous doses (in- Brugesic; Buprifen†; Buprodol; Butilene†; Dologesic; Femicaps; Femmex salicylate has been given in oral doses of up to 2.25 g daily in
fused over 15 minutes) are given at 24-hour intervals; the initial Plus; Ibucaps; Ibufen; Ibufenac†; Ibuprin; Ibuprox†; Ibutan; Lumbax; Max; divided doses. It has also been given as a rectal suppository and
dose is equivalent to 10 mg/kg of ibuprofen followed by two fur- Maydol; Mestral; Motrin; Pedibu. has been applied topically as a 5% gel for the relief of muscular
ther doses of 5 mg/kg. If, 48 hours after this course of therapy the Multi-ingredient: Arg.: Aliviagrip; Bioneural B12†; Buscapina Fem; Butid- and rheumatic pain.
ductus remains open, a second course may be given, but if this iona†; Causalon Gesic†; Deep Relief†; Dexprofeno; Espasmo Ibupirac†; Es- Preparations
produces no response surgery may be necessary. Ibuprofen injec- pasmo Motrax†; Espasmofin; Ibu Evanol Plus; Ibu-Buscapina†; Ibu-Tetralgin;
tion, when given as the base, should be used undiluted, but if Ibudolofrix; Ibudristan; Ibumar Migra†; Ibunastizol; Ibupirac Fem; Ibupirac Proprietary Preparations (details are given in Part 3)
Flex; Ibupirac Migra; Mensalgin; Migral II; Novo Wilpan†; Roveril; Supragesic; Ital.: Selezen.
necessary it may be reconstituted with sodium chloride 0.9% or Austral.: Dimetapp Headcold & Flu; Nurofen Cold & Flu; Nurofen Plus;
glucose 5% for injection. When given as the lysine salt, it should Panafen Plus; Sudafed Sinus & Anti-inflammatory Pain Relief; Tri-Profen
be diluted with sodium chloride 0.9% or glucose 5%. Cold & Flu†; Austria: Advil Cold; Ardinex; Belg.: Adulfen Codeine; Braz.:
Algi-Itamanil†; Algi-Reumatril; Algifen†; Fymnal†; Reuplex; Canad.: Advil
For a suggestion that ibuprofen might be a better choice than in-
dometacin for the treatment of patent ductus arteriosus, see p.68.
Cold & Sinus; Advil Cold & Sinus Plus; Childrens Advil Cold; Dristan Sinus†; Indometacin (BAN, rINN)
Robax Platinum; Sudafed Sinus Advance; Vicks DayQuil Sinus & Pain Relief;
Chile: Adona; Artritapsin; Butartrol; Deucodol Plus; Dioran†; Dolnix; Dolo Indometacina; Indometacinas; Indométacine; Indometacinum; In-
Preparations Winasorb; Dolo-Niofen; Dolo-Octirona; Dolonase; Gedol†; Ibupirac Com- dometacyna; Indometasiini; Indometasin; Indomethacin (USAN).
BP 2008: Ibuprofen Cream; Ibuprofen Gel; Ibuprofen Oral Suspension; Ibu- puesto; Ibupirac Flu; Ipson-D; Midol†; Neo Butartrol; Niofen Flu; Predual [1-(4-Chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid.
profen Tablets; DI†; Silartrin†; Termo-Niofen; Cz.: Advil Cold; Ardinex†; Ibu-Hepa; Ibu-
USP 31: Ibuprofen and Pseudoephedrine Hydrochloride Tablets; Ibuprofen fein†; Modafen; Fin.: Ardinex; Burana-C; Fr.: Anadvil Rhume; Cliptol; Nuro- Индометацин
Oral Suspension; Ibuprofen Tablets. fen Rhume; Rhinadvil; Rhinathiol Rhume†; Rhinureflex; Vicks Rhume†; Gr.: C 19 H 16ClNO 4 = 357.8.
Proprietary Preparations (details are given in Part 3) Nurofen CF; Vicks; Hung.: Advil Cold; Algoflex-M; Deep Relief; Nurofen
Cold & Flu; Rhinathiol Cold; India: Acks; Anaflam; Answell; Bruace; Cipgesic C AS — 53-86-1.
Arg.: Actron; Acuilfem; Afebril; Algioprofen†; Atomo Desinflamante Ibu;
Bistryl†; Brunal†; Butidiona; Causalon Ibu; Copiron; Dolocox†; Dolorsyn; Plus; Combiflam; Duoflam; Duoflam Plus; Emflam Plus; Flexon; Flexon-MR; ATC — C01EB03; M01AB01; M02AA23; S01BC01.
Druisel; Fabogesic; Febratic; Fontol; Ibu; Ibu Evanol; Ibu-Lady†; Ibu-Novalgi- Ibu-Proxyvon; Ibuflamar-P; Ibugesic Plus; Ibugesic-M; Reactine Forte; Re- ATC Vet — QC01EB03; QM01AB01; QM02AA23;
na; Ibubenitol; Ibucalmin; Ibucler; Ibufabra; Ibufix; Ibulam; Ibumar; Ibumultin; ducin-A†; Robiflam; Somaflam; Indon.: Aknil; Axalan; Iremax; Limasip; Neo
Rheumacyl; Neuralgin; Shelrod-Plus; Irl.: Advil Cold & Flu; Codafen Conti- QS01BC01.
Ibup; Ibupirac; Ibupiretas; Ibuprofenix; Ibuprofex; Ibusi; Ibusol; Ibusumal; Ib-
utenk; Ibuxim; Ibuzidine; Kesan†; Matrix; Motrax†; Novo Geniol; Oxibut; nus†; Nurofen Cold & Flu; Nurofen Plus; Israel: Nurofen Cold & Flu; Ital.:
Pakurat; Paraflex Crema†; Ponstil Mujer; Ponstin; Ponstinetas; Salivia; Sindol; Solviflu; Vicks Flu-Action; Jpn: Colgen Kowa IB Toumei; Mex.: Algitrin; Bi-
Teprix; Tonal; Vefren; Austral.: ACT-3; Actiprofen; Advil; Brufen; Bugesic†; pasmin Compuesto NF†; Carbager-Plus; Dualgos; Sinutab Advance; NZ:
Dimetapp Pain & Fever Relief; Hexal Compufen†; Nurofen; Proven; Rafen; Nurofen Cold & Flu; Nurofen Plus; Philipp.: Alaxan; Anoflam; Brustan; O Cl
Tri-Profen; Austria: Advil; Aktren; Avallone; Brufen; Dismenol Neu; Dolgit; Flexigesic; Muskelax; Restolax; Selxan; Pol.: Ardinex; Dip Rilif; Ibalgin Sport;
Dolibu; Dolofort; Duafen; Ibu; Ibudol; Ibufem; Ibugel; Ibumetin; Ibupron; Ibu- Ibuprom Zatoki; Metafen; Modafen; Nurofen Antigrip; Nurofen Plus; Rus.:
rem†; Ibutop; Imbun; Kratalgin; Momento; Nurofen; ratioDolor; Tabcin; Brustan (Брустан); Ibuclin (Ибуклин); Novigan (Новиган); Nurofen Plus
Urem†; Belg.: Adulfen Lysine; Advil Mono; Brufen; Buprophar; Dolofin; Ep- (Нурофен Плюс); S.Afr.: Advil CS; Dentopain; Gen-Payne; Ibucod; Ibumol; N
silon; Extrapan; Ibu-Slow†; Ibumed; Ibutop; Junifen; Malafene; Nurofebryl; Ibupain; Ibupain Forte; Lotem; Mybucod; Mybulen; Mypaid; Myprodol;
Nurofen Cold & Flu; Sinumax IB; Spain: Nurofen Complex; Salvarina; CH3
Nurofen; Optalidon Nieuwe Formule; Perdofemina; Perdophen; Perviam;
Provenol; Siprofen†; Spidifen; Braz.: Actiprofen; Advil; Algiflex; Algy-Flan- Swed.: Ardinex; Switz.: Ibufen-L; Thai.: Alaxan PI; Brustan; Cetan; Dolo-
gen; Kintal†; Rumatifen-Plus; Skelan; Turk.: Nurofen Cold & Flu; UAE: Profi- H3CO
deril†; Alivium; Artril; Dalsy; Doraplax†; Doretrim†; Dorigren; Frenador†;
Ib-Profeno†; Ibufran; Ibupril; Ibuprofan; Lombalgina; Motrin; Parartrin; nal Cold & Sinus; Profinal FM; Profinal XP; UK: Codafen Continus†; Cupro- COOH
Spidufen; Uniprofen; Canad.: Advil; Motrin; Novo-Profen; Chile: Actron; fen Plus; Deep Relief; Lemsip Flu 12Hr; Lemsip Pharmacy Powercaps; Non-
Advil†; Bediatil; Bladex†; Deucodol; Dolorub; Fenpic†; Fortapal; Ibu; Ibu-4†; Drowsy Sudafed Dual Relief Max; Nurofen Cold & Flu; Nurofen Plus; Nuro-
Ibu-6†; Ibupirac; Ipson; Kin; Motrin; Niofen; Pediaprofen; Pironal; Pyriped; fen Sinus; Orbifen Cold & Flu; Solpadeine Migraine; Solpaflex; USA: Advil Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
Tifen†; Cz.: Advil; Baroc; Brufen; Dolgit; Ibalgin; Ibumax; Irfen†; Nurofen; Allergy Sinus; Advil Cold & Sinus; Advil PM; Anadar Cold & Flu; Childrens Viet.
Nurofen Advance; Nurofen Stopgrip; Pabiprofen; Panafen; Pedea; Solpaflex; Advil Cold; Childrens Ibuprofen Cold; Childrens Motrin Cold; Combunox;
Dimetapp Childrens Cold & Fever; Dimetapp Sinus; Dristan Sinus; Ibudone; Ph. Eur. 6.2 (Indometacin). A white or yellow, crystalline pow-
Tomaflex; Urgo; Denm.: Apain; Brufen; Ibumetin; Ibureumin; Ibutop; Ipren; der. Practically insoluble in water; sparingly soluble in alcohol.
Pedea; Solpaflex†; Fin.: Brufen; Burana; Ibumax; Ibumetin; Ibusal; Ibuxin; Fr.: Motrin IB Sinus; Reprexain; Sine-Aid IB; Vicoprofen; Venez.: Brudol; Bruge-
Advil; Anadvil; Antarene; Brufen; Dolgit; Doltaque; Ergix; Expanfen; Ge- sina; Colfene; Femmexultra; Ibucoden. Protect from light.
lufene; Hemagene Tailleur; Ibualgic†; Ibutop; Intralgis; Nureflex; Nurofen; USP 31 (Indomethacin). A pale yellow to yellow-tan, crystalline
Nurofentabs; Nuroflash; Pedea; Solufen; Spedifen; Spifen; Upfen; Ger.: Ad- powder having not more than a slight odour. It exhibits polymor-
vel; Aktren; Contraneural; Dismenol N; Dolgit; Dolo Sanol; Dolo-Puren; phism. Practically insoluble in water; soluble 1 in 50 of alcohol,
Dolodoc; Dolormin; Esprenit; Eudorlin Extra; Eudorlin Migrane; Gyno-Neu-
ralgin; Gynofug†; Ibu; Ibu Benuron; ibu-Attritin; Ibu-ratiopharm; Ibubeta; Ibu- Ibuproxam (rINN) 1 in 30 of chloroform, and 1 in 40 of ether. Protect from light.
dolor; Ibuflam; Ibuhexal; Ibumerck; Ibuphlogont†; Ibuprof†; Ibutad; Ibutop; Stability. Indometacin is unstable in alkaline solution.
Ilvico grippal†; Imbun; Jenaprofen; Kontagripp; Mensoton; Migranin Ibupro- Ibuproxamum. 4-Isobutylhydratropohydroxamic acid.
fen; Novogent†; Nurofen; Optalidon; Opturem; Parsal; Pedea; Pfeil†;
Phamoprofen†; ratioDolor†; Schmerz-Dolgit; Spalt; Tabalon; Tempil†; Tis- Ибупроксам Indometacin Sodium (BANM, rINNM)
pol Ibu-DD; Togal Akut Ibuprofen; Trauma-Dolgit; Urem; Gr.: Advil; Algof- C 13 H 19NO 2 = 221.3.
ren; Brufen; Buscofem; Nurofen; Rozovin†; Hong Kong: Advil; Bifen; Indometacina sódica; Indométacine Sodique; Indomethacin Sodi-
Brufen†; Bupogesic; Dolo-Spedifen†; Ibufac; Ibupen; Neutropain; Nurofen; C AS — 53648-05-8. um (USAN); Indomethacin Sodium Trihydrate; Natrii Indometaci-
Perofen; Profen; Rupan†; Schufen; Spedifen; Hung.: Advil; Algoflex; Dolgit; num. Sodium 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-
Huma-Profen; Ibulos†; Ibumax; Ibutop; Melfen; Nurofen; Solpaflex; Sped- ATC — M01AE13.
ifen; India: Brufen; Butafen†; Cipgesic; Emflam; Ibugesic; Ibupal; Indon.: ATC Vet — QM01AE13. acetate, trihydrate.
Anafen; Arthrifen; Bufect; Dofen; Dolofen-F; Febryn; Fenris; Iprox; Lexapro- Натрий Индометацин
fen; Nofena; Ostarin; Prifen; Profen; Proris; Rhelafen; Ribunal; Shelrofen;
Spedifen; Yariven; Irl.: Advil; Brufen; Bufigen; Fenopine; Ibugel; Melfen; C 19 H 15ClNNaO 4 ,3H 2 O = 433.8.
Nurofen; Phorpain; Proflex; Solfen†; Israel: Adex; Advil; Artofen; Ibufen; C AS — 74252-25-8.
OH CH3
Ibuleve; Nurofen; Ital.: Algofen; Antalfebal; Antalfort; Antalgil; Antalisin; Ar- Pharmacopoeias. In US.
fen; Benflogin; Brufen; Buscofen; Calmine; Cibalgina Due Fast; Dolocyl; HN USP 31 (Indomethacin Sodium). Protect from light.
Dolofast; Edenil; Faspic; Ganaprofene†; Gineflor; Ginenorm; Moment;
Nureflex; Nurofast; Nurofen; Nurosolv; Pedea; Subitene; Zafen†; Malay- CH3
Incompatibility. Indometacin sodium injection is reconstituted
sia: Bifen; Brugesic†; Ibufac; Ibufen†; Nurofen; Perofen; Rupan†; Spedifen; with preservative-free sodium chloride for injection 0.9% or pre-
Mex.: ABKI; Actron; Adivon; Advil; Aflusil; Ainex; Aldofen; Algidol; Bestafen; O
Carone; Citalgan; Dadicil; Days; Dibufen; Dipofen; Diprodol; Dolprin; Dol- CH3 servative-free water for injection. Preparations containing glu-
profen; Dolval; Dolver; Eufenil; Febratic; Fidoin-Q; Flexafen; Gelidol; Gob- cose should not be used; reconstitution at a pH below 6 may
 Ibuproxam/Indometacin 67
cause precipitation of indometacin. Visual incompatibility has indometacin was retinotoxic, although to what degree was uncer- given indometacin and those receiving indometacin
been reported between indometacin sodium injection and tolazo- tain. For reference to effects on the optic nerve associated with should be monitored during treatment for signs of
line hydrochloride,1 7.5 and 10% glucose injection, calcium glu- indometacin, see p.97.
conate, dobutamine, dopamine, cimetidine,2 gentamicin sulfate, 1. Graham CM, Blach RK. Indomethacin retinopathy: case report
bleeding. Electrolytes and renal function should also
levofloxacin,3 and tobramycin sulfate.4 A pH below 6 may ac- and review. Br J Ophthalmol 1988; 72: 434–8. be monitored and if anuria or marked oliguria is evi-
count for the visual incompatibility of indometacin sodium and Effects on the gastrointestinal tract. Nausea, vomiting, dent at the time of a scheduled second or third dose, it
several of these drugs. dyspepsia, gastrointestinal lesions, and serious reactions includ- should be delayed until renal function has returned to
1. Marquardt ED. Visual compatibility of tolazoline hydrochloride ing gastrointestinal bleeding, ulceration, and perforation have normal.
with various medications during simulated Y-site injection. Am J occurred in patients receiving indometacin. Although it is well
Hosp Pharm 1990; 47: 1802–3.
established that NSAIDs can produce adverse effects on the up- False-negative results in the dexamethasone suppres-
2. Ishisaka DY, et al. Visual compatibility of indomethacin sodium sion test have been reported in patients taking indomet-
trihydrate with drugs given to neonates by continuous infusion. per gastrointestinal tract, indometacin and other NSAIDs can
Am J Hosp Pharm 1991; 48: 2442–3. also affect the large intestines.1 Giving indometacin to preterm acin.
3. Saltsman CL, et al. Compatibility of levofloxacin with 34 medi- neonates increases the risk of small bowel perforation and necr-
Breast feeding. Convulsions in a one-week old breast-fed in-
cations during simulated Y-site administration. Am J Health-Syst otising enterocolitis.2-4 Risk seems to be increased in very-low-
Pharm 1999; 56: 1458–90. fant appeared to be associated with maternal ingestion of in-
birth-weight or extremely premature infants.
4. Thompson DF, Heflin NR. Incompatibility of injectable in- dometacin;1 the child had normal motor and mental development
1. Oren R, Ligumsky M. Indomethacin-induced colonic ulceration
domethacin with gentamicin sulfate or tobramycin sulfate. Am J
and bleeding. Ann Pharmacother 1994; 28: 883–5.
at the age of 1 year and seizures had not recurred.
Hosp Pharm 1992; 49: 836–8. Indometacin has been detected in breast milk, but some
2. Grosfeld JL, et al. Increased risk of necrotizing enterocolitis in
Stability. A reconstituted solution of indometacin sodium premature infants with patent ductus arteriosus treated with in- workers2,3 and the BNF consider that the amount is so small that
500 micrograms/mL was stable for 14 days when stored at 2° to domethacin. Ann Surg 1996; 224: 350–7. it should not constitute a contra-indication to breast feeding. The
6° in either the manufacturer’s original glass vial or in a polypro- 3. Shorter NA, et al. Indomethacin-associated bowel perforations: American Academy of Pediatrics4 also states that indometacin is
a study of possible risk factors. J Pediatr Surg 1999; 34: 442–4.
pylene syringe.1 4. Fujii AM. Neonatal necrotizing enterocolitis with intestinal per-
usually compatible with breast feeding despite acknowledging
1. Walker SE, et al. Stability of reconstituted indomethacin sodium foration in extremely premature infants receiving early in- the above case report of convulsions. However, licensed product
trihydrate in original vials and polypropylene syringes. Am J domethacin treatment for patent ductus arteriosus. J Perinatol information recommends that indometacin should not be used in
Health-Syst Pharm 1998; 55: 154–8. 2002; 22: 535–40. nursing mothers.
Effects on the joints. For references to concern that NSAIDs 1. Eeg-Olofsson O, et al. Convulsions in a breast-fed infant after
Adverse Effects and Treatment such as indometacin may accelerate the rate of cartilage destruc- maternal indomethacin. Lancet 1978; ii: 215.
2. Beaulac-Baillargeon L, Allard G. Distribution of indomethacin
As for NSAIDs in general, p.96. tion in patients with osteoarthritis, see Effects on Bone, under in human milk and estimation of its milk to plasma ratio in vitro.
Adverse effects are more frequent with indometacin NSAIDs, p.96. Br J Clin Pharmacol 1993; 36: 413–16.
Effects on the kidneys. Acute renal failure,1 nephrotic syn- 3. Lebedevs TH, et al. Excretion of indomethacin in breast milk. Br
than with many other NSAIDs, the most common be- J Clin Pharmacol 1991; 32: 751–4.
ing gastrointestinal disturbances, headache, vertigo, drome,2 and renal papillary necrosis3 have been reported in pa- 4. American Academy of Pediatrics. The transfer of drugs and oth-
tients given indometacin. There have been suggestions that miso- er chemicals into human milk. Pediatrics 2001; 108: 776–89.
dizziness, and lightheadedness. Gastrointestinal perfo- prostol might reduce the risk of indometacin-induced renal tox- Correction. ibid.; 1029. Also available at:
ration, ulceration, and bleeding may also occur; rarely, icity.4,5 h t tp : / /a a p po l i c y. a a pp u b l ica ti o n s .o rg/ c g i / c o nt e n t / f u ll /
intestinal strictures have been reported. Other adverse pediatrics%3b108/3/776 (accessed 07/11/07)
Renal impairment has also occurred in neonates given indomet-
effects include depression, drowsiness, tinnitus, confu- acin intravenously for patent ductus arteriosus. Although rare, The elderly. After a study1 of the pharmacokinetics of indomet-
sion, insomnia, psychiatric disturbances, syncope, con- and usually reversible, the effect may be serious in neonates with acin in the elderly it was suggested that the maintenance dose of
pre-existing renal disorders.6 Serious or fatal renal toxicity has indometacin in elderly patients should be reduced by 25%. The
vulsions, coma, peripheral neuropathy, blurred vision, been reported in neonates exposed to indometacin due to mater- total clearance of indometacin in elderly subjects had been re-
corneal deposits and other ocular effects, oedema and nal ingestion.7 The renal effects of prenatal indometacin may be duced when compared with that in young subjects; this was
weight gain, hypertension, haematuria, skin rashes, prolonged.8 thought to be due to reduced hepatic metabolism in the elderly.
pruritus, urticaria, stomatitis, alopecia, and hypersensi- 1. Chan X. Fatal renal failure due to indomethacin. Lancet 1987; ii: 1. Oberbauer R, et al. Pharmacokinetics of indomethacin in the eld-
340. erly. Clin Pharmacokinet 1993; 24: 428–34.
tivity reactions. Leucopenia, purpura, thrombocytope- 2. Boiskin I, et al. Indomethacin and the nephrotic syndrome. Ann
nia, aplastic anaemia, haemolytic anaemia, agranulo- Intern Med 1987; 106: 776–7.
Pregnancy. See Premature Labour under Uses and Administra-
3. Mitchell H, et al. Indomethacin-induced renal papillary necrosis tion, below.
cytosis, epistaxis, hyperglycaemia, hypoaldosteronism in juvenile chronic arthritis. Lancet 1982; ii: 558–9.
and hyperkalaemia, and vaginal bleeding have been re- 4. Weir MR, et al. Minimization of indomethacin-induced reduc- Interactions
ported. There have also been reports of hepatitis, jaun- tion in renal function by misoprostol. J Clin Pharmacol 1991;
For interactions associated with NSAIDs, see p.99.
31: 729–35.
dice, and renal failure. Hypersensitivity reactions may 5. Wong F, et al. The effect of misoprostol on indomethacin-in- Anti-inflammatory doses of aspirin decrease indomet-
also occur in aspirin-sensitive patients. Rectal irritation duced renal dysfunction in well-compensated cirrhosis. J Hepa-
tol 1995; 23: 1–7. acin blood concentrations by about 20%. Diflunisal de-
and bleeding has been reported occasionally in patients 6. Cuzzolin L, et al. NSAID-induced nephrotoxicity from the fetus creases the renal clearance and increases plasma con-
who have received indometacin suppositories. to the child. Drug Safety 2001; 24: 9–18.
7. van der Heijden BJ, et al. Persistent anuria, neonatal death, and centrations of indometacin. Use of diflunisal with
Adverse effects associated with the use of indometacin renal microcystic lesions after prenatal exposure to indometh- indometacin has also resulted in fatal gastrointestinal
injection in premature neonates may also include acin. Am J Obstet Gynecol 1994; 171: 617–23. haemorrhage, and the two should not be used together.
haemorrhagic, renal, gastrointestinal, metabolic, and 8. Butler-O’Hara M, D’Angio CT. Risk of persistent renal insuffi-
ciency in premature infants following the prenatal use of in- Plasma concentrations of indometacin are likely to be
coagulation disorders; pulmonary hypertension, intrac- domethacin for suppression of preterm labor. J Perinatol 2002; increased in patients receiving probenecid.
ranial bleeding, fluid retention, and exacerbation of in- 22: 541–6.
Antibacterials. Indometacin has been reported to increase
fection may also occur. Effects on the liver. Cholestasis occurred in a 52-year-old
plasma concentrations of aminoglycosides.
woman several days after starting indometacin;1 liver function
Effects on the blood. There were 1261 reports of adverse re- values returned to normal once indometacin was stopped. Antipsychotics. Severe drowsiness and confusion have been
actions to indometacin reported to the UK CSM between June 1. Cappell MS, et al. Indomethacin-associated cholestasis. J Clin reported in patients given haloperidol with indometacin.1
1964 and January 1973. These included 157 reports of blood dis- Gastroenterol 1988; 10: 445–7. 1. Bird HA, et al. Drowsiness due to haloperidol/indomethacin in
orders (25 fatal) including thrombocytopenia (35; 5 fatal), aplas- combination. Lancet 1983; i: 830–1.
tic anaemia (17; no fatalities), and agranulocytosis or leucopenia Hypersensitivity. Hypersensitivity reactions including acute
(21; 3 fatal).1 Subsequently, the First Report from the Interna- asthma have been reported after use of indometacin supposito- Bone modulating drugs. Indometacin has been reported to
tional Agranulocytosis and Aplastic Anemia Study confirmed a ries,1 eye drops,2 or capsules3 by patients who were aspirin-sen- increase the bioavailability of tiludronate, see p.1106.
significant relationship between the use of indometacin and sitive or had a history of asthma. Desmopressin. The effect of desmopressin may be enhanced
agranulocytosis and aplastic anaemia.2 Neutropenia has also 1. Timperman J. A fatal asthmatic attack following administration by indometacin.
of an indomethacin suppository. J Forensic Med 1971; 18: 30–2.
been noted in a premature infant with patent ductus arteriosus 2. Sheehan GJ, et al. Acute asthma attack due to ophthalmic in-
after use of indometacin.3 Digoxin. In addition to increasing digoxin serum concentrations
domethacin. Ann Intern Med 1989; 111: 337–8. (see p.1263), combination of digoxin with indometacin has been
Although use of indometacin in 20 women being treated for pre- 3. Johnson NM, et al. Indomethacin-induced asthma in aspirin-sen- reported to reduce the half-life of the latter in premature neonates
mature labour did not affect maternal prothrombin or activated sitive patients. BMJ 1977; 2: 1291.
(see Half-life under Pharmacokinetics, below).
partial thromboplastin time, maternal bleeding time during ther-
apy was increased.4 However, no cases of neonatal intraventricu- Precautions Parasympathomimetics. The manufacturer of acetylcholine
lar haemorrhage or maternal postpartum haemorrhage were As for NSAIDs in general, p.98. chloride ophthalmic preparations has stated that there have been
seen. reports that acetylcholine and carbachol have been ineffective
1. Cuthbert MF. Adverse reactions to non-steroidal antirheumatic
Indometacin should be used with caution in patients when used in patients treated with topical (ophthalmic) NSAIDs.
drugs. Curr Med Res Opin 1974; 2: 600–10. with epilepsy, parkinsonism, or psychiatric disorders.
2. The International Agranulocytosis and Aplastic Anemia Study. Dizziness may affect the performance of skilled tasks Pharmacokinetics
Risks of agranulocytosis and aplastic anemia: a first report of
their relation to drug use with special reference to analgesics. such as driving. Patients on long-term indometacin Indometacin is readily absorbed from the gastrointesti-
JAMA 1986; 256: 1749–57. therapy should be examined regularly for adverse ef- nal tract in adults; peak plasma concentrations are
3. Bengtsson B-OS, et al. Indomethacin-associated neutropenia fects, and the BNF particularly recommends periodic reached about 2 hours after a dose. Absorption may be
with subsequent Gram-negative sepsis in a preterm infant: cause
or coincidence? J Perinatol 2006; 26: 381–3. blood and ophthalmic examinations. Rectal use should slowed by food or by aluminium- or magnesium-con-
4. Lunt CC, et al. The effect of indomethacin tocolysis on maternal be avoided in patients with proctitis and haemorrhoids. taining antacids. In premature neonates, absorption of
coagulation status. Obstet Gynecol 1994; 84: 820–2.
In addition indometacin should not be given to oral indometacin is poor and incomplete. The bioavail-
Effects on cerebral blood flow. See Patent Ductus Arteriosus ability of rectal suppositories in adults has been report-
under Uses and Administration, below. neonates with untreated infection, with significant re-
nal impairment, or with necrotising enterocolitis. In- ed to be comparable with or slightly less than the bioa-
Effects on the eyes. Severe and irreversible retinopathy, pre- vailability with oral dosage forms.
sumably due to long-term ingestion of high doses of indometacin
fants who are bleeding (especially gastrointestinal
occurred in a 33-year-old man.1 A summary of previous litera- bleeding or intracranial haemorrhage) or who have Indometacin is about 99% bound to plasma proteins. It
ture reports of indometacin-induced ocular effects indicated that thrombocytopenia or coagulation defects should not be is distributed into synovial fluid, the CNS, and placen-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
68 Analgesics Anti-inflammatory Drugs and Antipyretics
ta. Low concentrations have been distributed into oral dose of 0.5 to 1 mg/kg twice daily in those aged 1 month to severe intraventricular haemorrhage were considered; however,
breast milk. The terminal plasma half-life has been re- 18 years; higher doses may sometimes be required. when outcomes were considered individually, there was a signif-
Indometacin is also used in the treatment of patent ductus arte- icant reduction in intraventricular haemorrhage in boys when
ported to range from 2.6 to 11.2 hours in adults. The compared with girls. The authors considered the results to be a
riosus in premature infants; see below for further details includ-
terminal half-life in neonates has been reported to be ing doses. consequence of an unfavourable effect of indometacin in girls
between 12 and 28 hours (see also below). Indomet- rather than any positive effects in boys. Any true difference in
Bartter’s syndrome. The treatment of Bartter’s syndrome can effect between the sexes remains to be confirmed.
acin is metabolised in the liver to its glucuronide con- often be difficult (see p.1670). Blocking the kinin-prostaglandin
jugate and to desmethylindomethacin, desbenzoylin- axis with a cyclo-oxygenase inhibitor such as indometacin im- Indometacin does not appear to prevent the progression of exist-
domethacin, desmethyl-desbenzoylindomethacin, and proves hypokalaemia and other clinical features (including ing haemorrhage.13
growth retardation) in children with the syndrome.1-5 1. Ment LR, et al. Randomized indomethacin trial for prevention
to their glucuronides. Some indometacin undergoes N- of intraventricular hemorrhage in very low birth weight infants.
deacylation. Indometacin and its conjugates undergo 1. Littlewood JM, et al. Treatment of childhood Bartter’s syndrome J Pediatr 1985; 107: 937–43.
with indomethacin. Lancet 1976; ii: 795. 2. Rennie JM, et al. Early administration of indomethacin to pre-
enterohepatic circulation. Excretion of indometacin 2. Seidel C, et al. Pre-pubertal growth in the hyperprostaglandin E term infants. Arch Dis Child 1986; 61: 233–8.
and its metabolites is mainly in the urine with lesser syndrome. Pediatr Nephrol 1995; 9: 723–8. 3. Bada HS, et al. Indomethacin reduces the risks of severe intra-
3. Craig JC, Falk MC. Indomethacin for renal impairment in neo- ventricular hemorrhage. J Pediatr 1989; 115: 631–7.
amounts appearing in the faeces. natal Bartter’s syndrome. Lancet 1996; 347: 550. 4. Ment LR, et al. Low-dose indomethacin and prevention of intra-
4. Mourani CC, et al. Bartter syndrome in a neonate: early treat- ventricular hemorrhage: a multicenter randomized trial. Pediat-
◊ References. ment with indomethacin. Pediatr Nephrol 2000; 14: 143–5. rics 1994; 93: 543–50.
1. Moise KJ, et al. Placental transfer of indomethacin in the human 5. Vaisbich MH, et al. Bartter syndrome: benefits and side effects 5. Volpe JJ. Brain injury caused by intraventricular hemorrhage: is
pregnancy. Am J Obstet Gynecol 1990; 162: 549–54. of long-term treatment. Pediatr Nephrol 2004; 19: 858–63. indomethacin the silver bullet for prevention? Pediatrics 1994;
2. Mannila A, et al. Plasma and cerebrospinal fluid concentrations 93: 673–7.
Diabetes insipidus. Indometacin and other prostaglandin syn- 6. Ment LR, et al. Neurodevelopmental outcome at 36 months’
of indomethacin in children after intravenous administration. J thetase inhibitors have been reported to decrease urine volume in
Clin Pharmacol 2007; 47: 94–100. corrected age of preterm infants in the multicenter indomethacin
all types of nephrogenic diabetes insipidus (p.2179). intraventricular hemorrhage prevention trial. Pediatrics 1996;
Half-life. The plasma half-life of indometacin in premature in- References. 98: 714–18.
7. Ment LR, et al. Outcome of children in the indomethacin intra-
fants can be variable but appears to be inversely proportional to 1. Rosen GH, et al. Indomethacin for nephrogenic diabetes insipid- ventricular hemorrhage prevention trial. Pediatrics 2000; 105:
post-natal age and weight.1,2 One population model suggests that us in a four-week-old infant. Clin Pharm 1986; 5: 254–6. 485–91.
for an infant of 1.17 kg, half-life would be 22.3 hours at a post- 2. Libber S, et al. Treatment of nephrogenic diabetes insipidus with 8. Vohr BR, et al. School-age outcomes of very low birth weight
natal age of 8 days, but 16.1 hours at 25 days (and only prostaglandin synthesis inhibitors. J Pediatr 1986; 108: 305–11. infants in the indomethacin intraventricular hemorrhage preven-
3. Allen HM, et al. Indomethacin in the treatment of lithium-in- tion trial. Abstract: Pediatrics 2003; 111: 874. Full version:
11.2 hours if also receiving digoxin).2 duced nephrogenic diabetes insipidus. Arch Intern Med 1989; http://pediatrics.aappublications.org/cgi/content/full/111/4/
1. Wiest DB, et al. Population pharmacokinetics of intravenous in- 149: 1123–6. e340 (accessed 07/11/07)
domethacin in neonates with symptomatic patent ductus arterio- 4. Martinez EJ, et al. Lithium-induced nephrogenic diabetes insip- 9. Schmidt B, et al. Long-term effects of indomethacin prophylax-
sus. Clin Pharmacol Ther 1991; 49: 550–7. idus treated with indomethacin. South Med J 1993; 86: 971–3. is in extremely-low-birth-weight infants. N Engl J Med 2001;
2. Smyth JM, et al. Intravenous indometacin in preterm infants 5. Hohler T, et al. Indomethacin treatment in amphotericin B in- 344: 1966–72.
with symptomatic patent ductus arteriosus: a population pharma- duced nephrogenic diabetes insipidus. Clin Investig 1994; 72: 10. Fowlie PW, Davis PG. Prophylactic indomethacin for preterm
cokinetic study. Br J Clin Pharmacol 2004; 58: 249–58. 769–71. infants: a systematic review and meta-analysis. Arch Dis Child
6. Lam SS, Kjellstrand C. Emergency treatment of lithium-induced Fetal Neonatal Ed 2003; 88: F464–F466.
diabetes insipidus with nonsteroidal anti-inflammatory drugs. 11. Ment LR, et al. Prevention of intraventricular hemorrhage by
Uses and Administration Ren Fail 1997; 19: 183–8. indomethacin in male preterm infants. J Pediatr 2004; 145:
832–4.
Indometacin, an indole acetic acid derivative, is an Malignant neoplasms. In common with some other NSAIDs 12. Ohlsson A, et al. Male/female differences in indomethacin ef-
NSAID (p.99). It is used in musculoskeletal and joint (see p.100) it has been suggested that indometacin might possess fects in preterm infants. J Pediatr 2005; 147: 860–2.
disorders including ankylosing spondylitis, osteoar- some antineoplastic activity.1 Some NSAIDs such as indomet- 13. Ment LR, et al. Low-dose indomethacin therapy and extension
acin may also be of value for the differential diagnosis and the of intraventricular hemorrhage: a multicenter randomized trial.
thritis, rheumatoid arthritis, and acute gout, and in peri- management of neoplastic fever, as they appear to be more effec- J Pediatr 1994; 124: 951–5.
articular disorders such as bursitis and tendinitis. It tive in reducing this type of fever than against fever associated Patent ductus arteriosus. In the fetal circulation the ductus
may also be used in inflammation, pain, and oedema with infections.2 Indometacin has also been tried for the treat- arteriosus connects the pulmonary artery and the descending aor-
following orthopaedic procedures, in mild to moderate ment of fever and flu-like symptoms associated with interleukin- ta. After birth, various mechanisms, including a fall in prosta-
pain in conditions such as dysmenorrhoea, and it has 2 therapy although there has been concern over exacerbation of glandin concentration, trigger its closure but in some infants the
renal toxicity (see NSAIDs, under Interactions, p.736). ductus arteriosus fails to close, a condition known as persistent
been used in the management of postoperative pain as 1. Mertens WC, et al. Effect of indomethacin plus ranitidine in ad- patent ductus arteriosus. This condition may be found in infants
an adjunct to opioids, and in the treatment of fever. In- vanced melanoma patients on high-dose interleukin-2. Lancet with congenital heart defects but is more commonly seen in pre-
dometacin is also used as the sodium salt to close pat- 1992; 340: 397–8. mature neonates, especially those with respiratory distress syn-
2. Engervall P, et al. Antipyretic effect of indomethacin in malig- drome.
ent ductus arteriosus in premature infants (see below). nant lymphoma. Acta Med Scand 1986; 219: 501–5.
• Some infants may be asymptomatic or have only slight clini-
The usual initial oral dose in chronic musculoskeletal Neonatal intraventricular haemorrhage. Indometacin has cal symptoms and no immediate intervention is required. In
and joint disorders is 25 mg two or three times daily been tried prophylactically to prevent the development of intra- many cases spontaneous closure will occur after several
increased, if required, by 25 to 50 mg at weekly inter- ventricular haemorrhage in neonates at risk (see p.1050). Several months, or else surgical ligation may be performed if clinical
mechanisms have been proposed for its possible action including symptoms persist.
vals to 150 to 200 mg daily. To alleviate night pain and reduction of cerebral flow as a result of vasoconstriction, reduc-
morning stiffness, up to 100 mg of the total daily dose • In some infants a patent ductus arteriosus is necessary for
tion of oxygen free-radical damage, and accelerated maturation
maintaining some oxygenation of the blood, for example in
may be given orally, or rectally as a suppository, on re- of blood vessels around the ventricles. Early studies1-3 of the use
pulmonary artery atresia or transposition of the great arteries.
tiring. Alternatively, the total daily dose may be given of indometacin for prevention of intraventricular haemorrhage
These infants require treatment with a prostaglandin such as
produced conflicting results. A subsequent large multicentre
rectally as 100 mg in the morning and at night. The study4 (the Indomethacin Intraventricular Haemorrhage Preven-
alprostadil or dinoprostone to maintain patency of the ductus
total daily combined oral and rectal dose should not ex- arteriosus until surgery can be performed to correct the mal-
tion Trial, IIHP) suggested that indometacin could reduce the
ceed 200 mg. In acute gout the daily dose is 150 to formation.
incidence and severity of intraventricular haemorrhage, especial-
200 mg in divided doses until all symptoms and signs ly for the more severe forms. Neonates with a birth-weight of • Infants with haemodynamically significant ductus arteriosus,
600 to 1250 g were given indometacin in a dose of signs of heart failure, and who require ventilation should un-
subside; in dysmenorrhoea up to 75 mg daily has been dergo treatment to close the patent ductus arteriosus.
100 micrograms/kg intravenously at 6 to 12 hours after delivery
suggested. Modified-release preparations of indomet- and then every 24 hours for 2 additional doses. There was, how- Initial management involves fluid restriction, diuretics, correc-
acin are available for use once or twice daily. For doses ever, concern5 that an unusually large number of neonates with tion of anaemia, and support of respiration. Chlorothiazide and
in children, see below. severe intraventricular haemorrhage in the control group might furosemide are diuretics commonly used. There has been con-
have biased the findings. cern that furosemide might delay closure in infants with respira-
Indometacin has been used as eye drops, usually of 0.1 A concern with the use of indometacin is the possibility that it tory distress syndrome.1,2 A systematic review3 concluded that
or 0.5%, to prevent miosis during cataract surgery; may produce cerebral ischaemia due to its vasoconstrictor action this did not seem to be the case, and that the diuretic might reduce
the usual dose is 2 drops, repeated after 2 hours, on the and therefore increase the risk of developmental handicaps. Fol- adverse renal effects of indometacin; however, the evidence for
day before surgery, then 2 drops 3 hours before and 2 low-up at 3 years,6 at 4 ⁄ years,7 and at 8 years of age8 in the this was limited and it was felt that there was not enough evi-
infants included in the IIHP study reported no adverse effects on dence to support the use of furosemide in infants treated with
drops 1 hour before surgery. The eye drops may then be indometacin.
cognitive or motor development. However, another large multi-
instilled up to 6 times daily postoperatively to prevent centre study9 (the Trial of Indomethacin Prophylaxis in Preterms, If initial treatment fails to control symptoms after 24 to 48 hours
cystoid macular oedema; treatment should be contin- TIPP) in extremely-low-birth-weight infants (less than 1000 g) then indometacin is generally given to promote closure of the
ued until inflammatory signs have disappeared. In- found that although indometacin reduced the incidence of severe ductus.1,4-6 The benefits of treatment with indometacin as soon as
dometacin eye drops have also been used in other in- haemorrhage, it did not improve survival without neurosensory symptoms become apparent, rather than delaying treatment until
impairment at 18 months. A subsequent systematic review10 also signs of congestive failure develop, have been debated.7,8 Early
flammatory eye disorders in doses similar to those used concluded that indometacin prophylaxis did not improve surviv- treatment may significantly reduce the morbidities arising from
to prevent oedema. al free of neurosensory disability although, again, the incidence a persistent patent ductus arteriosus.7 However, delaying treat-
Meglumine indometacin and indometacin farnesil, of severe intraventricular haemorrhage was reduced. ment until the end of the first week of life can allow for sponta-
Further analysis of the data from the IIHP study has suggested neous closure and avoid the need of exposing infants to the toxic
a lipid soluble ester of indometacin effects of indometacin.8
that indometacin might reduce intraventricular haemorrhage in
(C34H40ClNO4 = 562.1), have also been given for boys but have little effect in girls;11 verbal scores at ages 3 to 8 Indometacin probably leads to closure of the ductus through in-
painful and inflammatory conditions. A complex of in- years were also higher in those boys treated with indometacin hibition of prostaglandin synthesis. It is given as the sodium salt
dometacin and L-arginine, known as indoarginine, has when compared to a control group of boys treated with saline; no in three intravenous doses at 12- to 24-hour intervals; each dose
also been used. differences in scores were noted in indometacin-treated girls and should be infused over 20 to 30 minutes. Indometacin sodium
their control group. Re-analysis of data from the TIPP study12 in injection is reconstituted with preservative-free sodium chloride
Administration in children. Although indometacin is not li- extremely-low-birth-weight neonates suggested a weak gender 0.9% for injection or water for injection; glucose solutions
censed in the UK for the treatment of rheumatic diseases such difference in the effect of indometacin treatment when all prima- should not be used (see Incompatibility, above). The dose of in-
as juvenile idiopathic arthritis in children, the BNFC suggests an ry outcomes such as death, cerebral palsy, cognitive delay, and dometacin sodium (expressed as indometacin) depends upon the
 Indometacin/Infliximab 69
age of the neonate and the following doses have been suggested 16. Ohlsson A, et al. Ibuprofen for the treatment of patent ductus Preparations
based upon the age at the first dose: arteriosus in preterm and/or low birth weight infants. Available
in The Cochrane Database of Systematic Reviews; Issue 1. BP 2008: Indometacin Capsules; Indometacin Suppositories;
• less than 48 hours old: 200 micrograms/kg initially followed Chichester: John Wiley; 2008 (accessed 16/07/08). USP 31: Indomethacin Capsules; Indomethacin Extended-release Cap-
by two further doses of 100 micrograms/kg each sules; Indomethacin for Injection; Indomethacin Oral Suspension; In-
17. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent duc- domethacin Suppositories; Indomethacin Topical Gel.
• 2 to 7 days old: three doses of 200 micrograms/kg each tus arteriosus in preterm and/or low birth weight infants. Avail-
able in The Cochrane Database of Systematic Reviews; Issue 1. Proprietary Preparations (details are given in Part 3)
• over 7 days old: 200 micrograms/kg initially followed by two Chichester: John Wiley; 2006 (accessed 07/11/07). Arg.: Agilex; IM 75; Indotex; Klonametacina; Austral.: Arthrexin; Indocid;
further doses of 250 micrograms/kg each 18. Heyman E, et al. Closure of patent ductus arteriosus with oral Indocid PDA; Austria: Flexidin; Indo; Indobene; Indocid; Indocollyre; Indo-
ibuprofen suspension in premature newborns: a pilot study. hexal; Indomelan; Indoptol; Liometacen; Luiflex; Ralicid; Belg.: Dolcidium;
If, 48 hours after this course of therapy the ductus remains open Indocid; Indocollyre; Luiflex; Braz.: Agilisin; Indocid; Indocid Colirio†; Meta-
Pediatrics 2003; 112: 1170.
or re-opens, a second course may be used, but if this produces no Full version: http://pediatrics.aappublications.org/cgi/reprint/ cidil†; Canad.: Indocid PDA; Indocid†; Indotec†; Novo-Methacin; Nu-Indo;
response (which may be the case in 25% of infants treated4,9) 112/5/e354.pdf (accessed 07/11/07) Rhodacine; Chile: Flexono; Moviflex; Cz.: Bonidon†; Elmetacin; Indobene;
surgery may be necessary. Indocollyre; Vonum Cutan; Denm.: Confortid; Indocid†; Fin.: Confortid;
Polyhydramnios. Reports1-3 of the beneficial effects of in- Indocid; Indometin; Fr.: Chrono-Indocid; Indocid; Indocollyre; Ger.: Confor-
Indometacin has been given orally where the injection is unavail- dometacin in the management of polyhydramnios (an excessive tid; Elmetacin; Indo; Indo Top; Indo-paed; Indo-Phlogont†; Indocolir; Indo-
able, but absorption of oral indometacin is poor and incomplete contin†; Indomet-ratiopharm; Indomet-ratiopharm m†; Indomet†; Indomis-
accumulation of amniotic fluid). Polyhydramnios is a feature of al†; Inflam; Mobilat Akut Indo; Rheubalmin Indo; Sigadoc†; Gr.: Begincalm†;
in premature neonates. the neonatal variant of Bartter’s syndrome (see also above). Dolcispray; Fortathrine; Hastel; Indocid; Indomethol; Itapredin; Reumacid;
A decreased need for surgical closure and reduced recurrences 1. Cabrol D, et al. Treatment of symptomatic polyhydramnios with Reumadolor; Hong Kong: Indocid; Indocin PDA; Indocollyre; Indogesic†;
were seen in neonates in whom standard intravenous indomet- indomethacin. Eur J Obstet Gynecol Reprod Biol 1996; 66: Indomet†; Hung.: Elmetacin; Indobene; Indocollyre; India: Idicin†; Indocap;
acin therapy was then followed by maintenance therapy (intrave- 11–15. Indocid; Indon.: Dialon; Irl.: Cidomel†; Flexin Continus; Indocid PDA; In-
docid†; Israel: Indocollyre; Indomed; Indoptic†; Indotard; Indovis; Ital.: Im-
nous indometacin 200 micrograms/kg daily for an additional 5 2. Abhyankar S, Salvi VS. Indomethacin therapy in hydramnios. J et†; Indocid; Indocollirio; Indom; Indoxen; Liometacen; Metacen; Jpn: Ca-
days).10 Prolonged therapy using high doses of up to 1 mg/kg as Postgrad Med 2000; 46: 176–8. tlep; Idomethine; Infree; Malaysia: Arthrexin†; Domicap†; Indo; Indocid†;
a single dose every 12 hours has also been used with some 3. Kriplani A, et al. Indomethacin therapy in the treatment of poly- Indomen; Mex.: Antalgin; Artaxol; Biometacin; Draxil; Grindocin†; Indaflex;
success in a few infants who have not responded to standard hydramnios due to placental chorioangioma. J Obstet Gynaecol Indocarsil; Indocid; Indoman; Indotrin; Italon; Labymetacyn†; Malival; Mefazil;
Res 2001; 27: 245–8. Soltacina; Stratasin; Neth.: Dometin†; Indocid; Indocid PDA; Indocollyre;
regimens.11 Similar beneficial findings were reported12 in Indoptol†; Norw.: Confortid; Indocid; NZ: Arthrexin; Elmetacin†; Indocid
infants given prolonged low-dose indometacin therapy Premature labour. The most common approach to postpon- PDA; Rheumacin; Philipp.: Infree; Vi-Gel; Pol.: Elmetacin; Indocollyre;
(100 micrograms/kg daily for 6 days). An additional benefit was ing premature labour (p.2003) with drugs has historically been Metindol; Port.: Autritis; Dolovin; Elmetacin; Indocid; Indocollyre; Indogel;
a lower incidence of adverse effects; fewer infants had a rise in Indospray; Reumacide; Rus.: Indomin (Индомин); Indotard (Индотард)†;
with a selective beta2 agonist. However, as prostaglandins have a Indovis (Индовис)†; Metindol (Метиндол); S.Afr.: Acuflex; Adco-Indogel;
serum creatinine or urea concentrations. However, a systematic role in uterine contraction and cervical ripening and dilatation, Aflamin; Arthrexin; Betacin; Elmetacin; Flamaret; Flamecid; Indocid; Medi-
review13 has suggested that such regimens are no more effective prostaglandin synthetase inhibitors such as indometacin have flex†; Methocaps; Nisaid; Restameth-SR†; Singapore: Indo; Indocollyre; In-
than the shorter standard regimens, and found an increased rather also been used. Comparative studies1,2 have shown that indomet- domen; Spain: Aliviosin; Artrinovo; Flogoter; Inacid; Indocaf; Indolgina; In-
than decreased incidence of adverse effects (including a trend to- donilo; Mederreumol†; Neo Decabutin; Reumo†; Reusin; Swed.:
acin and ritodrine are equally effective in inhibiting uterine con- Confortid; Indomee; Switz.: Bonidon; Elmetacin; Indo-Mepha†; Indocid; In-
wards increased risk of necrotising enterocolitis1,6). Prolonged tractions and delaying delivery in patients in preterm labour who dophtal; Thai.: Ammi-Indocin; Bucin†; Docin; Elmego; Elmetacin; Idc; Indo-
treatment with indometacin could not be recommended.13 Pro- have intact membranes and in whom the gestational age is less cid; Indocin; Indocollyre; Indomed; Indono; Inflamate; Inthacine; Liometacen;
phylactic treatment or treatment of asymptomatic ductus with in- than or equal to 34 weeks. In one study2 an initial oral loading Metindo; Satogesic; Turk.: Endol; Endosetin; Indocolir; Inomet; UAE: Roth-
dometacin has been tried in premature infants, and there is good dose of indometacin 50 mg was given, followed by 25 to 50 mg acin; UK: Flexin Continus†; Indocid PDA; Indocid†; Indolar SR; Indomax†;
evidence to suggest that this is effective in reducing the risk of Indomod†; Pardelprin; Rimacid; Slo-Indo; USA: Indocin; Venez.: Cevimin;
orally every 4 hours until contractions stopped and then by a Elmetacin; Indocid; Melior†; Romazulan†.
symptomatic patent ductus arteriosus and intraventricular haem- maintenance dose of 25 mg every 4 to 6 hours. In the other com-
orrhage (see above) in such patients;7,14,15 however, prophylactic Multi-ingredient: Austria: Vonum; Fin.: Indalgin; Fr.: Indobiotic; Ger.:
parative study1 indometacin was given as a 100-mg rectal sup- Inflam†; Ital.: Difmetre; Jpn: Vantelin; Mex.: Artridol; Malival Compuesto;
treatment has not been shown to significantly reduce the risk of pository followed by 25 mg orally every 4 hours for 48 hours; if Morlan; Reupat; Port.: Indobiotic; Rus.: Indovasin (Индовазин); Spain:
short-term pulmonary complications such as bronchopulmonary regular uterine contractions persisted 1 to 2 hours after the initial Artri; Fiacin; Switz.: Indobiotic†; Ralur†; Turk.: Indobiotic.
dysplasia. Systematic reviews14,15 have also found no evidence suppository, an additional 100-mg suppository was given before
of either benefit or harm in neurological development or other beginning oral therapy. Terbutaline was given for maintenance
longer term outcomes. therapy.
Some other NSAIDs have also been tried in the treatment of pat- Unfortunately indometacin can constrict the ductus arteriosus,3-5
Infliximab (BAN, rINN)
ent ductus arteriosus. Ibuprofen appears to be effective in closing which may lead to pulmonary hypertension,2 and has also been cA2; CenTNF; Infliksimab; Infliksimabi; Infliximabum. Immu-
a patent ductus arteriosus,16 and it has been suggested that ibu- associated with bronchopulmonary dysplasia,6 reduced volume
profen might be a better choice than indometacin as, unlike in- noglobulin G (human-mouse monoclonal cA2 heavy chain anti-
of amniotic fluid (oligohydramnios)2,4 and possible renal dam- human tumor necrosis factor), disulfide with human-mouse
dometacin, it does not have adverse effects on renal, mesenteric, age (see Effects on the Kidneys, above) in the fetus. Another
and cerebral haemodynamics. However, a recent systematic monoclonal cA2 light chain, dimer.
complication is that prenatal indometacin exposure may increase
review16 found no significant difference in the effectiveness of both the incidence and severity of patent ductus arteriosus in pre- Инфликсимаб
ibuprofen compared to indometacin and, although the risk of ol- mature infants,7,8 as shown by the increased need for post-natal C AS — 170277-31-3.
iguria was reduced with ibuprofen, the risk for chronic lung dis- indometacin therapy and surgical ligation in such infants. How- ATC — L04AB02.
ease may be increased. Ibuprofen is also effective when used ever, there is evidence to suggest that there is no significant in- ATC Vet — QL04AB02.
prophylactically; however, there have been reports of pulmonary crease in the risk of neonatal complications in infants exposed to
hypertension with such use and ibuprofen is not recommended.17 indometacin tocolysis when compared with control groups of in-
Oral therapy with ibuprofen has also been tried.18
Adverse Effects, Treatment, and Precau-
fants who received either no treatment or tocolysis with drugs
1. Bhatt V, Nahata MC. Pharmacologic management of patent duc- other than indometacin.9,10
tions
tus arteriosus. Clin Pharm 1989; 8: 17–33. Acute infusion reactions during or within 1 to 2 hours
The evidence for any overall benefit of indometacin in delaying
2. Anonymous. Delayed closure of the ductus. Lancet 1983; ii:
labour is equivocal,11-13 and it is generally reserved as a second- of infusion are common with infliximab, and other
436.
3. Brion LP, Campbell DE. Furosemide for prevention of morbid- line tocolytic or for use with an intravenous tocolytic when an TNF inhibitors, particularly with the first or second
ity in indomethacin-treated infants with patent ductus arterio- additive effect is required. dose. Symptoms include fever, chills, pruritus, urticar-
sus. Available in The Cochrane Database of Systematic Re-
views; Issue 3. Chichester: John Wiley; 2001 (accessed 1. Morales WJ, et al. Efficacy and safety of indomethacin versus ia, dyspnoea, chest pain, and hypertension or hypoten-
ritodrine in the management of preterm labor: a randomized
07/11/07).
study. Obstet Gynecol 1989; 74: 567–72. sion. Mild reactions may respond to a reduced rate of
4. Silove ED. Pharmacological manipulation of the ductus arterio- infusion or a temporary interruption. If reactions are
sus. Arch Dis Child 1986; 61: 827–9. 2. Besinger RE, et al. Randomized comparative trial of indometh-
5. Barst RJ, Gersony WM. The pharmacological treatment of pat- acin and ritodrine for the long-term treatment of preterm labor. more severe, therapy should be stopped. Pretreatment
ent ductus arteriosus: a review of the evidence. Drugs 1989; 38: Am J Obstet Gynecol 1991; 164: 981–8.
3. Moise KJ, et al. Indomethacin in the treatment of premature la-
with paracetamol, corticosteroids, and antihistamines
249–66.
6. Archer N. Patent ductus arteriosus in the newborn. Arch Dis bor: effects on the fetal ductus arteriosus. N Engl J Med 1988; may be considered. TNF inhibitors should only be giv-
Child 1993; 69: 529–32. 319: 327–31. en where facilities for resuscitation are available. De-
7. Clyman RI. Recommendations for the postnatal use of in- 4. Hallak M, et al. Indomethacin for preterm labor: fetal toxicity in
domethacin: an analysis of four separate treatment strategies. J a dizygotic twin gestation. Obstet Gynecol 1991; 78: 911–13. layed reactions have occurred 3 to 12 days after inflix-
Pediatr 1996; 128: 601–7. 5. Vermillion ST, et al. The effect of indomethacin tocolysis on imab treatment; symptoms include myalgia, arthralgia,
8. Van Overmeire B, et al. Early versus late indomethacin treat- fetal ductus arteriosus constriction with advancing gestational fever, and rash. Similar delayed reactions may also be
ment for patent ductus arteriosus in premature infants with res- age. Am J Obstet Gynecol 1997; 177: 256–61.
piratory distress syndrome. J Pediatr 2001; 138: 205–11. 6. Eronen M, et al. Increased incidence of bronchopulmonary dys- seen when infliximab has been restarted after an ex-
9. Gersony WM, et al. Effects of indomethacin in premature in- plasia after antenatal administration of indomethacin to prevent tended period without treatment (see below).
fants with patent ductus arteriosus: results of a national collab- preterm labor. J Pediatr 1994; 124: 782–8.
orative study. J Pediatr 1983; 102: 895–906. 7. Norton ME, et al. Neonatal complications after the administra- Other, common, adverse effects include nausea and
10. Hammerman C, Aramburo MJ. Prolonged indomethacin thera- tion of indomethacin for preterm labor. N Engl J Med 1993; 329: vomiting, abdominal pain, diarrhoea, fatigue, dizzi-
py for the prevention of recurrences of patent ductus arteriosus. 1602–7.
J Pediatr 1990; 117: 771–6. 8. Hammerman C, et al. Indomethacin tocolysis increases post-na-
ness, headache, and back pain. Antibodies to inflixi-
11. Sperandio M, et al. Effectiveness and side effects of an escalat- tal patent ductus arteriosus severity. Abstract: Pediatrics 1998; mab (human antichimeric antibodies) may develop,
ing, stepwise approach to indomethacin treatment for sympto- 102: 1202–3. Full version:
matic patent ductus arteriosus in premature infants below 33 http://pediatrics.aappublications.org/cgi/content/full/102/5/e56
and are associated with an increased incidence of hy-
weeks of gestation. Pediatrics 2005; 116: 1361–6. (accessed 07/11/07) persensitivity reactions. Antinuclear antibodies and
12. Rennie JM, Cooke RWI. Prolonged low dose indomethacin for
persistent ductus arteriosus of prematurity. Arch Dis Child
9. Vermillion ST, Newman RB. Recent indomethacin tocolysis is anti-double-stranded-DNA antibodies have also devel-
not associated with neonatal complications in preterm infants.
1991; 66: 55–8. Am J Obstet Gynecol 1999; 181: 1083–6. oped with TNF inhibitor therapy. A lupus-like syn-
13. Herrera C, et al. Prolonged versus short course of indomethacin drome has occurred rarely; treatment should be
10. Loe SM, et al. Assessing the neonatal safety of indomethacin
for the treatment of patent ductus arteriosus in preterm infants. tocolysis: a systematic review with meta-analysis. Obstet Gyne- stopped if it develops.
Available in The Cochrane Database of Systematic Reviews; Is- col 2005; 106: 173–9.
sue 2. Chichester: John Wiley; 2007 (accessed 07/11/07).
14. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin 11. Macones GA, Robinson CA. Is there justification for using in- Infections are common in patients treated with inflixi-
for preventing mortality and morbidity in preterm infants. domethacin in preterm labor? An analysis of neonatal risks and mab or other drugs that inhibit TNF, and most often
Available in The Cochrane Database of Systematic Reviews; Is- benefits. Am J Obstet Gynecol 1997; 177: 819–24.
sue 3. Chichester: John Wiley; 2002 (accessed 07/11/07). 12. Panter KR, et al. The effect of indomethacin tocolysis in pre- affect the upper respiratory tract and the urinary tract.
15. Cooke L, et al. Indomethacin for asymptomatic patent ductus term labour on perinatal outcome: a randomised placebo-con- TNF inhibitors have also been associated rarely with
arteriosus in preterm infants. Available in The Cochrane Data- trolled trial. Br J Obstet Gynaecol 1999; 106: 467–73.
base of Systematic Reviews; Issue 1. Chichester: John Wiley; 13. Macones GA, et al. The controversy surrounding indomethacin
the development of serious opportunistic infections,
2003 (accessed 07/11/07). for tocolysis. Am J Obstet Gynecol 2001; 184: 264–72. sepsis, pneumonia, and onset or reactivation of tuber-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
70 Analgesics Anti-inflammatory Drugs and Antipyretics
culosis (see below), particularly in patients with under- recommendations are given for the TNF inhibitors Effects on the CNS. Aseptic meningitis developed in a patient
lying conditions predisposing them to infections; in adalimumab and etanercept, although UK licensed in- after his fifth injection of infliximab for rheumatoid arthritis.1
Similar symptoms also occurred after a sixth injection.
some cases death has resulted. TNF inhibitors should formation for etanercept only advises caution in pa-
Two patients with inflammatory bowel disease developed acute
not be given to patients with severe infection, including tients with heart failure. motor neuropathy with multiple conduction blocks following in-
active tuberculosis, abscesses, and opportunistic infec- ◊ General references. fliximab treatment; both patients improved after infliximab was
tions, and should be stopped if these develop. Patients 1. Hansen RA, et al. Serious adverse events with infliximab: anal- stopped.2 Similar adverse effects were reported in 2 further pa-
should be evaluated for latent and active tuberculosis ysis of spontaneously reported adverse events. Clin Gastroenter- tients:3 one was taking etanercept for rheumatoid arthritis and the
ol Hepatol 2007; 5: 729–35. other infliximab for ankylosing spondylitis. Three cases of bilat-
before beginning therapy; if evidence of latent tubercu-
Carcinogenicity. Malignancies, especially lymphomas, have eral optic neuropathy associated with infliximab therapy have
losis is found, the risks and benefits of treatment should been seen in patients treated with TNF inhibitors for rheumatoid also been reported.4 Other neuropathies have been associated
be considered carefully and chemoprophylaxis should arthritis and Crohn’s disease;1 however, the suggestion of a caus- with TNF inhibitor treatment, including Guillain-Barré syn-
be started before giving a TNF inhibitor. They should al relationship is controversial. A meta-analysis2 in 2006 identi- drome.5
also be used with care in those with chronic infections, fied 24 published reports of malignancies in 3493 study patients 1. Marotte H, et al. Infliximab-induced aseptic meningitis. Lancet
with rheumatoid arthritis who had received at least one dose of a 2001; 358: 1784.
a history of recurrent infections, or with underlying 2. Singer OC, et al. Acute neuropathy with multiple conduction
TNF inhibitor (adalimumab or infliximab) along with 2 cases in
conditions that may predispose to infections. Patients 1512 control patients; further, unpublished, cases were also blocks after TNFα monoclonal antibody therapy. Neurology
2004; 63: 1754.
with fistulising Crohn’s disease with suppurative fistu- found using FDA data to give 29 malignancies in the treatment 3. Richez C, et al. Neuropathy resembling CIDP in patients receiv-
las should not be given infliximab until possible infec- groups and 3 in the control groups. Based on these figures, there ing tumor necrosis factor- α blockers. Neurology 2005; 64:
tion sources such as abscesses have been ruled out. Pa- was a 3.3-fold increase in the risk of malignancy in patients re- 1468–70.
ceiving TNF inhibitors when compared with controls. These re- 4. ten Tusscher MPM, et al. Bilateral anterior toxic optic neuropa-
tients should be instructed to seek medical advice if thy and the use of infliximab. BMJ 2003; 326: 579.
sults have, however, been criticised3 on a number of points in-
symptoms suggestive of tuberculosis (such as persist- cluding the difficulty in applying them to current practice 5. Stübgen J-P. Tumor necrosis factor-α antagonists and neuropa-
ent cough, weight loss, or low grade fever) occur. Pa- thy. Muscle Nerve 2008; 37: 281–92.
because etanercept was not included in the analysis, and, in par-
tients should be monitored for signs of infection after ticular, the unexpectedly low rate of malignancies in the control Effects on the heart. The FDA has reported1 on 47 patients
stopping treatment: for adalimumab and infliximab, groups. Other studies in patients with rheumatoid arthritis4,5 and who developed heart failure during long-term therapy with TNF
Crohn’s disease6 have generally concluded that the overall risk of antibodies (etanercept and infliximab) for arthritic conditions or
which both have long half-lives, monitoring should malignancies is not significantly increased in patients taking Crohn’s disease. Of these, 38 developed new-onset heart failure,
continue for 5 or 6 months, respectively; because of its TNF inhibitors when compared with patients who have not taken 19 having documented risk factors for heart failure, and 9 had
relatively shorter half-life, the elimination of etaner- these drugs. Some studies4,7 in patients with rheumatoid arthritis exacerbation of existing heart failure. The median time to new-
cept may be quicker. have, however, shown a possible increased risk of lymphoma onset heart failure was 3.5 months. However, studies2-4 investi-
with TNF inhibitor treatment, but caution in interpreting these gating a possible association between TNF inhibitors and the de-
There have been rare reports of severe hepatic reac- results was recommended as they were based on a small number velopment of heart failure have been equivocal and further inves-
tions such as acute liver failure, jaundice, hepatitis, and of cases; in addition, the background risk of lymphoma is in- tigation is warranted.
cholestasis with infliximab; some cases have been fatal creased in rheumatoid arthritis regardless of treatment. The risk Preliminary investigations on the use of infliximab in the treat-
or required transplantation. Patients with signs or of malignancies with TNF inhibitors requires further study. ment of moderate to severe heart failure failed to show any clin-
symptoms of hepatotoxicity should be evaluated and Rare cases of hepatosplenic T-cell lymphoma have been seen in ical improvement in patients given infliximab 5 mg/kg or
adolescents and young adults given infliximab for the treatment 10 mg/kg when compared with placebo;5 in addition, those given
infliximab should be stopped in those patients with of Crohn’s disease. In July 2006, the manufacturer was aware of the higher dose had an increased risk of death or hospitalisation
jaundice or marked elevations in liver enzyme values. 6 cases of this type of lymphoma in 5 adolescents aged 12 to 19 due to worsening heart failure.
Infliximab and other TNF inhibitors have also been as- years and one 31-year-old adult;8 4 of the 6 cases occurred in 1. Kwon HJ, et al. Case reports of heart failure after therapy with a
sociated with the reactivation of hepatitis B in chronic males. The treatment duration ranged from 1 or 2 infusions to tumor necrosis factor antagonist. Ann Intern Med 2003; 138:
over 4 years of therapy; in all cases, patients were also taking or 807–11.
carriers, which has resulted in fatalities in some cases. 2. Jacobsson LTH, et al. Treatment with tumor necrosis factor
had taken azathioprine or 6-mercaptopurine. This type of lym-
Patients at risk of hepatitis B infection should be phoma is aggressive and 5 of the above patients died. A causal
blockers is associated with a lower incidence of first cardiovas-
cular events in patients with rheumatoid arthritis. J Rheumatol
screened before starting treatment; it is recommended relationship was not clearly established although it could neither 2005; 32: 1213–18.
that carriers treated with a TNF inhibitor are closely be excluded. Further cases have since been reported.9 3. Curtis JR, et al. Heart failure among younger rheumatoid arthri-
monitored during, and for several months after stop- 1. Brown SL, et al. Tumor necrosis factor antagonist therapy and tis and Crohn’s patients exposed to TNF-α antagonists. Rheuma-
lymphoma development: twenty-six cases reported to the Food tology (Oxford) 2007; 46: 1688–93.
ping, treatment. and Drug Administration. Arthritis Rheum 2002; 46: 3151–8. 4. Listing J, et al. Does tumor necrosis factor α inhibition promote
Blood dyscrasias, including leucopenia, thrombocyto- 2. Bongartz T, et al. Anti-TNF antibody therapy in rheumatoid ar- or prevent heart failure in patients with rheumatoid arthritis? Ar-
thritis and the risk of serious infections and malignancies: sys- thritis Rheum 2008; 58: 667–77.
penia, pancytopenia, and aplastic anaemia, have been tematic review and meta-analysis of rare harmful effects in ran- 5. Chung ES, et al. Randomized, double-blind, placebo-controlled,
reported rarely with TNF inhibitors; in some cases the domized controlled trials. JAMA 2006; 295: 2275–85. pilot trial of infliximab, a chimeric monoclonal antibody to tu-
Correction. ibid.; 2482. mor necrosis factor-α, in patients with moderate-to-severe heart
outcome was fatal. They should be used with caution 3. Dixon W, Silman A. Is there an association between anti-TNF failure: results of the Anti-TNF Therapy Against Congestive
in patients with a history of blood dyscrasias. monoclonal antibody therapy in rheumatoid arthritis and risk of Heart failure (ATTACH) trial. Circulation 2003; 107: 3133–40.
malignancy and serious infection? Commentary on the meta-
Rare, and sometimes fatal, cases of interstitial lung dis- analysis by Bongartz et al. Arthritis Res Ther 2006; 8: 111. Effects on the lungs. Infliximab treatment has been associated
ease including pulmonary fibrosis and pneumonitis 4. Geborek P, et al. Tumour necrosis factor blockers do not increase with a fatal exacerbation of previously asymptomatic fibrosing
have been reported with TNF inhibitors. overall tumour risk in patients with rheumatoid arthritis, but may alveolitis in 3 patients with chronic rheumatoid arthritis;1 all 3
be associated with an increased risk of lymphomas. Ann Rheum patients were also taking azathioprine and prednisolone. There
Infliximab and other TNF inhibitors are also associated Dis 2005; 64: 699–703. was no evidence of infection or other underlying causes for the
5. Setoguchi S, et al. Tumor necrosis factor α antagonist use and
with an increased incidence of malignancies including cancer in patients with rheumatoid arthritis. Arthritis Rheum decline in respiratory function.
lymphoma (see also Carcinogenicity, below), although 2006; 54: 2757–64. Correction. ibid.; 3134. 1. Ostor AJK, et al. Fatal exacerbation of rheumatoid arthritis asso-
6. Biancone L, et al. Infliximab and newly diagnosed neoplasia in ciated fibrosing alveolitis in patients given infliximab. BMJ
occurrences are rare. Some groups of patients treated Crohn’s disease: a multicentre matched pair study. Gut 2006; 55: 2004; 329: 1266.
with TNF inhibitors may already have an increased 228–33.
7. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the ef- Effects on the skin. Patients with rheumatoid arthritis receiv-
background risk of developing malignancies, regard- ing TNF inhibitor therapy are more likely to develop adverse
fect of methotrexate and anti-tumor necrosis factor therapy in
less of drug treatment. Care has been advocated in pa- 18,572 patients. Arthritis Rheum 2004; 50: 1740–51. skin reactions than those who are not.1 Of 289 patients taking
tients with a history of malignancy. 8. Schering, Canada. Health Canada endorsed important safety in- TNF inhibitors (infliximab, etanercept, adalimumab, and lener-
formation on Remicade (infliximab) (issued 24th July, 2006). cept), 72 (25%) reported 128 dermatological events including
Anaphylactic reactions have been reported rarely with Available at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/
hpfb-dgpsa/pdf/medeff/remicade_3_hpc-cps-eng.pdf (accessed
skin infections, eczema, drug-related eruptions, and malignan-
TNF inhibitors. Infliximab should be avoided in pa- cies such as actinic keratosis; of the 289 patients not taking TNF
29/08/08)
tients with a history of hypersensitivity to the drug or 9. Mackey AC, et al. Hepatosplenic T cell lymphoma associated inhibitors, 37 (13%) reported dermatological events.
other murine proteins. with infliximab use in young patients treated for inflammatory In another review,2 cutaneous adverse effects were seen in 35 out
bowel disease. J Pediatr Gastroenterol Nutr 2007; 44: 265–7. of 150 patients receiving TNF inhibitors (adalimumab, etaner-
TNF inhibitors have been associated in rare cases with
Delayed reactions. Ten of 37 patients with Crohn’s disease re- cept, or infliximab) for rheumatic disorders; cases included der-
seizures and clinical or radiological worsening of de- treated with infliximab after a 2 to 4 year period without treat- matitis herpetiformis and leucocytoclastic vasculitis although ec-
myelinating disorders such as multiple sclerosis or op- ment had delayed hypersensitivity reactions, of which 6 were zematous and skin infections were more common or infectious.
tic neuritis; care is required in prescribing it to patients considered serious. None of the patients had had infusion-related Perhaps unexpectedly, psoriasis-like lesions were seen in 8 pa-
with such disorders or symptoms suggestive of their adverse effects with their original infliximab therapy. Adverse tients, 6 of whom had no history of psoriasis; similar effects have
onset. reactions developed in 9 of the 23 patients originally treated with also been noted in other patients with rheumatoid arthritis3 or
a discontinued liquid formulation, and in 1 of the 14 patients who Crohn’s disease.4
Worsening and, in some cases, new-onset heart failure previously received the marketed formulation, leading to specu- Rare cases of serious skin reactions have been associated with
has been reported with TNF inhibitors (see Effects on lation that the formulation may have been a contributing factor. TNF inhibitor treatment.5 Since approval in 1998, the FDA has
the Heart, below). (NYHA class III or IV). In the UK, Effects on blood lipids. A 35-year-old man with psoriatic ar- received 15 cases of erythema multiforme, 5 cases of Stevens-
infliximab is contra-indicated in patients with moder- thritis and psoriasis developed markedly elevated triglyceride Johnson syndrome, and 1 case of toxic epidermal necrolysis as-
ate to severe heart failure; however, US licensed prod- levels and a mildly increased total cholesterol level after a single sociated with infliximab; cases for etanercept, approved in the
infusion of infliximab;1 tests prior to therapy had shown a mild same year, included 13 reports of erythema multiforme, and 4
uct information advises that doses up to 5 mg/kg may reports each of Stevens-Johnson syndrome and toxic epidermal
hypertriglyceridaemia for which he had received no treatment.
be used in such patients. It should be used with caution No further doses of infliximab were given and his triglyceride necrolysis. For adalimumab, which was marketed late in 2002,
in patients with mild heart failure (NYHA class I or II). levels subsequently improved. there have been 4 cases of erythema multiforme and 2 of Ste-
All patients with heart failure should be closely moni- 1. Antoniou C, et al. Elevated triglyceride and cholesterol levels vens-Johnson syndrome.
tored and infliximab stopped in those who develop after intravenous antitumour necrosis factor-α therapy in a pa- 1. Flendrie M, et al. Dermatological conditions during TNF-α-
tient with psoriatic arthritis and psoriasis vulgaris. Br J Dermatol blocking therapy in patients with rheumatoid arthritis: a prospec-
new or worsening symptoms of heart failure. Similar 2007; 156: 1090–1. tive study. Arthritis Res Ther 2005; 7: R666–R676.
 Infliximab 71
2. Lee H-H, et al. Cutaneous side-effects in patients with rheumatic Pharmacokinetics mab should only be used in patients with severe dis-
diseases during application of tumour necrosis factor-α antago-
nists. Br J Dermatol 2007; 156: 486–91. Infliximab shows linear pharmacokinetics. It is distrib- ease who have had an inadequate response to
3. Dereure O, et al. Psoriatic lesions induced by antitumour necro- uted primarily in the vascular compartment and, after conventional treatment; however, in the USA it may be
sis factor-α treatment: two cases. Br J Dermatol 2004; 151: single doses, has a terminal elimination half-life of 8 to used in early treatment, to reduce the signs and symp-
506–7.
4. Verea MM, et al. Psoriasiform eruption induced by infliximab. 9.5 days. After repeated doses, infliximab has been de- toms. The initial dose is 5 mg/kg, repeated at 2 and 6
Ann Pharmacother 2004; 38: 54–7. tected in serum for at least 8 weeks. weeks and then every 6 to 8 weeks; if there is no re-
5. FDA. Tumor necrosis factor alpha (TNF-α) antagonists: serious sponse after 2 doses no further treatment should be giv-
skin reactions. FDA Drug Safety Newsletter 2007; 1: 18–20. ◊ References.
Available at: http://www.fda.gov/cder/dsn/2008_winter/ 1. Klotz U, et al. Clinical pharmacokinetics and use of infliximab. en.
2008_winter.pdf (accessed 17/06/08) Clin Pharmacokinet 2007; 46: 645–60. Infliximab is also used in the treatment of active and
Infection. There have been spontaneous reports of onset or re- progressive psoriatic arthritis; in the UK, its use is
activation of tuberculosis in patients treated with infliximab, in- Uses and Administration limited to patients who have had an inadequate re-
cluding cases of miliary tuberculosis and unusual extrapulmo- Infliximab is a chimeric monoclonal antibody to tu- sponse to standard DMARD but, as before, US li-
nary disease.1 The UK CSM noted in February 2001 that there mour necrosis factor α (TNF), a pro-inflammatory
had been 28 such reports worldwide. The US manufacturers sub- censed product information allows earlier use. In the
sequently reported2 (in October 2001) that other serious oppor-
mediator. Elevated levels of TNF have been found in USA, it may be given with or without methotrexate;
tunistic infections, including histoplasmosis, listeriosis, and the affected tissues and fluids of patients with rheuma- however, UK product information only recommends
pneumocystosis had occurred, and had led to some deaths; the toid arthritis, ankylosing spondylitis, and psoriatic ar- use without methotrexate in those patients who are
number of reported cases of tuberculosis had risen to 84. Further thritis, and Crohn’s disease and ulcerative colitis. Ele-
opportunistic infections also continued to be reported; FDA data
intolerant of or have contra-indications to such treat-
vated TNF levels are also found in psoriatic plaques. ment. It is given in a single dose of 5 mg/kg, repeated
up to August 2002 included reports of candidiasis, coccidioid-
omycosis, nocardiosis, aspergillosis, and infections due to non- Infliximab is given by intravenous infusion over a usu- at 2 and 6 weeks and then every 8 weeks thereafter.
tuberculous mycobacteria.3 Health Canada reported4 in October al period of not less than 2 hours; shorter infusion times Guidance issued by NICE in the UK recommends that
2004 that it had received 188 and 109 reports of infections asso- have been used in some patients with rheumatoid ar- treatment with infliximab is stopped after 12 weeks in
ciated with infliximab and etanercept, respectively, from January
2000 to May 2004. Of these, 10 and 2 reports were of tuberculo-
thritis (see below for further details). those who show an inadequate response.
sis associated with infliximab and etanercept, respectively. The Infliximab is used with methotrexate in the manage- Infliximab is used in the treatment of moderate to se-
FDA also received 25 reports of tuberculosis associated with ment of moderate to severe, active rheumatoid vere plaque psoriasis. Its use is usually limited to pa-
etanercept between November 1998 and March 2002.5 Although tients in whom other treatments are not suitable. Inflix-
the majority of patients also had a history of treatment with im-
arthritis to reduce the signs and symptoms of the dis-
munosuppressants including corticosteroids, the inhibition of ease, delay structural damage, and improve physical imab is given in a dose of 5 mg/kg, repeated at 2 and 6
TNF may affect normal immune responses and predispose pa- function; in the UK it is licensed for use in patients who weeks, then every 8 weeks thereafter. Treatment
tients to opportunistic infections. have had an inadequate response to standard disease- should be stopped after 14 weeks (4 doses) in patients
Guidelines6 have been issued by the British Thoracic Society to modifying antirheumatic drugs (DMARDs) although, who show no response.
quantify the risks of reactivation of tuberculosis with TNF inhib- in severe progressive cases, it may be used in patients If the signs and symptoms of rheumatoid arthritis or
itors and to advise on the treatment of such infection in patients not previously treated with methotrexate or other
being assessed for TNF inhibitor therapy. Crohn’s disease recur infliximab may be readminis-
1. CSM/MCA. Infliximab (Remicade) and tuberculosis. Current
DMARDs; in the USA it may be used for treating early tered if within 16 weeks of the last infusion. Readmin-
Problems 2001; 27: 7. Also available at: rheumatoid arthritis. Infliximab is given in a dose of istration after a drug-free interval of more than 16
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ 3 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks weeks may be associated with an increased risk of de-
FILE&dDocName=CON007458&RevisionSelectionMethod=
LatestReleased (accessed 13/06/08) thereafter. For the first 3 doses infliximab should be in- layed hypersensitivity (see Delayed Reactions, above)
2. Schaible TF [Centocor, Inc.]. Important drug warning (issued 5th fused for at least 2 hours; however, UK licensed prod- and consequently is not recommended. Recommenda-
October, 2001). Available at: http://www.fda.gov/medwatch/ uct information suggests that subsequent infusion
safety/2001/remicadeTB_deardoc.pdf (accessed 13/06/08) tions regarding the readministration of infliximab for
3. Wallis RS, et al. Granulomatous infectious diseases associated times may be reduced to a minimum period of 1 hour other indications (other than those detailed above) have
with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38: in those who tolerate the initial infusions. A clinical re- not been established. Limited data from readministra-
1261–5. Correction. ibid.; 39: 1254–5. sponse is usually achieved within 12 weeks of starting
4. Health Canada. Infliximab (Remicade) and etanercept (Enbrel):
tion with a single dose of infliximab in psoriasis after
serious infections and tuberculosis. Can Adverse React News treatment. Patients with an inadequate response during an interval of 20 weeks suggest reduced efficacy and a
2004; 14 (4): 2–3. Also available at: this period or who later relapse may benefit by increas- higher incidence of mild to moderate infusion reac-
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/
medeff/carn-bcei_v14n4-eng.pdf (accessed 29/08/08)
ing the dose: in the UK, a maximum dose of 7.5 mg/kg tions when compared with the initial regimen.
5. Mohan AK, et al. Tuberculosis following the use of etanercept, every 8 weeks (with increases made in steps of For details of infliximab use in children, see below.
a tumor necrosis factor inhibitor. Clin Infect Dis 2004; 39: 1.5 mg/kg) is recommended whereas, in the USA, a
295–9.
maximum dose of 10 mg/kg is allowed. Alternatively, Administration in children. Infliximab is licensed for use in
6. British Thoracic Society Standards of Care Committee. BTS rec- moderate to severe, active Crohn’s disease in children aged 6
ommendations for assessing risk and for managing Mycobacte- a dose of 3 mg/kg may be given as often as every 4 years and over who have not responded to conventional therapy,
rium tuberculosis infection and disease in patients due to start weeks in such patients. Continuing therapy in those or who have contraindication for or are intolerant of such treat-
anti-TNF-α treatment. Thorax 2005; 60: 800–5.
Also available at: http://www.brit-thoracic.org.uk/Portals/0/ who show no response within the first 12 weeks of ments; doses are the same as those used in adults (see above). UK
C li n i cal %2 0 In fo rm at i o n/ A n t i %2 0T N F%2 0 Treat m en t / treatment or after dose adjustment should be carefully licensed product information suggests that the dosage interval
Guidelines/antitnf_treatment.pdf (accessed 13/06/08) may be adjusted to maintain any benefits; however, further treat-
reconsidered: in the UK NICE recommends that inflix- ment is unlikely to be of use in patients not responding within the
imab be withdrawn if there is no adequate response first 10 weeks.
Interactions
within 6 months of starting treatment. Although unlicensed for such use in the UK, infliximab has also
Live vaccines should not be given with infliximab or
Patients with moderate to severe, active Crohn’s dis- been used in children with fistulising Crohn’s disease; the BNFC
other drugs that inhibit TNF as the effect of such drugs recommends that those aged 6 to 18 years may be treated with
on vaccine efficacy or the risk of infection transmission ease unresponsive to conventional treatment may be the same dosage regimen that is used for this indication in adults
is unknown. The use of TNF inhibitors with the inter- given a single infliximab dose of 5 mg/kg. This may be (see above).
leukin-1 receptor antagonist anakinra may increase the followed by a maintenance regimen of additional infu- Asthma. TNF inhibitors such as infliximab have been investi-
risk of serious infections and neutropenia; such combi- sions of 5 mg/kg at 2 and 6 weeks after the initial infu- gated in the treatment of refractory asthma (p.1108).1,2 There is
nations are not recommended. A similar interaction has sion and then every 8 weeks, or the drug may be read- some evidence that only a minority of patients will respond to
been seen with TNF inhibitors and the co-stimulation ministered when signs and symptoms of the disease such therapy, and that the benefits and risks must therefore be
recur (but see below). UK licensed product informa- carefully assessed.2
blocker abatacept. 1. Erin EM, et al. The effects of a monoclonal antibody directed
tion does not recommend further doses in patients who against tumor necrosis factor-α in asthma. Am J Respir Crit Care
Abatacept. Use of the TNF inhibitor etanercept with abatacept are unresponsive after the first 2 doses; in the USA, a Med 2006; 174: 753–62.
has resulted in an increase in the incidence of serious adverse 2. Brightling C, et al. Targeting TNF-alpha: a novel therapeutic ap-
effects including serious infections; in addition, there was no in- patient is not considered to be unresponsive until 3 dos-
proach for asthma. J Allergy Clin Immunol 2008; 121: 5–10.
crease in clinical benefit.1 Combinations of abatacept with TNF es have been given. A similar regimen is used in pa-
inhibitors are not recommended by UK licensed product infor- tients with fistulising Crohn’s disease although therapy Inflammatory bowel disease. Infliximab is used in adults for
mation. the treatment of Crohn’s disease1-11 and ulcerative colitis8,12-16
should not be considered ineffective until after the third (see Inflammatory Bowel Disease, p.1697); it has also been used
1. Weinblatt M, et al. Selective costimulation modulation using dose of infliximab. US product information suggests in children in the treatment of inflammatory bowel disease,17-20
abatacept in patients with active rheumatoid arthritis while re-
ceiving etanercept: a randomised clinical trial. Ann Rheum Dis that doses of up to 10 mg/kg may be used in patients particularly Crohn’s disease.
2007; 66: 228–34. who relapse after an initial response. Infliximab is also In the treatment of Crohn’s disease, guidance issued in the UK by
used in the treatment of moderate to severe, active ul- NICE recommends that infliximab is used in patients with severe
Anakinra. The incidence of serious infections, injection site re-
disease when treatment with immunomodulators and corticoster-
actions, and neutropenia is increased when anakinra is given cerative colitis in patients unresponsive to convention- oids has failed or is not tolerated, and when surgery is inappro-
with the TNF inhibitor etanercept.1 In addition, the combination al therapy; the recommended dose is 5 mg/kg given as priate.21
did not provide any further clinical benefit when compared to
etanercept alone. Similar findings may be expected if anakinra is
a regimen similar to that used for Crohn’s disease (see In the treatment of ulcerative colitis, guidance issued by NICE
given with other TNF inhibitors. above). Therapy should not be considered ineffective recommends against the use of infliximab in subacute manifes-
until after the third dose of infliximab. tations of moderately to severely active disease (defined as that
1. Genovese MC, et al. Combination therapy with etanercept and
anakinra in the treatment of patients with rheumatoid arthritis which would normally be managed in an outpatient setting, and
who have been treated unsuccessfully with methotrexate. Arthri-
In the treatment of ankylosing spondylitis, UK li- does not require hospitalisation or the consideration of urgent
tis Rheum 2004; 50: 1412–19. censed product information recommends that inflixi- surgical intervention).22 The use of infliximab in acute manifes-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
72 Analgesics Anti-inflammatory Drugs and Antipyretics
tations of moderately to severely active ulcerative colitis is under 7. Poulalhon N, et al. A follow-up study in 28 patients treated with 9. Tynjälä P, et al. Infliximab and etanercept in the treatment of
review by NICE. infliximab for severe recalcitrant psoriasis: evidence for efficacy chronic uveitis associated with refractory juvenile idiopathic ar-
and high incidence of biological autoimmunity. Br J Dermatol thritis. Ann Rheum Dis 2007; 66: 548–50.
1. Present DH, et al. Infliximab for the treatment of fistulas in pa- 2007; 156: 329–36. 10. Ardoin SP, et al. Infliximab to treat chronic noninfectious uvei-
tients with Crohn’s disease. N Engl J Med 1999; 340: 1398–405. tis in children: retrospective case series with long-term follow-
8. NICE. Infliximab for the treatment of adults with psoriasis:
2. Rutgeerts P, et al. Efficacy and safety of retreatment with anti- Technology Appraisal Guidance 134 (issued January 2008). up. Am J Ophthalmol 2007; 144: 844–849.
tumor necrosis factor antibody (infliximab) to maintain remis- 11. Pipitone N, et al. Infliximab for the treatment of Neuro-Behçet’s
sion in Crohn’s disease. Gastroenterology 1999; 117: 761–9. Ava i l a b l e a t : h t t p : / / w w w. ni c e .o rg . u k / n i c e m e d i a / p d f /
TA134Guidance.pdf (accessed 22/08/08) disease: a case series and review of the literature. Arthritis
3. Hanauer SB, et al. ACCENT I Study Group. Maintenance inf- Rheum 2008; 59: 285–90.
liximab for Crohn’s disease: the ACCENT I randomised trial. Rheumatoid arthritis. TNF inhibitors play an increasingly
Lancet 2002; 359: 1541–9. important role in the management of rheumatoid arthritis; they Vasculitic syndromes. For a preliminary report on the use of
4. Rutgeerts P, et al. Comparison of scheduled and episodic treat- infliximab in Takayasu’s arteritis, see p.1514. Infliximab has also
ment strategies of infliximab in Crohn’s disease. Gastroenterol- tend to be reserved for patients who are unresponsive to more
conventional disease-modifying drugs, although some favour been investigated in the management of Kawasaki disease
ogy 2004; 126: 402–13.
5. Sands BE, et al. Infliximab maintenance therapy for fistulizing use earlier in management. (p.2228) in patients who are unresponsive to standard treat-
Crohn’s disease. N Engl J Med 2004; 350: 876–85. ment.1-3
Some references to the use of infliximab in rheumatoid arthritis
6. Panaccione R, et al. Canadian Association of Gastroenterology (p.11) and juvenile idiopathic arthritis (p.10). 1. Burns JC, et al. Infliximab treatment for refractory Kawasaki
Clinical Practice Guidelines: the use of infliximab in Crohn’s syndrome. J Pediatr 2005; 146: 662–7.
disease. Can J Gastroenterol 2004; 18: 503–8. Also available 1. Maini R, et al. ATTRACT Study Group. Infliximab (chimeric 2. Saji T, Kemmotsu Y. Infliximab for Kawasaki syndrome. J Pedi-
at: h t t p : / / w w w. c a g - a c g . o r g / u p l o a d s / g u i d e l i n e s / anti-tumour necrosis factor alpha monoclonal antibody) versus atr 2006; 149: 426.
Infliximab%20guidelines%202004.pdf (accessed 13/06/08) placebo in rheumatoid arthritis patients receiving concomitant
3. O’Connor MJ, Saulsbury FT. Incomplete and atypical Kawasaki
7. Siddiqui MAA, Scott LJ. Infliximab: a review of its use in methotrexate: a randomised phase III trial. Lancet 1999; 354:
disease in a young infant: severe, recalcitrant disease responsive
Crohn’s disease and rheumatoid arthritis. Drugs 2005; 65: 1932–9.
to infliximab. Clin Pediatr (Phila) 2007; 46: 345–8.
2179–2208. Correction. ibid. 2006; 66: 1359. 2. Lipsky PE, et al. Anti-Tumor Necrosis Factor Trial in Rheuma-
8. Rutgeerts P, et al. Review article: infliximab therapy for inflam- toid Arthritis with Concomitant Therapy Study Group. Inflixi- Preparations
matory bowel disease — seven years on. Aliment Pharmacol mab and methotrexate in the treatment of rheumatoid arthritis. N
Ther 2006; 23: 451–63. Engl J Med 2000; 343: 1594–1602. Proprietary Preparations (details are given in Part 3)
9. Rutgeerts P, et al. Scheduled maintenance treatment with inflix- 3. Maini RN, et al. Anti-Tumor Necrosis Factor Trial in Rheuma- Arg.: Remicade†; Revellex†; Austral.: Remicade; Belg.: Remicade; Braz.:
imab is superior to episodic treatment for the healing of mucosal toid Arthritis with Concomitant Therapy Study Group. Sustained Remicade; Canad.: Remicade; Chile: Remicade; Cz.: Remicade; Denm.:
ulceration associated with Crohn’s disease. Gastrointest Endosc improvement over two years in physical function, structural Remicade; Fin.: Remicade; Fr.: Remicade; Ger.: Remicade; Gr.: Remicade;
2006; 63: 433–42. damage, and signs and symptoms among patients with rheuma- Hong Kong: Remicade; Hung.: Remicade; Indon.: Remicade; Irl.: Remi-
10. Lémann M, et al. Groupe d’Etude Therapeutique des Affections toid arthritis treated with infliximab and methotrexate. Arthritis cade; Israel: Remicade; Ital.: Remicade; Jpn: Remicade; Malaysia: Remi-
Inflammatoires du Tube Digestif (GETAID). Infliximab plus Rheum 2004; 50: 1051–65. cade; Mex.: Remicade; Neth.: Remicade; Norw.: Remicade; NZ: Remi-
azathioprine for steroid-dependent Crohn’s disease patients: a 4. Quinn MA, et al. Very early treatment with infliximab in addi- cade; Philipp.: Remicade; Pol.: Remicade; Port.: Remicade; Rus.:
randomized placebo-controlled trial. Gastroenterology 2006; tion to methotrexate in early, poor-prognosis rheumatoid arthritis Remicade (Ремикейд); S.Afr.: Revellex; Singapore: Remicade; Spain:
130: 1054–61. Remicade; Swed.: Remicade; Switz.: Remicade; Thai.: Remicade; Turk.:
reduces magnetic resonance imaging evidence of synovitis and Remicade; UK: Remicade; USA: Remicade; Venez.: Remicade.
11. Osterman MT, Lichtenstein GR. Infliximab in fistulizing damage, with sustained benefit after infliximab withdrawal: re-
Crohn’s disease. Gastroenterol Clin North Am 2006; 35: sults from a twelve-month randomized, double-blind, placebo-
795–820. controlled trial. Arthritis Rheum 2005; 52: 27–35.
12. Probert CS, et al. Infliximab in moderately severe glucocorti- 5. Voulgari PV, et al. Infliximab therapy in established rheumatoid
coid resistant ulcerative colitis: a randomised controlled trial.
arthritis: an observational study. Am J Med 2005; 118: 515–20. Isonixin (rINN)
Gut 2003; 52: 998–1002.
13. Rutgeerts P, et al. Infliximab for induction and maintenance 6. Ruperto N, et al. Paediatric Rheumatology International Trials Isonixine; Isonixino; Isonixinum. 2-Hydroxy-N-(2,6-dimethylphe-
Organisation. Pediatric Rheumatology Collaborative Study
therapy for ulcerative colitis. N Engl J Med 2005; 353:
Group. A randomized, placebo-controlled trial of infliximab plus
nyl)nicotinamide.
2462–76. Correction. ibid. 2006; 354: 2200.
14. Lawson MM, et al. Tumour necrosis factor alpha blocking methotrexate for the treatment of polyarticular-course juvenile Изониксин
agents for induction of remission in ulcerative colitis. Available rheumatoid arthritis. Arthritis Rheum 2007; 56: 3096–3106. C 14 H 14N 2 O 2 = 242.3.
in The Cochrane Database of Systematic Reviews; Issue 3. 7. NICE. Adalimumab, etanercept and infliximab for the treatment
of rheumatoid arthritis: Technology Appraisal Guidance 130 (is- C AS — 57021-61-1.
Chichester: John Wiley; 2006 (accessed 13/06/08).
15. Aberra FN, Lichtenstein GR. Infliximab in ulcerative colitis. sued October 2007). Available at: http://www.nice.org.uk/
Gastroenterol Clin North Am 2006; 35: 821–36. nicemedia/pdf/TA130guidance.pdf (accessed 13/06/08)
16. Gisbert JP, et al. Systematic review: Infliximab therapy in ulcer- Sarcoidosis. For a mention of possible benefit from infliximab
ative colitis. Aliment Pharmacol Ther 2007; 25: 19–37. CH3
17. Baldassano R, et al. Infliximab (REMICADE) therapy in the in sarcoidosis, see p.1512. H
treatment of pediatric Crohn’s disease. Am J Gastroenterol Spondyloarthropathies. References to the use of infliximab N N
2003; 98: 833–8.
18. Hyams J, et al. REACH Study Group. Induction and mainte-
in the treatment of ankylosing spondylitis and psoriatic arthritis
nance infliximab therapy for the treatment of moderate-to-se- (p.13). In the UK, NICE considers that TNF inhibitors should be O OH
vere Crohn’s disease in children. Gastroenterology 2007; 132: reserved for severe active psoriatic arthritis unresponsive to at CH3
863–73. least 2 standard disease-modifying drugs; etanercept or adalimu-
19. de Ridder L, et al. Infliximab use in children and adolescents mab are preferred to infliximab.
with inflammatory bowel disease. J Pediatr Gastroenterol Nutr Profile
2007; 45: 3–14. 1. Brandt J, et al. Infliximab in the treatment of active and severe Isonixin is an NSAID (p.96) that has been used in the manage-
20. Veres G, et al. Infliximab therapy in children and adolescents ankylosing spondylitis. Clin Exp Rheumatol 2002; 20 (Suppl
28): S106–S110. ment of pain and inflammation associated with musculoskeletal
with inflammatory bowel disease. Drugs 2007; 67: 1703–23. and joint disorders. It has been used in doses of 400 mg two to
21. NICE. Guidance on the use of infliximab for Crohn’s disease: 2. Brandt J, et al. Successful short term treatment of severe undif-
Technology Appraisal Guidance 40 (issued April 2002). Avail- ferentiated spondyloarthropathy with the anti-tumor necrosis four times daily by mouth or by rectal suppository. It has also
a b l e a t : h t t p : / / w w w. n i c e . o r g . u k / n i c e m e d i a / p d f / factor-alpha monoclonal antibody infliximab. J Rheumatol been applied topically as a 2.5% cream.
NiceCROHNS40GUIDANCE.pdf (accessed 13/06/08) 2002; 29: 118–22.
22. NICE. Infliximab for subacute manifestations of ulcerative col- 3. Collantes-Estévez E, et al. Infliximab in refractory spondyloar- Preparations
itis: Technology Appraisal Guidance 140 (issued April 2008). thropathies: a multicentre 38 week open study. Ann Rheum Dis Proprietary Preparations (details are given in Part 3)
Av ailabl e at: http://www.n ic e.org.uk/nicemedia/pdf/ 2003; 62: 1239–40. Spain: Nixyn.
TA140Guidance.pdf (accessed 28/07/08) 4. Robinson DM, Keating GM. Infliximab: in ankylosing spondyli-
tis. Drugs 2005; 65: 1283–91. Multi-ingredient: Spain: Nixyn.
Leprosy. Infliximab has been used1 in the treatment of recurrent 5. NICE. Etanercept and infliximab for the treatment of adults with
type 2 (erythema nodosum leprosum) lepra reactions (see Lepro- psoriatic arthritis: Technology Appraisal Guidance 104 (issued
sy, p.176). However, 2 cases of rapidly progressive leprosy de- July 2006). Available at: http://www.nice.org.uk/nicemedia/pdf/
veloping in patients given infliximab for rheumatoid arthritis TA104guidance.pdf (accessed 13/06/08) Kebuzone (rINN)
have also been described;2 reversal (type 1) reactions occurred in 6. Rott S, et al. Successful treatment of severe psoriatic arthritis Kebuzona; Kébuzone; Kebuzonum; Ketophenylbutazone. 4-(3-
both when infliximab was stopped. with infliximab in an 11-year-old child suffering from linear pso-
riasis along lines of Blaschko. Br J Dermatol 2007; 157: 191–2. Oxobutyl)-1,2-diphenylpyrazolidine-3,5-dione.
1. Faber WR, et al. Treatment of recurrent erythema nodosum lep-
rosum with infliximab. N Engl J Med 2006; 355: 739. Uveitis. Infliximab has been tried with some success in the Кебузон
2. Scollard DM, et al. Development of leprosy and type 1 leprosy treatment of uveitis (p.1515) including that associated with C 19 H 18N 2 O 3 = 322.4.
reactions after treatment with infliximab: a report of 2 cases. Behçet’s syndrome (p.1499). Uveitis can also develop as a com- C AS — 853-34-9.
Clin Infect Dis 2006; 43: e19–e22. plication of other inflammatory disorders such as rheumatoid ATC — M01AA06.
Psoriasis. Infliximab is used in the treatment of moderate to se- arthritis; treatment with infliximab may improve ocular symp- ATC Vet — QM01AA06.
vere plaque psoriasis (p.1583).1-8 In the UK, NICE recommends8 toms in addition to its effect on the primary disorder.
that it be reserved for severe cases, unresponsive to standard ther- References.
apies (including ciclosporin, methotrexate, and PUVA) or where 1. Murphy CC, et al. Tumor necrosis factor alpha blockade with
such therapies cannot be used. infliximab for refractory uveitis and scleritis. Ophthalmology
1. Benoit S, et al. Treatment of recalcitrant pustular psoriasis with 2004; 111: 352–6.
infliximab: effective reduction of chemokine expression. Br J 2. Bodaghi B, et al. Therapeutic use of infliximab in sight threat-
ening uveitis: retrospective analysis of efficacy, safety, and lim- O
Dermatol 2004; 150: 1009–12.
2. Gottlieb AB, et al. Infliximab induction therapy for patients with iting factors. Ann Rheum Dis 2005; 64: 962–4. N
severe plaque-type psoriasis: a randomized, double-blind, place- 3. Braun J, et al. Decreased incidence of anterior uveitis in patients O
with ankylosing spondylitis treated with the anti-tumor necrosis N
bo-controlled trial. J Am Acad Dermatol 2004; 51: 534–42.
factor agents infliximab and etanercept. Arthritis Rheum 2005;
3. Reich K, et al. EXPRESS study investigators. Infliximab induc- 52: 2447–51.
tion and maintenance therapy for moderate-to-severe psoriasis: a H 3C
phase III, multicentre, double-blind trial. Lancet 2005; 366:
4. Richards JC, et al. Infliximab for juvenile idiopathic arthritis- O
associated uveitis. Clin Experiment Ophthalmol 2005; 33:
1367–74. 461–8.
4. Reich K, et al. Improvement in quality of life with infliximab 5. Lindstedt EW, et al. Anti-TNF-α therapy for sight threatening Profile
induction and maintenance therapy in patients with moderate-to- uveitis. Br J Ophthalmol 2005; 89: 533–6. Kebuzone, a phenylbutazone derivative, is an NSAID (p.96). It
severe psoriasis: a randomized controlled trial. Br J Dermatol 6. Saurenmann RK, et al. Tumour necrosis factor alpha inhibitors has been given for musculoskeletal, joint, and soft-tissue disor-
2006; 154: 1161–8. in the treatment of childhood uveitis. Rheumatology (Oxford)
5. Smith CH, et al. Infliximab for severe, treatment-resistant pso- ders in oral doses of up to 1.5 g daily in divided doses. Kebuzone
2006; 45: 982–9.
riasis: a prospective, open-label study. Br J Dermatol 2006; 155: 7. Kahn P, et al. Favorable response to high-dose infliximab for
has also been given as the sodium salt by intramuscular injection
160–9. refractory childhood uveitis. Ophthalmology 2006; 113: in doses equivalent to 1 g of base once or twice daily.
6. Menter A, et al. A randomized comparison of continuous vs. in- 860–4.e2.
termittent infliximab maintenance regimens over 1 year in the 8. Guignard S, et al. Efficacy of tumour necrosis factor blockers in
Porphyria. Kebuzone is considered to be unsafe in patients with
treatment of moderate-to-severe plaque psoriasis. J Am Acad reducing uveitis flares in patients with spondylarthropathy: a porphyria because it has been shown to be porphyrinogenic in
Dermatol 2006; 56: 31.e1–15. retrospective study. Ann Rheum Dis 2006; 65: 1631–4. animals or in-vitro systems.
 Isonixin/Ketoprofen 73
Preparations Renal impairment. The elimination half-life and unbound
Proprietary Preparations (details are given in Part 3) plasma concentrations of dexketoprofen are increased in patients
Austria: Ketazon†; Cz.: Ketazon†. O CH3 with renal impairment given racemic ketoprofen;1,2 this appears
Multi-ingredient: Austria: Rheumesser; Cz.: Ketazon Compositum†. to be principally attributable to impaired renal clearance of the
acyl-glucuronide conjugates in a stereoselective fashion, with
COOH subsequent hydrolysis of the unstable conjugate back to the agly-
cone producing increased plasma-ketoprofen concentrations.2,3
Ketobemidone Hydrochloride (BANM, rINNM) The authors of one study suggested3 that dosage adjustments of
Cétobémidone, chlorhydrate de; Cetobemidone Hydrochloride; racemic ketoprofen were indicated only for patients with moder-
Cetobemidoni hydrochloridum; Hidrocloruro de cetobemidona; (dexketoprofen) ately severe renal failure (creatinine clearance of less than
Ketobemidon-hydrochlorid; Ketobemidonhydroklorid; Keto- 20 mL/minute).
bemidoni Hydrochloridum; Ketobemidonihydrokloridi; Ketobem- For advice on the dose of dexketoprofen in patients with renal
idono hidrochloridas. 1-(4-m-Hydroxyphenyl-1-methyl-4-
Adverse Effects, Treatment, and Precau- impairment see under Uses and Administration, below. See also
piperidyl)propan-1-one hydrochloride. tions Adverse Effects and Precautions, above.
Кетобемидона Гидрохлорид As for NSAIDs in general, p.96. 1. Hayball PJ, et al. The influence of renal function on the enanti-
oselective pharmacokinetics and pharmacodynamics of ketopro-
C 15 H 21NO 2 ,HCl = 283.8. When ketoprofen is given intramuscularly there may fen in patients with rheumatoid arthritis. Br J Clin Pharmacol
C AS — 469-79-4 (ketobemidone); 5965-49-1 (ketobemi- be pain at the injection site and occasionally tissue 1993; 36: 185–93.
done hydrochloride). damage. Topical preparations containing ketoprofen 2. Grubb NG, et al. Stereoselective pharmacokinetics of ketoprofen
ATC — N02AB01. and ketoprofen glucuronide in end-stage renal disease: evidence
ATC Vet — QN02AB01. may cause application site reactions. Ketoprofen sup- for a ‘futile cycle’ of elimination. Br J Clin Pharmacol 1999; 48:
positories may cause local irritation; rectal use should 494–500.
3. Skeith KJ, et al. The influence of renal function on the pharma-
be avoided in patients with a history of proctitis or cokinetics of unchanged and acyl-glucuroconjugated ketoprofen
CH3 haemorrhoids. Ketoprofen should be used with caution enantiomers after 50 and 100 mg racemic ketoprofen. Br J Clin
Pharmacol 1996; 42: 163–9.
in patients with renal or hepatic impairment; it should
N
not be used in those with severe renal impairment. Interactions
Dexketoprofen should be avoided in patients with For interactions associated with NSAIDs, see p.99.
HO moderate to severe renal or severe hepatic impairment, Probenecid delays the excretion of ketoprofen and de-
CH3 and in those with severe heart failure. creases its extent of protein binding resulting in
O Effects on the skin. Contact and photoallergic dermatitis has increased plasma-ketoprofen concentrations. Not un-
been seen after topical use of ketoprofen.1,2 A retrospective expectedly, a similar interaction may be seen with
(ketobemidone) study3 found that of the 139 cases of contact reactions to topical dexketoprofen and probenecid.
NSAIDs reported to the Spanish Pharmacovigilance System be-
Pharmacopoeias. In Eur. (see p.vii). tween 1996 and 2001, 84 involved ketoprofen (16 allergy; 68
Ph. Eur. 6.2 (Ketobemidone Hydrochloride). White or almost photoallergy). Totals for other NSAIDs included piroxicam (21), Pharmacokinetics
white, crystalline powder. Freely soluble in water; soluble in al- etofenamate (10), piketoprofen (5), salicylates (4), fepradinol Ketoprofen is readily absorbed from the gastrointesti-
cohol; very slightly soluble in dichloromethane. A 1% solution (3), diclofenac (3), indometacin (2). phenylbutazone (2), benzy- nal tract; peak plasma concentrations occur about 0.5
in water has a pH of 4.5 to 5.5. damine (2), aceclofenac (1), naproxen (1), and mabuprofen (1). to 2 hours after an oral dose. When ketoprofen is given
Analysis indicated that the number of reports for topical ketopro-
Profile fen was disproportionately high in relation to its usage. with food, the bioavailability is not altered but the rate
Ketobemidone is an opioid analgesic (p.101). It has been given 1. Matthieu L, et al. Contact and photocontact allergy to ketopro- of absorption is slowed. Ketoprofen is well absorbed
as the hydrochloride orally, by injection, or rectally, sometimes fen: the Belgian experience. Contact Dermatitis 2004; 50: from the intramuscular and rectal routes; only a small
with an antispasmodic. 238–41.
2. Hindsén M, et al. Photoallergic contact dermatitis from ketopro-
amount of percutaneous absorption occurs after topical
◊ References. fen in southern Sweden. Contact Dermatitis 2006; 54: 150–7. application. Ketoprofen is 99% bound to plasma pro-
1. Al-Shurbaji A, Tokics L. The pharmacokinetics of ketobemi- 3. Diaz RL, et al. Greater allergenicity of topical ketoprofen in con-
done in critically ill patients. Br J Clin Pharmacol 2002 54: teins and substantial concentrations of drug are found
tact dermatitis confirmed by use. Contact Dermatitis 2006; 54:
583–6. 239–43. in the synovial fluid. The elimination half-life in plas-
2. Jylli L, et al. Comparison of the analgesic efficacy of ketobemi- ma is about 1.5 to 4 hours. Ketoprofen is metabolised
done and morphine for management of postoperative pain in Hypersensitivity. Life-threatening asthma, urticaria, and an-
children: a randomized, controlled study. Acta Anaesthesiol gioedema developed in 2 aspirin-sensitive patients after taking mainly by conjugation with glucuronic acid, and is ex-
Scand 2004; 48: 1256–9. ketoprofen 50 mg by mouth.1 Cardiac and respiratory arrest oc- creted mainly in the urine.
Preparations curred in an asthmatic patient shortly after taking ketoprofen.2 Ketoprofen possesses a chiral centre. It is usually given
Proprietary Preparations (details are given in Part 3) Life-threatening asthma has also occurred after topical applica-
Denm.: Ketodur†; Norw.: Ketodur†; Ketorax; Swed.: Ketodur†; Ketogan tion of ketoprofen.3 as the racemate but its pharmacological actions appear
Novum. There has been a report4 of delayed skin hypersensitivity in a pa- to be due largely to the (S)-enantiomer, dexketoprofen.
Multi-ingredient: Denm.: Ketogan; Norw.: Ketogan; Swed.: Ketogan. tient who used a topical gel containing ketoprofen. The reaction The pharmacokinetics of ketoprofen appear to exhibit
recurred on rechallenge to ketoprofen gel but not to a similar gel little stereoselectivity (but see under Renal Impair-
containing diclofenac. The authors of the report noted that the ment, above).
UK CSM had received 15 reports of skin reactions to ketoprofen
Ketoprofen (BAN, USAN, rINN) gel, including two each of dermatitis and urticaria. ◊ References.
See also Effects on the Skin, above. 1. Debruyne D, et al. Clinical pharmacokinetics of ketoprofen af-
Ketoprofeeni; Ketoprofén; Ketoprofenas; Kétoprofène; Ketopro- ter single intravenous administration as a bolus or infusion. Clin
feno; Ketoprofenum; RP-19583. (RS)-2-(3-Benzoylphenyl)propi- 1. Frith P, et al. Life-threatening asthma, urticaria, and angioœde- Pharmacokinet 1987; 12: 214–21.
ma after ketoprofen. Lancet 1978; ii: 847–8. 2. Flouvat B, et al. Pharmacokinetics of ketoprofen in man after
onic acid. 2. Schreuder G. Ketoprofen: possible idiosyncratic acute bronchos- repeated percutaneous administration. Arzneimittelforschung
Кетопрофен pasm. Med J Aust 1990; 152: 332–3. 1989; 39: 812–15.
C 16 H 14O 3 = 254.3. 3. Kashiwabara K, Nakamura H. Analgesic-induced asthma caused 3. Jamali F, Brocks DR. Clinical pharmacokinetics of ketoprofen
by 2.0% ketoprofen adhesive agents, but not by 0.3% agents. In- and its enantiomers. Clin Pharmacokinet 1990; 19: 197–217.
C AS — 22071-15-4 (ketoprofen); 57469-78-0 (ketopro- tern Med 2001; 40: 124–6. 4. Geisslinger G, et al. Pharmacokinetics of ketoprofen enantiom-
fen lysine); 57495-14-4 (ketoprofen sodium). 4. Oh VMS. Ketoprofen gel and delayed hypersensitivity dermati- ers after different doses of the racemate. Br J Clin Pharmacol
ATC — M01AE03; M02AA10. tis. BMJ 1994; 309: 512. 1995; 40: 73–5.
5. Barbanoj MJ, et al. Pharmacokinetics of dexketoprofen tromet-
ATC Vet — QM01AE03; QM02AA10. Myasthenia gravis. There has been a brief report1 of a cholin- amol in healthy volunteers after single and repeated oral doses.
ergic crisis precipitated by a single oral dose of ketoprofen 50 mg J Clin Pharmacol 1998; 38: 33S–40S.
in a patient with well-controlled myasthenia gravis. The patient 6. Kokki H, et al. Pharmacokinetics of ketoprofen syrup in small
O CH3 had previously noted a similar but milder reaction with aspirin, children. J Clin Pharmacol 2000; 40: 354–9.
7. Barbanoj M-J, et al. Clinical pharmacokinetics of dexketopro-
but not with paracetamol. fen. Clin Pharmacokinet 2001; 40: 245–62.
1. McDowell IFW, McConnell JB. Cholinergic crisis in myasthenia 8. Kokki H, et al. Pharmacokinetics of intravenous and rectal ke-
COOH gravis precipitated by ketoprofen. BMJ 1985; 291: 1094. toprofen in young children. Clin Pharmacokinet 2003; 42:
373–9.
Pancreatitis. Pancreatitis has been associated with ketoprofen 9. Valles J, et al. Clinical pharmacokinetics of parenteral dexketo-
use.1,2 profen trometamol in healthy subjects. Methods Find Exp Clin
1. Cobb TK, Pierce JR. Acute pancreatitis associated with ketopro- Pharmacol 2006; 28 (suppl A): 7–12.
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. fen. South Med J 1992; 85: 430–1. 10. Valles J, et al. Single and repeated dose pharmacokinetics of
Ph. Eur. 6.2 (Ketoprofen). A white or almost white, crystalline 2. Mété D, et al. Pancréatite aiguë et kétoprofène. Gastroenterol dexketoprofen trometamol in young and elderly subjects. Meth-
powder. M.p. 94° to 97°. Practically insoluble in water; freely Clin Biol 2001; 25: 721–2. ods Find Exp Clin Pharmacol 2006; 28 (suppl A): 13–19.
soluble in alcohol, in acetone, and in dichloromethane.
Photosensitivity. Ketoprofen causes photosensitivity
USP 31 (Ketoprofen). Store in airtight containers.
reactions1,2 and cross-sensitivity to other drugs, notably the fi-
Uses and Administration
brates bezafibrate, ciprofibrate, and fenofibrate, has also been re- Ketoprofen, a propionic acid derivative, is an NSAID
Dexketoprofen Trometamol (BANM, rINNM) ported. The cross reactions were attributed to the benzoyl ketone (p.99). Its anti-inflammatory properties may be weaker
(S)-(+)-Dexketoprofen Trometamol; Dexkétoprofène Trométa- structure that the drugs have in common. than those of some other NSAIDs. Ketoprofen is a ra-
mol; Dexketoprofeno trometamol; Dexketoprofenum Trometa- See also Effects on the Skin (above). cemic mixture; in animal studies the S-(+) enantiomer,
molum. 1. Bagheri H, et al. Photosensitivity to ketoprofen: mechanisms dexketoprofen, has about twice the analgesic activity
Декскетопрофен Трометамол and pharmacoepidemiological data. Drug Safety 2000; 22:
339–49. of ketoprofen by weight.
C AS — 22161-81-5 (dexketoprofen). 2. Veyrac G, et al. Bilan de l’enquête nationale sur les effets indé-
ATC — M01AE17. sirables cutanés du kétoprofène gel enregistrés entre le
Ketoprofen is used in musculoskeletal and joint disor-
ATC Vet — QM01AE17. 01/09/1996 et le 31/08/2000. Therapie 2002; 57: 55–64. ders such as ankylosing spondylitis, osteoarthritis, and
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
74 Analgesics Anti-inflammatory Drugs and Antipyretics
rheumatoid arthritis, and in peri-articular disorders toflex; Prontoket; Toprec†; Denm.: Orofen; Orudis; Fin.: Keto; Ketomex; tion, increases in blood urea and creatinine, acute renal
Ketorin; Orudis; Zon; Fr.: Bi-Profenid; Ketum; Profenid; Topfena; Toprec;
such as bursitis and tendinitis. It is also used in dys- Ger.: Alrheumun; Effekton mit Ketoprofen; Gabrilen; Ketolist†; Orudis†; failure, oedema, hyponatraemia, hyperkalaemia, uri-
menorrhoea, postoperative pain, in painful and inflam- Phardol Schmerz; Spondylon; Sympal; Togal Mobil-Gel mit ketoprofen; Gr.: nary frequency or retention, nephrotic syndrome, flank
Drastirel; Farbovil; Ketodur†; Menaril; Nosatel; Oruvail; Profinject†; Totifen;
matory conditions such as acute gout or soft-tissue dis- Viaxal; Hong Kong: Fastum; Mohrus; Orudis; Oruvail; Hung.: Algoflex; pain with or without haematuria, purpura, thrombocy-
orders, and to reduce fever. Dexketoprofen is used in Fastum; Ketodex; Ketospray; Profenid; Prontoket; India: Rofenid†; Indon.: topenia, epistaxis, inhibition of platelet aggregation, in-
Altofen; Fetik; Kaltrofen; Ketesse; Ketros; Lantiflam; Molaflam; Nasaflam; Na-
the treatment of mild to moderate pain such as muscu- zovell; Ovurila; Profecom; Profenid; Profika; Pronalges; Protofen; Remapro; creased bleeding time, postoperative wound haemor-
loskeletal pain, dysmenorrhoea, or dental pain. Rematof; Rhetoflam; Suprafenid; Irl.: Fastum; Keral; Orudis†; Orugesic; rhage, haematoma, flushing or pallor, and pancreatitis.
Oruvail; Israel: Ketonal†; Oruvail; Profenid; Ital.: Alket; Artrosilene; Deske-
In the treatment of rheumatic disorders a usual oral dai- to; Dolgosin; Enantyum; Euketos; Fastum; Flexen; Ibifen; Isofenal; Keplat; Ket- Severe skin reactions including Stevens-Johnson syn-
ly dose of ketoprofen is 100 to 200 mg in 2 to 4 divided artrium; Ketesse; Ketodol; Ketofarm; Ketoplus; Ketoselect; Lasonil CM; Me- drome and Lyell’s syndrome have been reported. Liver
profen; Oki; Orudis; Reuprofen; Toprek; Zepelindue†; Jpn: Mohrus;
doses; modified-release formulations taken once daily Malaysia: Apo-Keto; Fastum; Kenhancer; Ketotop†; Orudis; Oruvail†; function changes may occur; hepatitis and liver failure
may also be used. Some licensed product information Provail†; Mex.: Arket; Arthril; Bibix; Efiken; K-Profen; Keduril†; Ketoflex; have been reported. There may be pain at the site of
Orudis; Painsik; Profenid; Stadium; Neth.: Enantyum; Orudis; Oruvail; Os-
suggests initial oral doses of 75 mg three times daily or corel; Rilies; Stadium; Norw.: Orudis; Zon; NZ: Orudis; Oruvail; Philipp.: injection.
50 mg four times daily increased as needed to a maxi- Ketotop; Orudis; Udzapen; Pol.: Bi-Profenid; Dexak; Fastum; Febrofen; Ke- Ketorolac eye drops may produce transient stinging
tonal; Ketoprom; Ketopronil; Ketores; Ketospray; Profenid; Ultrafastin;
mum of 300 mg daily in divided doses. Ketoprofen Port.: Ar trofene†; Deflogix†; Enantyum; Fastum; Keplat; Ketesse; and other minor symptoms of ocular irritation. As with
may also be given rectally as suppositories in a dose of Ketofene†; Profenid; Quetral; Rus.: Artrosilen (Артрозилен); Bystrumgel some other NSAIDs used in the eye, ketorolac has
(Быструмгель); Dexalgin 25 (Дексалгин 25); Fastum (Фастум); Febrofid
100 mg at night or 100 mg twice daily. It is recom- (Феброфид); Flexen (Флексен); Ketonal (Кетонал); Oki (Оки); S.Afr.: been implicated in reports of corneal toxicity (see
mended that the total daily combined oral and rectal Fastum; Ketoflam; Myproflam; Orucote†; Oruject†; Oruvail; Singapore: p.45).
Apo-Keto; Fastum; Kefentech; Kenhancer; Ketotop†; Oruvail; Provail†;
dose should not exceed 200 mg. The usual oral dose Spain: Adolquir; Arcental; Badyket†; Enangel; Enantyum; Extraplus; Fastum; Incidence of adverse effects. Adverse effects reported with
for the treatment of other painful conditions including Ketesgel; Ketesse; Ketosolan; Orudis; Pyrsal; Quiralam; Quirgel; Swed.:
Orudis; Prodon; Siduro; Zon; Switz.: Fastum; Ketesse; Thai.: Fastum; Ka- ketorolac are mainly those common to all NSAIDs with gastroin-
dysmenorrhoea is 25 to 50 mg every 6 to 8 hours. For profen; Lolita; Oruvail; Profenid; Rofepain; Vestam; Turk.: Fastjel; Keto; testinal reactions being the most frequent followed by haemato-
details on the use of ketoprofen in patients with hepatic Ketofen; Profenid; UK: Keral; Ketocid; Ketovail; Ketozip†; Larafen; Orudis; logical, renal, hypersensitivity, and then neurological reactions.
Oruvail; Powergel; Tiloket; USA: Orudis†; Oruvail†; Venez.: Dolomax; Kel- From 1990 to 1993, 97 reactions with a fatal outcome were re-
or renal impairment, see below. fen; Keto; Keydol; Lindilan; Orofeno; Peindol; Profenid; Profenol†.
ported worldwide.1 The causes of death were: gastrointestinal
Ketoprofen may be given by deep intramuscular injec- Multi-ingredient: Gr.: Profenil†; Mex.: Bifebral; Reumophan. bleeding or perforation (47 cases); renal impairment or insuffi-
tion into the gluteal muscle for acute exacerbations of ciency (20); anaphylaxis or asthma (7); haemorrhagic reactions
musculoskeletal, joint, peri-articular and soft-tissue (4); and unexplained or miscellaneous causes (19). Concern over
the safety of ketorolac has led to adverse reactions being moni-
disorders and in the management of pain after ortho- Ketorolac Trometamol (BANM, rINNM) tored closely and to the implementation of restrictions on dose
paedic surgery. Doses of 50 to 100 mg may be given and duration of treatment (see Uses and Administration, below).
Ketorolaakkitrometamoli; Kétorolac trométamol; Ketorolac
every 4 hours, up to a maximum dose of 200 mg in 24 Tromethamine (USAN); Ketorolaco trometamol; Ketorolacum A postmarketing surveillance study2 examined the risks of
hours for up to 3 days. In some countries, ketoprofen parenteral ketorolac in 9 900 patients given 10 272 courses of
Trometamoli; Ketorolacum trometamolum; Ketorolak Trometa-
has also been given intravenously in similar doses. ketorolac. The results indicated a dose-response relationship
mol; Ketorolak z trometamolem; Ketorolaktrometamol; Ketoro- with average daily ketorolac dose for both gastrointestinal bleed-
Ketoprofen may be applied as a 2.5% gel for local pain lak-trometamol; RS-37619-00-31-3. (±)-5-Benzoyl-2,3-dihydro- ing and operative site bleeding, the expected major risks, and an
relief. Doses vary slightly between preparations: typi- 1H-pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hy- association between gastrointestinal bleeding and therapy for
cally, they are applied 2 to 4 times daily for up to 10 droxymethyl)-1,3-propanediol (1 : 1). over 5 days. The risk of serious gastrointestinal bleeding and op-
days. Кеторолак Трометамол erative site bleeding was higher for elderly patients [licensed
C 19 H 24N 2 O 6 = 376.4. product information recommends that the elderly should not re-
Dexketoprofen is given orally as the trometamol salt. ceive daily parenteral doses greater than 60 mg]. Although the
C AS — 74103-06-3 (ketorolac); 74103-07-4 (ketorolac
Doses are expressed in terms of the base; dexketopro- trometamol).
overall associations between ketorolac use and both gastrointes-
fen trometamol 36.9 mg is equivalent to about 25 mg tinal bleeding and operative site bleeding are small, the risk be-
ATC — M01AB15; S01BC05. comes clinically important as doses increase, in elderly patients,
of dexketoprofen. Usual doses are 12.5 mg every 4 to ATC Vet — QM01AB15; QS01BC05. and, for gastrointestinal bleeding only, when used for longer than
6 hours or 25 mg every 8 hours; the total daily dose 5 days.
should not exceed 75 mg. Elderly patients should be US product information has consequently emphasised that
started on a total daily dose not exceeding 50 mg. Dose O ketorolac is a potent NSAID and is indicated only for the short-
reductions are also necessary in patients with hepatic or N term management of moderate to severe pain and not for minor
COOH or chronic painful conditions; its use carries many risks and re-
renal impairment, see below. It is usually recommend-
lated adverse effects can be serious especially when used inap-
ed that NSAIDs are taken with or after food to reduce propriately. After examining data from the above study the EU
any adverse gastrointestinal effects; however, licensed Committee for Proprietary Medicinal Products adopted the opin-
product information for dexketoprofen states that ab- (ketorolac) ion that ketorolac had a narrow therapeutic margin but that it was
sorption is delayed if the drug is taken with food and indicated for the short-term management of moderate to severe
acute postoperative pain.
therefore recommends that in acute pain dexketopro- Pharmacopoeias. In Eur. (see p.vii) and US. Further references to ketorolac’s adverse effects are given be-
fen should be given at least 30 minutes before food. Ph. Eur. 6.2 (Ketorolac Trometamol). A white or almost white, low.3-12
Ketoprofen has also been used as the lysine and as the crystalline powder. Freely soluble in water and in methyl alco- 1. CSM/MCA. Ketorolac: new restrictions on dose and duration of
sodium salt. hol; slightly soluble in alcohol; practically insoluble in dichlo- treatment. Current Problems 1993; 19: 5–6. Also available at:
romethane. A 1% solution in water has a pH of 5.7 to 6.7. Protect http://www.mhra.gov.uk/home/idcplg?IdcService=GET_
◊ Reviews. from light. FILE&dDocName=CON2024455&RevisionSelectionMethod=
1. Mauleón D, et al. Preclinical and clinical development of dexke- LatestReleased (accessed 07/11/07)
USP 31 (Ketorolac Tromethamine). A white to off-white, crys- 2. Strom BL, et al. Parenteral ketorolac and risk of gastrointestinal
toprofen. Drugs 1996; 52: 24–46. talline powder. Freely soluble in water and in methyl alcohol; and operative site bleeding: a postmarketing surveillance study.
Administration in hepatic or renal impairment. No spe- slightly soluble in alcohol, in dehydrated alcohol, and in tetrahy- JAMA 1996; 275: 376–82.
cific dosage recommendations for racemic ketoprofen in patients drofuran; practically insoluble in acetone, in acetonitrile, in butyl 3. Rotenberg FA, Giannini VS. Hyperkalemia associated with
ketorolac. Ann Pharmacother 1992; 26: 778–9.
with hepatic or renal impairment are given by UK licensed prod- alcohol, in dichloromethane, in dioxan, in ethyl acetate, in hex- 4. Boras-Uber LA, Brackett NC. Ketorolac-induced acute renal
uct information, although the drug is contra-indicated in severe ane, and in toluene. pH of a 1% solution in water is between 5.7 failure. Am J Med 1992; 92: 450–2. Correction ibid.; 93: 117.
renal impairment and it is advised that the dose be kept as low as and 6.7. Store in airtight containers at a temperature of 25°, ex- 5. Schoch PH, et al. Acute renal failure in an elderly woman fol-
possible and renal function be monitored in more moderate renal cursions permitted between 15° and 30°. Protect from light. lowing intramuscular ketorolac administration. Ann Pharmaco-
impairment (but see also Renal Impairment, above). In the USA, ther 1992; 26: 1233–6.
6. Goetz CM, et al. Anaphylactoid reaction following ketorolac
however, it has been recommended that patients with hepatic im- Adverse Effects and Treatment tromethamine administration. Ann Pharmacother 1992; 26:
pairment and a serum albumin concentration of less than 1237–8.
3.5 g/dL should be given a maximum initial daily dose of
As for NSAIDs in general, p.96. 7. Randi ML, et al. Haemolytic uraemic syndrome during treat-
100 mg orally. Patients with mild renal impairment should be Concern over the high incidence of reported adverse ment with ketorolac trometamol. BMJ 1993; 306: 186.
8. Fong J, Gora ML. Reversible renal insufficiency following
given a maximum daily dose of 150 mg and those with more se- effects with ketorolac trometamol has led to its with- ketorolac therapy. Ann Pharmacother 1993; 27: 510–12.
vere impairment (GFR less than 25 mL/minute per 1.73 m2 or drawal in some countries while in others its permitted 9. Corelli RL, Gericke KR. Renal insufficiency associated with in-
end-stage renal impairment) should not exceed a maximum daily tramuscular administration of ketorolac tromethamine. Ann
dose of 100 mg. dosage and maximum duration of treatment have been Pharmacother 1993; 27: 1055–7.
UK licensed product information for dexketoprofen recommends reduced. 10. Buck ML, Norwood VF. Ketorolac-induced acute renal failure
in a previously healthy adolescent. Pediatrics 1996; 98: 294–6.
a reduced initial daily dose of 50 mg orally in patients with mild Adverse effects reported include gastrointestinal dis- 11. Feldman HI, et al. Parenteral ketorolac: the risk for acute renal
to moderate hepatic or mild renal impairment. Dexketoprofen turbances including gastrointestinal bleeding (espe- failure. Ann Intern Med 1997; 126: 193–9.
should not be used in patients with severe hepatic or moderate to 12. Reinhart DJ, et al. Minimising the adverse effects of ketorolac.
severe renal impairment.
cially in the elderly), perforation, and peptic ulceration. Drug Safety 2000; 22: 487–97.
Hypersensitivity reactions such as anaphylaxis, rash,
Preparations Precautions
bronchospasm, laryngeal oedema, and hypotension
BP 2008: Ketoprofen Capsules; Ketoprofen Gel.
have also occurred. Other adverse effects reported in- As for NSAIDs in general, p.98.
Proprietary Preparations (details are given in Part 3)
Arg.: Enantyum; Helenil; Orudis†; Profenid†; Salicrem K; Austral.: Orudis; clude drowsiness, dizziness, headache, mental and sen- In light of the concern over the toxicity of ketorolac it
Oruvail; Austria: Keprodol†; Profenid; Prontoket; Belg.: Bi-Rofenid; Fas- sory changes, psychotic reactions, sweating, dry has been recommended that it should not be used dur-
tum; Rofenid; Braz.: Artrifenil; Artrinid; Artrosil; Bi-Profenid; Ceprofen; Fla-
mador; Ketop†; Profenid; Canad.: Apo-Keto; Novo-Keto; Orafen†; mouth, thirst, fever, convulsions, myalgia, aseptic ing pregnancy or labour and some recommend that it
Orudis†; Rhodis; Rhovail†; Chile: Bonil; Cirus; Desketo; Dolo-Ketazon; meningitis, hypertension, dyspnoea, pulmonary oede- should not be given to mothers who are breast feeding
Dolofar; Fastum; Flogofin; Profenid; Relatene; Talflex; Cz.: Bi-Profenid†;
Dexoket; Fastum; Keplat; Ketesse; Ketobene†; Ketonal; Profenid; Pron- ma, bradycardia, chest pain, palpitations, fluid reten- (but see below).
 Ketorolac Trometamol/Leflunomide 75
Ketorolac is contra-indicated in patients with a history dose is excreted in urine as unchanged drug and conju- 15 mg. In the UK, parenteral ketorolac is only recommended for
of hypersensitivity to aspirin or other NSAIDs, a histo- gated and hydroxylated metabolites, the remainder is those aged 16 and over; doses are as for adults (see above).
ry of asthma, nasal polyps, bronchospasm, or angio- excreted in the faeces. Oral ketorolac is not licensed for use in children.
edema, a history of peptic ulceration or gastrointestinal ◊ References. Administration in renal impairment. Ketorolac is contra-
bleeding, in patients with moderate or severe renal im- indicated in patients with moderate to severe renal impairment;
1. Kauffman RE, et al. Enantiomer-selective pharmacokinetics and
for suggested doses in less advanced renal impairment, see Uses
pairment, and in those with hypovolaemia or dehydra- metabolism of ketorolac in children. Clin Pharmacol Ther 1999;
and Administration, above.
65: 382–8.
tion. Ketorolac should not be given to patients with co- 2. Hamunen K, et al. Stereoselective pharmacokinetics of ketorolac
agulation or haemorrhagic disorders or those with in children, adolescents and adults. Acta Anaesthesiol Scand Preparations
1999; 43: 1041–6. USP 31: Ketorolac Tromethamine Injection; Ketorolac Tromethamine Tab-
confirmed or suspected cerebrovascular bleeding. It is 3. Dsida RM, et al. Age-stratified pharmacokinetics of ketorolac lets.
contra-indicated as a prophylactic analgesic before sur- tromethamine in pediatric surgical patients. Anesth Analg 2002;
Proprietary Preparations (details are given in Part 3)
gery and for intraoperative use because of its inhibitory 94: 266–70.
4. McAleer SD, et al. Pharmacokinetics and safety of ketorolac fol- Arg.: Acular ; Dolten; Kelac; Kemanat; Kerarer ; Ketopharm; Klenac;
effects on platelets; it should also not be given postop- lowing single intranasal and intramuscular administration in Nolarac†; Poenkerat; Sinalgico; Teledol; Tenkdol; Unicalm; Austral.: Acular;
Toradol; Austria: Acular; Belg.: Aculare; Taradyl; Braz.: Acular; Cetrolac;
eratively to those who have undergone procedures with healthy volunteers. J Clin Pharmacol 2007; 47: 13–18. Deocil†; Toradol; Toragesic; Canad.: Acular; Toradol; Chile: Acular; Brod-
a high risk of haemorrhage. ifac; Burten; Dilox; Dolgenal; Findedol†; Netaf; Poenkerat; Syndol; Denm.:
Uses and Administration Acular; Toradol; Fin.: Acular; Toradol; Fr.: Acular; Ger.: Acular; Gr.: Acu-
lar; Hong Kong: Acular; Keto; Toradol; India: Cadolac; Ketanov; Ketlur;
The total daily dose of ketorolac should be reduced in Ketorolac, a pyrrolizine carboxylic acid derivative Ketodrops; Ketonic†; Torolac; Indon.: Dolac; Ketopain; Lantipain; Remo-
the elderly and in patients weighing less than 50 kg. It structurally related to indometacin (p.66), is an NSAID pain; Rolac; Scelto; Toradol; Toramine; Torasic; Torpain; Trolac; Xevolac; Irl.:
Acular; Israel: Topadol; Ital.: Acular; Lixidol; Tora-Dol; Malaysia: Acular;
is recommended that patients with mild renal impair- (p.99). It is used principally as an analgesic. Ketanov†; Keto; Toradol; Mex.: Acularen; Ainelac; Aitornet; Alidol; Apo-
ment should receive a reduced dose of ketorolac and Ketorolac is used intramuscularly, intravenously, or toke; Brunacol; Celfax; Doket; Dolac; Dolcoplaz; Dolikan; Dolotor†;
Drometak; Efimerol; Estopein; Exorol; Findol†; Finlac; Geldako; Glicima;
undergo close monitoring of renal function. Ketorolac orally as the trometamol salt in the short-term manage- Godek; Italker; Kendolit; Koprak; Lacdol; Lacomin; Lenaken; Lorotec; Mavi-
should be used with caution in heart failure, hepatic im- ment of moderate to severe postoperative pain. How- dol; Onemer; Plusindol; Rapix; Rolesen; Rolodiquim; Rometran-K; Sebapain;
Supradol; Toloran; Toral; Torkol; Trodorol; Tromedal; Ultilap; Zafidol; Neth.:
pairment and conditions leading to reduction in blood ever, it should be noted that because of concerns over Acular; Norw.: Toradol; NZ: Acular; Philipp.: Acular; Ketanov; Ketomed;
volume or in renal blood flow. Ketorolac should be the high incidence of reported adverse effects with Kortezor; Toradol; Port.: Acular; Elipa; Toradol; Rus.: Adolor (Адолор);
Dolac (Долак); Ketalgin (Кеталгин); Ketanov (Кетанов); Ketorol
withdrawn if clinical symptoms of hepatotoxicity de- ketorolac its dosage and maximum duration of use are (Кеторол); S.Afr.: Acular; Tora-Dol; Singapore: Acular; Keto†; Toradol†;
velop. restricted. The recommended maximum duration for Spain: Acular; Algikey; Droal; Tonum; Toradol; Swed.: Toradol; Switz.: Ac-
ular; Tora-Dol; Thai.: Acular; Turk.: Acular; UK: Acular; Toradol; USA:
Drowsiness and dizziness may affect the performance parenteral therapy is 2 days in the UK, and patients Acular; Toradol†; Venez.: Acular†; Dolak; Kelac; Ketorel†; Ketorol†; Noto-
should be transferred to oral therapy as soon as possi- lac; Ocudol; Poenkerat.
of skilled tasks such as driving. Multi-ingredient: Mex.: Gammadol; Sinergix.
ble; oral use is limited to 7 days. In the USA it is rec-
Breast feeding. The concentration of ketorolac distributed into ommended that the maximum combined duration of
breast milk is very low and a study1 considered that the amount use of parenteral and oral ketorolac should not exceed
ingested by the infant would probably be too small to be harmful. 5 days. Leflunomide (BAN, USAN, rINN)
The American Academy of Pediatrics2 also states that there have
been no reports of any clinical effect on the infant associated with • In the UK the recommended initial dose by the HWA-486; Leflunomid; Leflunomida; Léflunomide; Leflunomidi;
the use of ketorolac by breast-feeding mothers, and that therefore parenteral route is 10 mg of ketorolac trometamol Leflunomidum; RS-34821; SU-101. α,α,α-Trifluoro-5-methyl-4-
it may be considered to be usually compatible with breast feed- followed by 10 to 30 mg every 4 to 6 hours as re- isoxazolecarboxy-p-toluidide.
ing. However, the BNF and both UK and US licensed product
information recommend that ketorolac should be avoided in
quired, although ketorolac may be given as often as Лефлуномид
mothers who are breast feeding. every 2 hours in the initial postoperative period if re- C 12 H 9 F 3N 2 O 2 = 270.2.
quired. The total maximum daily dose is 90 mg C AS — 75706-12-6.
1. Wischnik A, et al. The excretion of ketorolac tromethamine into
breast milk after multiple oral dosing. Eur J Clin Pharmacol (60 mg in the elderly, patients with mild renal im- ATC — L04AA13.
1989; 36: 521–4. pairment, and in those weighing less than 50 kg). In- ATC Vet — QL04AA13.
2. American Academy of Pediatrics. The transfer of drugs and oth- travenous injections should be given over at least 15
er chemicals into human milk. Pediatrics 2001; 108: 776–89. seconds. During transfer from parenteral to oral ther-
Correction. ibid.; 1029. Also available at: F3C
h tt p : // a a p p o l ic y. a a p p u b li c a t i o n s. o rg / c g i /c on t e n t /f u l l / apy the combined daily dose for all forms of ketoro- O
pediatrics%3b108/3/776 (accessed 07/11/07) lac trometamol should not exceed 90 mg (60 mg in
CH3
the elderly, patients with mild renal impairment, and N
Interactions in those weighing less than 50 kg) of which no more H
For interactions associated with NSAIDs, see p.99. than 40 mg should be given orally. O
N
• Regimens in use in the USA include a single intra-
Ketorolac should not be given to patients already re-
muscular dose of 60 mg or a single intravenous dose Pharmacopoeias. In Eur. (see p.vii) and US.
ceiving anticoagulants or to those who will require pro-
of 30 mg, or a multiple-dose regimen comprising Ph. Eur. 6.2 (Leflunomide). A white or almost white powder. It
phylactic anticoagulant therapy, including low-dose exhibits polymorphism. Practically insoluble in water; freely sol-
30 mg every 6 hours intramuscularly or intravenous-
heparin. The risk of ketorolac-associated bleeding is uble in methyl alcohol; sparingly soluble in dichloromethane.
ly, up to a maximum of 120 mg daily. These doses
also increased by other NSAIDs or aspirin and by pen- Protect from light.
should be halved in the elderly, those with renal im- USP 31 (Leflunomide). White to almost white powder. Practi-
toxifylline and use together should be avoided.
pairment, and those weighing less than 50 kg. cally insoluble in water; freely soluble in acetone, in acetonitrile,
Probenecid increases the half-life and plasma concen-
• The recommended oral dose in the UK is 10 mg in alcohol, in chloroform, in ethyl acetate, in isopropyl alcohol,
trations of ketorolac and the two drugs should not be and in methyl alcohol. Store at a temperature not exceeding 30°.
given together. every 4 to 6 hours (every 6 to 8 hours in the elderly)
to a maximum of 40 mg daily for a maximum dura-
Parasympathomimetics. Licensed product information for tion of 7 days. Adverse Effects, Treatment and Precautions
acetylcholine chloride ophthalmic preparations states that there Common adverse effects seen with leflunomide are hy-
• In the USA the recommended oral dose is 20 mg pertension, gastrointestinal disturbances (particularly
have been reports that acetylcholine and carbachol have been in-
effective when used in patients treated with topical (ophthalmic) (10 mg in the elderly, the renally impaired, and those diarrhoea), weight loss, headache, dizziness, leucope-
NSAIDs. weighing under 50 kg), followed by 10 mg every 4 nia, asthenia, paraesthesia, joint disorders and synovi-
to 6 hours to a maximum of 40 mg daily. tis, upper respiratory-tract infections, alopecia, ecze-
Pharmacokinetics For doses in children see Administration in Children, ma, and dry skin. Hypersensitivity reactions may occur
Ketorolac trometamol is absorbed after intramuscular below. and a few cases of Stevens-Johnson syndrome, ery-
or oral doses. At physiological pH ketorolac trometa- Ketorolac trometamol is used as 0.5% eye drops to re- thema multiforme, toxic epidermal necrolysis, or vas-
mol dissociates to form an anionic ketorolac molecule lieve ocular itching associated with seasonal allergic culitis have been reported. Hepatotoxicity has oc-
which is less hydrophilic than the trometamol salt. The conjunctivitis. Ketorolac trometamol eye drops 0.5% curred. It is usually mild and reversible but rare cases
peak plasma concentration of ketorolac is reached have also been used for the topical treatment of cystoid of severe, sometimes fatal, liver disease, including
within about 30 to 60 minutes; absorption after intra- macular oedema and for the prevention and reduction acute hepatic necrosis, have been seen particularly in
muscular injection may be slower than that after oral of inflammation associated with ocular surgery. In the the first 6 months of therapy. Other adverse effects that
doses in some individuals. Ketorolac is over 99% USA, a 0.4% eye drop is also available for postopera- have been reported include anxiety, peripheral neurop-
bound to plasma proteins. It does not readily penetrate tive ocular inflammation. athy, hypokalaemia, and mild hyperlipidaemia. There
the blood-brain barrier. Ketorolac crosses the placenta ◊ Reviews. have been rare reports of pancytopenia, agranulocyto-
and small amounts of drug are distributed into breast 1. Gillis JC, Brogden RN. Ketorolac: a reappraisal of its pharmaco- sis, and thrombocytopenia; these effects are more com-
milk. The terminal plasma half-life is about 4 to 6 dynamic and pharmacokinetic properties and therapeutic use in mon when leflunomide is given with other myelosup-
pain management. Drugs 1997; 53: 139–88.
hours, but is about 6 to 7 hours in the elderly and 9 to pressive drugs (see Interactions, below). There have
Administration in children. In the USA, children aged be-
10 hours in patients with renal dysfunction. The major tween 2 to 16 years may be given a single intramuscular dose of
been occasional reports of pancreatitis, interstitial lung
metabolic pathway is glucuronic acid conjugation; 1 mg/kg of ketorolac trometamol up to a maximum of 30 mg or disease, and severe infections, including fatal sepsis.
there is some para-hydroxylation. About 90% of a a single intravenous dose of 0.5 mg/kg up to a maximum of Renal failure has also been reported.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
76 Analgesics Anti-inflammatory Drugs and Antipyretics
The active metabolite of leflunomide, A-771726, has a weeks of stopping leflunomide but recurred on 2 separate occa- Pharmacokinetics
half-life of about 2 weeks. Consequently, the adverse sions when she took the drug again. After oral doses leflunomide undergoes first-pass
effects of leflunomide may continue even after therapy 1. Gensburger D, et al. Lupus erythematosus with leflunomide: in- metabolism in the liver and gut wall to A-771726 (ter-
duction or reactivation? Ann Rheum Dis 2005; 64: 153–5.
has been stopped. When severe reactions occur, a drug iflunomide), which is responsible for the majority of
Overdose. Unintentional overdoses with leflunomide have
washout procedure (see below) may be required. been reported in 2 patients. In one case, no adverse effects were
the in vivo activity. The bioavailability of leflunomide
Leflunomide should not be given to immunocompro- seen in a 40-year-old woman who had mistakenly taken both a after oral doses ranges from 82 to 95%. Peak plasma
mised patients or to patients with severe infections, he- 100-mg and a 20-mg tablet daily for 28 days;1 in another case, a concentrations of the active metabolite may occur from
70-year-old man who took 100 mg weekly, in addition to 20 mg 1 to 24 hours after a dose.
patic or moderate to severe renal impairment, severe daily, for over 2 years was found to have interstitial nephritis
hypoproteinaemia, or bone-marrow dysplasia. Patients which improved after leflunomide was stopped.2 In both cases, A-771726 is more than 99% bound to plasma proteins,
with a history of tuberculosis should be carefully mon- the 100-mg dose was meant to be taken for 2 or 3 days only as a mainly albumin. It is some further metabolism. About
itored because of the possibility of reactivation of the loading dose. 43% of a dose is eliminated in the urine, mainly as glu-
infection. Intra-uterine devices should be used with 1. Kamali S, et al. An unusual overdose of leflunomide in a patient curonides, and 48% is eliminated in the faeces via the
with rheumatoid arthritis. Ann Pharmacother 2004; 38: 1320–1.
caution during immunosuppressive treatment as there 2. Haydar AA, et al. Chronic overdose of leflunomide inducing in-
bile.
is an increased risk of infection. Live vaccines should terstitial nephritis. Nephrol Dial Transplant 2004; 19: 1334–5. A-771726 has an elimination half-life of about 2
be avoided for the same reason. Blood pressure should Pregnancy. Leflunomide is contra-indicated during pregnancy weeks, which is thought to be mainly due to enterohe-
be monitored regularly during therapy. as its active metabolite has been shown to be teratogenic in ani- patic recycling. Colestyramine or activated charcoal
mals. Pregnancy should therefore be excluded before beginning are able to interrupt recycling and can therefore accel-
In the UK, liver enzyme values should be checked be- therapy, and licensed product information states that reliable con-
fore beginning therapy and at fortnightly intervals dur- traception should be used in women of child-bearing potential erate drug elimination.
ing the first 6 months of treatment; US licensed product (UK product information also recommends reliable contracep- Studies in animals suggest that leflunomide or its
information recommends monthly monitoring for the tion in men treated with leflunomide). Women wishing to be-
come pregnant should wait for 2 years after stopping therapy, or
metabolites are distributed into breast milk.
first 6 months. Subsequent monitoring should be car- if this is infeasible, a washout procedure (see below) should be ◊ References.
ried out at 6- to 8-week intervals. Dosage should be re- performed and a waiting period of 6 weeks be observed from the
1. Rozman B. Clinical pharmacokinetics of leflunomide. Clin
duced if moderate elevations of liver enzyme values time plasma concentrations of the metabolite fall below Pharmacokinet 2002; 41: 421–30.
occur (see Administration in Hepatic Impairment, be- 20 nanograms/mL before attempting conception. A washout 2. Shi J, et al. Population pharmacokinetics of the active metabolite
low); for persistent or more severe elevations lefluno- procedure with a waiting period of at least 3 months is recom- of leflunomide in pediatric subjects with polyarticular course ju-
mended in men who wish to father children. Women who be- venile rheumatoid arthritis. J Pharmacokinet Pharmacodyn
mide should be stopped and washout procedures be- come pregnant during therapy should also undergo a washout 2005; 32: 419–39.
gun. Monitoring of liver enzymes should be continued procedure. 3. Chan V, et al. Population pharmacokinetics and association be-
after stopping therapy until they return to within the tween A77 1726 plasma concentrations and disease activity
Washout procedure. If serious adverse effects occur during measures following administration of leflunomide to people with
normal range. Blood counts should also be checked at leflunomide therapy, licensed product information recommends rheumatoid arthritis. Br J Clin Pharmacol 2005; 60: 257–64.
the same time as liver enzyme values. that a drug washout procedure is performed. This may also be
considered if a patient becomes pregnant while taking lefluno- Uses and Administration
Effects on the lungs. Up to December 2006, the Australian mide, or if it is necessary to swap to another disease-modifying
Adverse Drug Reactions Advisory Committee had received 142 antirheumatic drug such as methotrexate. Leflunomide has immunosuppressant and antiprolifer-
reports of respiratory symptoms with leflunomide use since its For the washout procedure, either 8 g of colestyramine is given
ative properties. It is used as a disease-modifying
introduction in 2000.1 Of these, 22 reports mentioned at least one orally 3 times daily or 50 g of activated charcoal is given orally antirheumatic drug in the treatment of active rheuma-
of the following serious reactions: pneumonitis (8), interstitial or via a nasogastric tube 4 times daily. Therapy is normally con- toid arthritis. It is also used in the treatment of active
lung disease (9), lung infiltration (4), or pulmonary fibrosis (3); tinued for 11 days, but should be repeated until plasma concen-
it was considered that all these were likely to represent interstitial psoriatic arthritis and has been investigated in the man-
trations of the primary metabolite A-771726 are below agement of various solid neoplasms.
lung disease. Four patients died, but relative causality was diffi- 20 nanograms/mL, verified by two separate tests at least 14 days
cult to assign as methotrexate was also given in many cases, apart. Because of the long half-life of the principal metabo-
however, several patients had been on methotrexate long-term
without any problems. It was recommended that the pulmonary lite, a loading dose of leflunomide is required to reach
status of patients should be considered before starting lefluno- Interactions steady-state concentrations relatively rapidly. Therapy
mide and monitored during treatment; if symptoms such as Increased adverse effects may occur if leflunomide is should start with an oral loading dose of 100 mg once
cough or dyspnoea develop or worsen, leflunomide may need to given with other hepatotoxic or myelosuppressive daily for 3 days. However, in practice, the loading dose
be stopped. drugs; these effects may also be seen when lefluno- may be omitted in those patients at an increased risk of
The risk of interstitial lung disease with leflunomide has also mide treatment is followed by such drugs without a adverse effects, particularly haematological or hepatic
been assessed using data from a large cohort study.2 This study drug washout procedure (above). The risks of com- effects. The maintenance dose is 10 to 20 mg once dai-
found that, overall, there was a twofold increase in the risk of
interstitial lung disease in patients treated with leflunomide com- bined use with other disease-modifying antirheumatic ly for rheumatoid arthritis and 20 mg once daily for
pared with those who did not receive leflunomide. However, drugs, particularly in the long term, have not been stud- psoriatic arthritis. Dose adjustments may be necessary
subgroup analysis showed that this increase was limited to those ied and such use is not advised in the UK; however, US in patients who develop abnormal liver enzyme values,
patients with a history of methotrexate use or interstitial lung dis- licensed product information recommends that if long- see below. The therapeutic effect usually starts after 4
ease; in those with no previous methotrexate use or no history of term combined use is necessary, liver enzyme values to 6 weeks of therapy and further improvements may
interstitial lung disease, there was no increased risk with lefluno-
mide. See also under Interactions, below. and blood counts should be monitored monthly rather occur for up to 6 months.
than every 6 to 8 weeks (see Adverse Effects, Treat-
1. Adverse Drug Reactions Advisory Committee (ADRAC). Leflu- Administration in hepatic impairment. Leflunomide is
nomide and interstitial lung disease. Aust Adverse Drug React ment, and Precautions, above). contra-indicated in patients with hepatic impairment. Patients
Bull 2006; 25: 22–3. Also available at: http://www.tga.gov.au/ who develop moderate elevations of liver enzyme values (de-
adr/aadrb/aadr0612.pdf (accessed 13/06/08) See above for precautions about use with live vaccines.
fined as transaminase levels 2 to 3 times the normal upper limit)
2. Suissa S, et al. Leflunomide use and the risk of interstitial lung Anticoagulants. For reference to the effect of leflunomide on while receiving leflunomide treatment should have their dose re-
disease in rheumatoid arthritis. Arthritis Rheum 2006; 54: the activity of warfarin, see under Immunosuppressants, p.1431.
1435–9.
duced to 10 mg daily; if necessary, monitoring of liver enzyme
Methotrexate. Leflunomide therapy has been rarely associat- values should also be performed at weekly intervals. If moderate
Effects on the nervous system. Peripheral neuropathy has ed with pancytopenia. Of the 18 cases (median age 65.5 years) elevations persist or if severe elevations occur, leflunomide
been associated with leflunomide use.1-3 Up to October 2006, the reported in one series, 14 patients were also receiving methotrex- should be stopped and washout procedures started (see above).
Australian Adverse Drug Reactions Advisory Committee had re- ate therapy.1 The pancytopenia was typically severe and required Inflammatory bowel disease. Leflunomide has been tried,
ceived 659 reports of adverse reactions associated with lefluno- hospitalisation; 5 patients had died, 4 of whom were also taking with some success, in the management of Crohn’s disease
mide, 30 of which mentioned neuropathy or peripheral neuropa- methotrexate. Time to onset of pancytopenia ranged from 11 (p.1697).
thy;4 leflunomide was the sole suspected drug in 24 of these days to 4 years. The authors concluded that the risk of pancyto-
cases. Recovery was noted after drug withdrawal in 6 patients, of penia during leflunomide treatment appeared to increase when References.
whom 3 underwent washout procedures; however, 15 patients used with methotrexate, and emphasised the importance of ongo- 1. Prajapati DN, et al. Leflunomide treatment of Crohn’s disease
had not recovered at the time of the reports and there was no in- ing monitoring of blood counts. patients intolerant to standard immunomodulator therapy. J Clin
formation on the remaining cases. Gastroenterol 2003; 37: 125–8.
Leflunomide therapy has also been rarely associated with inter-
1. Bonnel RA, Graham DJ. Peripheral neuropathy in patients treat- stitial lung disease including interstitial pneumonitis (see above). Rheumatoid arthritis. References to the use of leflunomide in
ed with leflunomide. Clin Pharmacol Ther 2004; 75: 580–5. Up to March 2006, the Centre for Adverse Reactions Monitoring rheumatoid arthritis (p.11).
2. Martin K, et al. Neuropathy associated with leflunomide: a case (CARM) in New Zealand2 had received 7 reports of pneumonitis 1. Strand V, et al. Treatment of active rheumatoid arthritis with
series. Ann Rheum Dis 2005; 64: 649–50. associated with leflunomide in patients who were also taking leflunomide compared with placebo and methotrexate. Arch In-
3. Metzler C, et al. Peripheral neuropathy in patients with systemic methotrexate. Of these, 4 had taken methotrexate (which is also tern Med 1999; 159: 2542–50.
rheumatic diseases treated with leflunomide. Ann Rheum Dis associated with pneumonitis) for more than 1 year. Respiratory 2. Prakash A, Jarvis B. Leflunomide: a review of its use in active
2005; 64: 1798–1800. symptoms developed 12 to 36 weeks after starting leflunomide rheumatoid arthritis. Drugs 1999; 58: 1137–64.
4. Adverse Drug Reactions Advisory Committee (ADRAC). Leflu- therapy; 5 patients recovered, 1 died, and another improved but 3. Emery P, et al. A comparison of the efficacy and safety of leflu-
nomide and peripheral neuropathy. Aust Adverse Drug React had some persisting respiratory impairment. nomide and methotrexate for the treatment of rheumatoid arthri-
Bull 2006; 25: 18–19. Also available at: http://www.tga.gov.au/ tis. Rheumatology (Oxford) 2000; 39: 655–65.
adr/aadrb/aadr0610.pdf (accessed 13/06/08) For advice on a drug washout procedure, see above. 4. McCarey DW, et al. Leflunomide in treatment of rheumatoid ar-
1. Chan J, et al. Leflunomide-associated pancytopenia with or thritis. Lancet 2002; 359: 1158.
Effects on the skin. A 58-year-old woman developed lupus without methotrexate. Ann Pharmacother 2004; 38: 1206–11. 5. Miceli-Richard C, Dougados M. Leflunomide for the treatment
erythematosus 1 month after starting leflunomide 20 mg daily 2. Savage R. Leflunomide and pneumonitis. Prescriber Update of rheumatoid arthritis. Expert Opin Pharmacother 2003; 4:
for treatment of Sjögren’s syndrome.1 The rash resolved within 4 2006; 27: 7–9. 987–97.
 Leflunomide/Lornoxicam 77
6. Maddison P, et al. Leflunomide in rheumatoid arthritis: recom- Levomethadone Hydrochloride (rINNM) ⊗ Lithium Salicylate
mendations through a process of consensus. Rheumatology (Ox-
ford) 2005; 44: 280–6. Correction. ibid.; 569. Hidrocloruro de levometadona; Levometadonhidroklorid; Lev- Lithium Salicylicum; Salicilato de litio.
7. Silverman E, et al. Long-term open-label preliminary study of ometadonhydroklorid; Levometadonihydrokloridi; Levometado- Лития Салицилат
the safety and efficacy of leflunomide in patients with polyartic- no hidrochloridas; Lévométhadone, chlorhydrate de; Levometh-
ular-course juvenile rheumatoid arthritis. Arthritis Rheum 2005; C 7 H 5 LiO 3 = 144.1.
52: 554–62. adon-hydrochlorid; Levomethadoni hydrochloridum; (−)-Metha-
C AS — 552-38-5.
8. Silverman E, et al. Leflunomide in Juvenile Rheumatoid Arthri- done Hydrochloride. (−)-6-Dimethylamino-4,4-diphenylheptan-
tis (JRA) Investigator Group. Leflunomide or methotrexate for 3-one hydrochloride.
juvenile rheumatoid arthritis. N Engl J Med 2005; 352: 1655–66.
Левометадона Гидрохлорид HO
Spondyloarthropathies. References to the use of leflunomide C 21 H 27 NO,HCl = 345.9.
in ankylosing spondylitis and psoriatic arthritis (see Spondyloar- Li+ -O
C AS — 125-58-6 (levomethadone); 5967-73-7 (levometh-
thropathies, p.13). adone hydrochloride).
1. Cuchacovich M, Soto L. Leflunomide decreases joint erosions O
and induces reparative changes in a patient with psoriatic arthri-
tis. Ann Rheum Dis 2002; 61: 942–3.
2. Kaltwasser JP, et al. Treatment of Psoriatic Arthritis Study Profile
Group. Efficacy and safety of leflunomide in the treatment of Lithium salicylate is a salicylic acid derivative (see Aspirin,
psoriatic arthritis and psoriasis: a multinational, double-blind,
randomized, placebo-controlled clinical trial. Arthritis Rheum
p.20) that has been used in rheumatic disorders, but its use cannot
2004; 50: 1939–50. be recommended because of the pharmacological effect of the
3. Haibel H, et al. Six months open label trial of leflunomide in lithium ion.
active ankylosing spondylitis. Ann Rheum Dis 2005; 64: 124–6.
H 3C
Lithium salicylate is used in homoeopathic medicine.
4. van Denderen JC, et al. Double blind, randomised, placebo con- N
trolled study of leflunomide in the treatment of active ankylosing O
spondylitis. Ann Rheum Dis 2005; 64: 1761–4. H3C
CH3
5. Schmitt J, Wozel G. Psoriasis-arthritis—Langzeit-therapie zwei- CH3
er Patienten mit Leflunomid. J Dtsch Dermatol Ges 2005; 2:
Lonazolac Calcium (rINNM)
763–6. Calcii Lonazolacum; Lonatsolaakkikalsium; Lonazolac Calcique;
(levomethadone)
6. Nash P, et al. Leflunomide improves psoriasis in patients with Lonazolaco cálcico; Lonazolacum Calcicum; Lonazolakkalcium.
psoriatic arthritis: an in-depth analysis of data from the TOPAS
study. Dermatology 2006; 212: 238–49. Pharmacopoeias. In Eur. (see p.vii). Calcium 3-(4-chlorophenyl)-1-phenylpyrazol-4-ylacetate.
Ph. Eur. 6.2 (Levomethadone Hydrochloride). A white or al- Кальций Лоназолак
Preparations most white, crystalline powder. Soluble in water; freely soluble C 34 H 24 CaCl 2 N 4 O 4 = 663.6.
USP 31: Leflunomide Tablets. in alcohol. Protect from light. C AS — 53808-88-1 (lonazolac); 75821-71-5 (lonazolac
Proprietary Preparations (details are given in Part 3) Profile calcium).
Arg.: Afiancen; Arava; Filartros; Inmunoartro; Lefluar; Molagar†; Austral.: Levomethadone is an opioid analgesic (p.101). It is the active ATC — M01AB09.
Arabloc; Arava; Austria: Arava; Belg.: Arava; Braz.: Arava; Canad.: Arava; ATC Vet — QM01AB09.
Chile: Arava; Artrimod; Cz.: Arava; Denm.: Arava; Fin.: Arava; Fr.: Arava; isomer of racemic methadone (p.82) and is used similarly, as the
Ger.: Arava; Gr.: Arava; Hong Kong: Arava; Hung.: Arava; India: Arava; hydrochloride, in the treatment of severe pain and in the manage-
Lara†; Lefumide; Rumalef; Indon.: Arava; Irl.: Arava; Israel: Arava; Ital.: ment of opioid dependence.
Arava; Malaysia: Arava; Mex.: Arava; Neth.: Arava; Norw.: Arava; NZ:
Arava; Philipp.: Arava; Pol.: Arava; Port.: Arava; Rus.: Arava (Арава); Preparations HO
S.Afr.: Arava; Singapore: Arava; Spain: Arava; Swed.: Arava; Switz.: Ar-
O
ava; Thai.: Arava; Turk.: Arava; UK: Arava; USA: Arava; Venez.: Arava. Proprietary Preparations (details are given in Part 3)
Ger.: L-Polamidon.

N
Levacetylmethadol (rINN)
Levorphanol Tartrate (BANM, rINNM) N
l-α-Acetylmethadol; LAAM (levacetylmethadol or levacetyl-
Levorphan Tartrate; Levorphanol Bitartrate; Lévorphanol, Tar-
methadol hydrochloride); LAM; Levacetilmetadol; Levacetyl-
trate de; Levorphanoli Tartras; Methorphinan Tartrate; Tartrato Cl
metadol; Lévacétylméthadol; Levacetylmethadolum; Levase-
de levorfanol. (−)-9a-Methylmorphinan-3-ol hydrogen tartrate
tyylimetadoli; Levomethadyl Acetate (USAN); l-Methadyl Acetate.
dihydrate. (lonazolac)
(−)-4-Dimethylamino-1-ethyl-2,2-diphenylpentyl acetate.
Леворфанола Тартрат
Левацетилметадол
C 17 H 23 NO,C 4 H 6 O 6,2H 2O = 443.5. Profile
C 23 H 31NO 2 = 353.5. C AS — 77-07-6 (levorphanol); 125-72-4 (anhydrous lev- Lonazolac calcium is an NSAID (p.96). It has been given orally
C AS — 1477-40-3 (levomethadyl); 34433-66-4 (le- orphanol tartrate); 5985-38-6 (levorphanol tartrate dihy- and rectally in the treatment of pain, inflammation, and muscu-
vacetylmethadol). drate). loskeletal and joint disorders.
ATC — N07BC03.
ATC Vet — QN07BC03. Preparations
HO Proprietary Preparations (details are given in Part 3)
Austria: Irritren†; Ger.: Argun†; arthro akut†; Port.: Atrilon†.
O

CH3 H
H3C O Lornoxicam (BAN, USAN, rINN)
H3C N NCH3 Chlorotenoxicam; Chlortenoxicam; CTX; Lornoksikaami; Lor-
CH3 noksikam; Lornoxicamum; Lornoxicanum; Lornoxikam; Ro-13-
CH3 9297; TS-110. 6-Chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-
thieno[2,3-e][1,2]-thiazine-3-carboxamide 1,1-dioxide.
(levorphanol)
Лорноксикам
Pharmacopoeias. In US. C 13 H 10 ClN 3 O 4 S 2 = 371.8.
USP 31 (Levorphanol Tartrate). A practically white, odourless, C AS — 70374-39-9.
Levacetylmethadol Hydrochloride (rINNM) crystalline powder. Soluble 1 in 50 of water and 1 in 120 of alco- ATC — M01AC05.
Hidrocloruro de levacetilmetadol; LAAM (levacetylmethadol or hol; insoluble in chloroform and in ether. Store at a temperature ATC Vet — QM01AC05.
levacetylmethadol hydrochloride); Lévacétylméthadol, Chlorhy- of 25°, excursions permitted between 15° and 30°.
drate de; Levacetylmethadoli Hydrochloridum; Levomethadyl Profile
Acetate Hydrochloride (USAN); MK-790. (−)-(3S,6S)-6-(Dimeth- Levorphanol tartrate, a phenanthrene derivative, is a potent opi- O CH3
ylamino)-4,4-diphenyl-3-heptanol acetate hydrochloride. O
oid analgesic (p.101) used in the management of moderate to se- S N HN
Левацетилметадола Гидрохлорид vere pain. The analgesic effect usually begins about 10 to 60
minutes after oral doses and lasts up to about 8 hours. A usual N
C 23 H 31NO 2 ,HCl = 390.0.
initial oral dose of levorphanol tartrate is 2 mg repeated in 6 to 8 O
C AS — 43033-72-3. hours if necessary; the dose may be increased to 3 mg every 6 to
ATC — N07BC03. 8 hours, adjusted according to response. The maximum initial Cl S OH
ATC Vet — QN07BC03. daily dose in non-opioid tolerant patients should not exceed
Profile 12 mg. Elderly or debilitated patients may require lower doses; Profile
Levacetylmethadol, a diphenylheptane derivative, is a long-act- initial doses should be reduced by 50% or more. Lornoxicam, an oxicam derivative, is an NSAID (p.96). It is used
ing opioid analgesic (p.104); it is a derivative of methadone Levorphanol tartrate has also been given by intramuscular, sub- in musculoskeletal and joint disorders such as osteoarthritis and
(p.84). It was used as the hydrochloride in the management of cutaneous, or slow intravenous injection for pain relief and for rheumatoid arthritis; it is also used in the treatment of other pain-
opioid dependence. However, the proarrhythmic effects led to its premedication. ful conditions including postoperative pain.
withdrawal in the EU and the USA. Preparations In the treatment of osteoarthritis and rheumatoid arthritis lornox-
icam is given in an initial oral daily dose of 12 mg in two or three
Preparations USP 31: Levorphanol Tartrate Injection; Levorphanol Tartrate Tablets. divided doses; if necessary the daily dose may be increased to a
Proprietary Preparations (details are given in Part 3) Proprietary Preparations (details are given in Part 3) maximum of 16 mg.
Irl.: OrLAAM†; Spain: OrLAAM†; USA: OrLAAM†. USA: Levo-Dromoran†. Lornoxicam is given in oral doses of 8 to 16 mg daily for the
treatment of pain. Similar doses may be given by intravenous or
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
78 Analgesics Anti-inflammatory Drugs and Antipyretics
intramuscular injection, although in rare cases the maximum in- mal (ULN) or in those taking other drugs known to cause clini- cations is less with lumiracoxib than with non-selective NSAIDs
itial daily dose may be increased to 24 mg. cally significant hepatic toxicity. All patients should have base- (diclofenac, naproxen, and ibuprofen).
◊ References. line liver function tests before starting lumiracoxib treatment; 1. Schnitzer TJ, et al. Comparison of lumiracoxib with naproxen
those in whom transaminases are more than 1.5 times the ULN and ibuprofen in the Therapeutic Arthritis Research and Gas-
1. Balfour JA, et al. Lornoxicam: a review of its pharmacology and trointestinal Event Trial (TARGET), reduction in ulcer compli-
therapeutic potential in the management of painful and inflam- should not start treatment. Liver function tests should be repeated
cations: randomised controlled trial. Lancet 2004; 364: 665–74.
matory conditions. Drugs 1996; 51: 639–57. monthly and lumiracoxib should be stopped in those patients 2. Hawkey CJ, et al. Gastrointestinal tolerability of lumiracoxib in
2. Skjodt NM, Davies NM. Clinical pharmacokinetics of lornoxi- with an increase in transaminases greater than 3 times the ULN; patients with osteoarthritis and rheumatoid arthritis. Clin Gas-
cam: a short half-life oxicam. Clin Pharmacokinet 1998; 34: in those with an increase greater than 2 times the ULN, liver troenterol Hepatol 2006; 4: 57–66.
421–8. function tests should be repeated in 7 days. Patients should be
3. Frizziero L, et al. Studio a lungo termine su efficacia e sicurezza Effects on the kidneys. Limited evidence of the renal toxicity
terapeutica di lornoxicam nell’artrite reumatoide. Minerva Med
advised to report any symptoms suggestive of liver toxicity such of the selective cyclo-oxygenase-2 (COX-2) inhibitors such as
2002; 93: 315–20. as anorexia, nausea, vomiting, abdominal pain, fatigue, dark lumiracoxib suggests that these NSAIDs appear to have effects
4. Thienthong S, et al. Treatment of pain after spinal surgery in the urine, and jaundice. on renal function similar to those of the non-selective NSAIDs
recovery room by single dose lornoxicam: a randomized, double Lumiracoxib should not be used in patients with ischaemic heart
blind, placebo-controlled trial. J Med Assoc Thai 2004; 87:
(see p.98).
650–5.
disease, cerebrovascular disease, or peripheral arterial disease. It
should be used with caution in patients with significant risk fac- Effects on the liver. In August 2007, the regulatory authority
5. Zhao H, et al. Application of lornoxicam to patient-controlled in Australia withdrew lumiracoxib from the market after reports
analgesia in patients undergoing abdominal surgeries. Chin Med tors for cardiovascular disease such as hypertension, hyperlipi-
Sci J 2005; 20: 59–62. daemia, and diabetes mellitus. of hepatotoxicity.1,2 In the 6 months since marketing, there had
been 8 reports of serious adverse liver reactions resulting in 2
Preparations Lumiracoxib is also contra-indicated in patients with inflamma- deaths and 2 transplantations. There was some concern that pre-
Proprietary Preparations (details are given in Part 3) tory bowel disease, moderate to severe heart failure (NYHA licensing clinical study data seemed to suggest that those patients
Arg.: Acabel†; Hypodol; Austria: Artok; Lornox; Xefo; Chile: Acabel†; class II to IV), and moderate to severe renal impairment associ- who developed elevated liver function tests while on lumiracox-
Cz.: Xefo; Denm.: Xefo; Ger.: Telos; Gr.: Xefo; Hung.: Xefo; Israel: Xefo; ated with a creatinine clearance of less than 50 mL/minute. Cau- ib would recover once the drug was stopped; however, in the 8
Ital.: Noxon; Taigalor; Jpn: Lorcam; Port.: Acabel; Bosporon; Rus.: Xefo- tion is recommended when using lumiracoxib in dehydrated pa-
cam (Ксефокам); S.Afr.: Xefo; Spain: Acabel; Bosporon; Swed.: Xefo; Australian cases, some patients did not improve because of the
Switz.: Xefo; Thai.: Xefo†; Turk.: Xefo; Venez.: Acabel. tients; it may be advisable to rehydrate patients before giving severity of the hepatic damage.
lumiracoxib.
In response to the Australian data, the MHRA in the UK reported
Effects on the cardiovascular system. There have been that it had received 16 reports of suspected adverse reactions to
Loxoprofen Sodium (rINNM) concerns about the adverse cardiovascular effects of selective lumiracoxib;3 of these, one was a case of hepatotoxicity in which
cyclo-oxygenase-2 (COX-2) inhibitors after the worldwide with- the patient recovered after the drug was withdrawn. Worldwide,
CS-600 (loxoprofen); Loxoprofène Sodique; Loxoprofeno sódi- drawal of rofecoxib (see p.121). The cardiovascular safety of the MHRA was aware of 11 reports of serious hepatotoxicity in-
co; Natrii Loxoprofenum. Sodium (±)-p-[(2-oxocyclopentyl)me- lumiracoxib has been assessed in the Therapeutic Arthritis Re- cluding 9 cases of liver failure, 2 deaths, and 3 liver transplants
thyl]hydratropate dihydrate. search and Gastrointestinal Event Trial (TARGET)1 which in- suspected to be at least possibly related to lumiracoxib use. The
Натрий Локсопрофен volved over 18 000 patients with osteoarthritis. Lumiracoxib dose used in most of the cases was higher than the maximum
C 15 H 17 O 3 Na,2H 2 O = 304.3. 400 mg daily (2 to 4 times the recommended dose) was com- dose of 100 mg daily that is recommended in the UK and other
C AS — 68767-14-6 (loxoprofen); 80382-23-6 (loxopro- pared against either naproxen 1 g daily, or ibuprofen 2.4 g daily; European countries. (Higher maximum daily doses have been li-
fen sodium dihydrate). low-dose aspirin (100 mg daily or less) was also allowed where censed in other countries; in Australia, the licensed maximum
indicated. After a planned treatment duration of 1 year, the inci- dose was 400 mg daily for some conditions.) At that time in the
dence of myocardial infarction, stroke, or cardiovascular death UK, new prescribing restrictions on the use of lumiracoxib in os-
with lumiracoxib was found to be similar to that for ibuprofen or teoarthritis were issued (see Adverse Effects and Precautions,
HO naproxen. More events were noted in the lumiracoxib versus above) while its safety was reviewed by European regulatory
naproxen subgroup than in the lumiracoxib versus ibuprofen authorities. However, lumiracoxib was withdrawn from the Ca-
O nadian market after Health Canada noted 4 cases of severe hepa-
group; however, this difference was not statistically significant
O and the authors considered that the higher number of patients totoxicity, including 2 in Canada, associated with the 100-mg
with a history of vascular risk in the lumiracoxib versus naproxen dose of lumiracoxib.4 Following the review of the risks and ben-
CH3
subgroup could explain this finding. In addition, it was noted that efits of lumiracoxib in October 2007, the MHRA reiterated its
the incidence of heart failure was less frequent with lumiracoxib earlier prescribing restrictions and stated the issue of hepatotox-
(loxoprofen) icity would continue to be monitored. They also advised that,
although, again, this was not significant; however, blood pres-
sure changes from baseline were significantly less likely with lu- worldwide up until then, there had been 19 cases of severe liver
Pharmacopoeias. In Jpn. miracoxib than with ibuprofen or naproxen. reactions, including 13 of liver failure, 2 deaths, and 3 liver trans-
Profile More recently, a meta-analysis2 by the manufacturer (which in- plants suspected to be possibly related to use of lumiracoxib.5
Loxoprofen sodium is an NSAID (p.96) given orally for the cluded the above study along with other published and unpub- However, in November 2007, after a further review of world-
management of pain and inflammation associated with muscu- lished clinical studies of lumiracoxib in the treatment of osteoar- wide safety data showed an increased number of serious liver
loskeletal and joint disorders or operative procedures. Loxopro- thritis and rheumatoid arthritis) has also found no evidence that reactions with the 100-mg dose which, in some cases, occurred
fen sodium is given as the dihydrate although doses are ex- the risk of thrombotic events with lumiracoxib is significantly with short-term use, the MHRA suspended the product licence
pressed in terms of the anhydrous salt. Anhydrous loxoprofen increased when compared to placebo, to naproxen (1 g daily), or for lumiracoxib.6 Subsequently, the EMEA7 has recommended
sodium 10 mg is equivalent to about 11.3 mg of loxoprofen so- to the NSAIDs diclofenac (150 mg daily), ibuprofen (2.4 g dai- its withdrawal in the EU.
dium dihydrate. A usual oral dose equivalent to 60 mg of the ly), celecoxib (up to 400 mg daily), and rofecoxib (25 mg daily) 1. Australian Therapeutic Goods Administration. Urgent advice re-
anhydrous form has been given three times daily. garding management of patients taking lumiracoxib (Prexige)
as a group. (issued 13th August, 2007). Available at: http://www.tga.gov.au/
Preparations For further details on the relative risk of cardiovascular throm- alerts/prexige.htm (accessed 08/11/07)
Proprietary Preparations (details are given in Part 3) botic events with NSAIDs, see p.97. 2. Adverse Drug Reactions Advisory Committee (ADRAC). With-
Arg.: Oxeno; Braz.: Loxonin; Jpn: Lobu; Loxonin; Mex.: Loxonin; drawal of lumiracoxib in Australia. Aust Adverse Drug React
For discussion and advice on the use of selective COX-2 inhibi- Bull 2008; 27: 6–7. Also available at:
Philipp.: Loxonin; Thai.: Loxonin; Venez.: Loxonin. tors in patients with cardiovascular or cerebrovascular disease, http://www.tga.health.gov.au/adr/aadrb/aadr0804.pdf (accessed
see under Celecoxib, p.34. 17/07/08)
1. Farkouh ME, et al. Comparison of lumiracoxib with naproxen 3. MHRA. New (interim) restrictions on prescription of lumiracox-
ib, following concerns over liver safety (issued 24th August,
Lumiracoxib (BAN, USAN, rINN) and ibuprofen in the Therapeutic Arthritis Research and Gas-
2007). Available at: http://www.mhra.gov.uk/Safetyinformation/
trointestinal Event Trial (TARGET), cardiovascular outcomes:
Cox-189; Lumiracoxibum. 2-{[(2-Chloro-6-fluorophenyl)ami- randomised controlled trial. Lancet 2004; 364: 675–84. Safetywarningsalertsandrecalls/Safetywarningsandmessag
no]-5-methylphenyl}acetic acid. esformedicines/CON2032098 (accessed 29/08/08)
2. Matchaba P, et al. Cardiovascular safety of lumiracoxib: a meta-
4. Health Canada. Withdrawal of market authorisation for Prexige.
Лумиракоксиб analysis of all randomized controlled trials ≥1 week and up to 1
(issued 4th October, 2007). Available at: http://www.hc-sc.gc.ca/
year in duration of patients with osteoarthritis and rheumatoid
C 15 H 13 ClFNO 2 = 293.7. arthritis. Clin Ther 2005; 27: 1196–1214.
ahc-asc/media/advisories-avis/2007/2007_141_e.html (accessed
C AS — 220991-20-8. 30/10/07)
ATC — M01AH06. Effects on the gastrointestinal tract. It is generally accept- 5. MHRA. Lumiracoxib and liver adverse reactions (issued 16th
ed that the inhibition of cyclo-oxygenase-1 (COX-1) plays a role October, 2007).
ATC Vet — QM01AH06. Available at: http://www.mhra.gov.uk/Safetyinformation/
in the adverse gastrointestinal effects of the NSAIDs, and that the Safetywarningsalertsandrecalls/Safetywarningsandmessag
selective inhibition of the other isoform, COX-2, by NSAIDs esformedicines/CON2032831 (accessed 29/08/08)
H3C such as lumiracoxib may cause less gastrotoxicity than that seen 6. MHRA. Lumiracoxib (Prexige): suspension of marketing au-
with the non-selective inhibition of the traditional NSAIDs. thorisations (issued 19th November, 2007).
However, licensed product information has stated that upper gas- Available at: http://www.mhra.gov.uk/Safetyinformation/
Safetywarningsalertsandrecalls/Safetywarningsandmessag
Cl trointestinal ulceration and bleeds, in some cases fatal, have oc- esformedicines/CON2033073 (accessed 29/08/08)
curred with lumiracoxib treatment; consequently it should be 7. EMEA. European Medicines Agency recommends withdrawal
HO used with caution in patients at risk of such events. of the marketing authorisations for lumiracoxib-containing med-
HN Results from controlled studies confirm that NSAIDs selective icines (issued 13th December, 2007). Available at: http://
www.emea.europa.eu/pdfs/human/press/pr/PR_Lumiracoxib_
O for COX-2 are associated with a lower incidence of serious gas- 57930107en.pdf (accessed 17/07/08)
trointestinal effects. A study1 in patients with osteoarthritis tak-
F ing lumiracoxib at supratherapeutic doses (400 mg daily) con- Interactions
cluded that there was a lower incidence of definite or probable For interactions associated with NSAIDs in general, see p.99.
Adverse Effects, Treatment, and Precautions upper gastrointestinal ulcer complications (bleeding, perforation, Lumiracoxib may cause liver toxicity and consequently it should
As for NSAIDs in general, p.96. or obstruction) after 12 months of treatment when compared not be used with other drugs known to cause clinically significant
Hypersensitivity reactions including anaphylaxis and angioede- with non-selective NSAIDS (ibuprofen 2.4 g daily or naproxen hepatotoxicity.
ma have occurred in patients receiving lumiracoxib; it should be 1 g daily). The incidence of endoscopically-detected ulcers was There is the possibility that lumiracoxib may decrease the clear-
stopped at the first signs of hypersensitivity. also less with lumiracoxib than with non-selective NSAIDs. ance of drugs that are cytochrome P450 CYP2C9 substrates and
Lumiracoxib use, particularly at high doses, may cause severe However, the use of low-dose aspirin appeared to nullify any caution is advised when it is given with CYP2C9 substrates that
liver toxicity (see Effects on the Liver, below) and its use is con- protective gastrointestinal effect of lumiracoxib. have a narrow therapeutic index such as phenytoin and warfarin.
tra-indicated in patients with hepatic disease. It should also not An analysis2 of pooled data from 15 pre-licensing studies in pa- Pharmacokinetics
be used in those with a history of drug-induced increases in tients with rheumatoid arthritis or osteoarthritis has also conclud- Lumiracoxib is absorbed from the gastrointestinal tract after oral
transaminase values greater than 3 times the upper limit of nor- ed that the risk of upper gastrointestinal ulcers and ulcer compli- use with peak plasma concentrations reached in about 2 hours.
 Loxoprofen Sodium/Meclofenamic Acid 79
Protein binding is at least 98%. Lumiracoxib undergoes exten- daily parenteral dose is equivalent to 4 g of aspirin for very se- doses of magnesium salicylate, expressed in terms of anhydrous
sive hepatic metabolism; several enzymes appear to be involved vere pain and to 6 g of aspirin for rheumatic disorders. magnesium salicylate, are about 300 to 600 mg every 4 hours for
including glucuronosyltransferase and cytochrome P450 isoen- Lysine aspirin is also used with metoclopramide in the treatment pain or fever.
zymes. The main oxidative pathway is mediated by the CYP2C9 of migraine. Preparations
isoenzyme; however, this does not appear to be the major path- Lysine aspirin has also been used in the management of throm- USP 31: Magnesium Salicylate Tablets.
way. Three major metabolites have been identified: 4′-hydroxy- boembolic disorders.
lumiracoxib, 5-carboxy-lumiracoxib, and 4′-hydroxy-5-car- Proprietary Preparations (details are given in Part 3)
boxy-lumiracoxib. The 4′-hydroxy metabolite is active as a Headache. Some references to the use of lysine aspirin, often Arg.: Rati Salil E†; Canad.: Herbogesic; USA: Backache Maximum Strength
Relief; Bayer Select Maximum Strength Backache; Doans; Magan; Mobidin;
cyclo-oxygenase-2 (COX-2) inhibitor although it is less potent with metoclopramide, in the treatment of migraine. Momentum Muscular Backache Formula; MST; Novasal; Nuprin Backache†.
than lumiracoxib. The plasma half-life of lumiracoxib is about 4 1. Tfelt-Hansen P, et al. The effectiveness of combined oral lysine Multi-ingredient: Cz.: Cholagol; Hung.: Cholagol; Rus.: Cholagol
hours. Slightly more of a dose is excreted in the urine (54%) than acetylsalicylate and metoclopramide compared with oral su- (Холагол); USA: Cafgesic Forte; Combiflex ES; Durabac Forte; Extra
in the faeces (about 43%); only about 5% of a dose is excreted matriptan for migraine. Lancet 1995; 346: 923–6. Strength Doans PM; Mobigesic; Painaid BRF Back Relief Formula; Tetra-Mag.
unchanged. 2. Diener HC. Efficacy and safety of intravenous acetylsalicylic
acid lysinate compared to subcutaneous sumatriptan and
◊ References. parenteral placebo in the acute treatment of migraine. A double-
1. Scott G, et al. Pharmacokinetics of lumiracoxib in plasma and blind, double-dummy, randomized, multicenter, parallel group Meclofenamic Acid (BAN, USAN, rINN)
synovial fluid. Clin Pharmacokinet 2004; 43: 467–78. study. Cephalalgia 1999; 19: 581–8.
3. Tfelt-Hansen P. The effectiveness of combined oral lysine ace- Acide Méclofénamique; Ácido meclofenámico; Acidum
Uses and Administration tylsalicylate and metoclopramide (Migpriv ) in the treatment of Meclofenamicum; CI-583; INF-4668. N-(2,6-Dichloro-m-
Lumiracoxib is an NSAID (p.99) reported to be a selective inhib- migraine attacks: comparison with placebo and oral sumatriptan. tolyl)anthranilic acid.
itor of cyclo-oxygenase-2 (COX-2). It has been withdrawn in Funct Neurol 2000; 15 (suppl 3): 196–201.
Меклофенамовая Кислота
many countries after reports of hepatotoxicity. In the UK, lumi- Nasal polyps. Two long-term controlled studies1 suggested that
racoxib was used in the treatment of osteoarthritis of the knee and C 14 H 11 Cl 2 NO 2 = 296.1.
topical (endonasal) lysine aspirin may be effective in preventing C AS — 644-62-2.
hip in an oral dose of 100 mg once daily. Higher doses of up to the recurrence of nasal polyps after surgical removal (see p.1508) ATC — M01AG04; M02AA18.
400 mg daily have been used in some countries but may be asso- in both aspirin-tolerant and aspirin-sensitive patients. This effect ATC Vet — QM01AG04; QM02AA18.
ciated with an increased risk of hepatotoxicity (see Effects on the may be attributed to the non-specific anti-inflammatory proper-
Liver, above). ties of lysine aspirin. Although no adverse effects were reported
◊ References. in this study, hypersensitivity reactions have been seen after use COOH Cl
1. Lyseng-Williamson KA, Curran MP. Lumiracoxib. Drugs 2004; of salicylates in the presence of nasal polyps (see Hypersensitiv- H
64: 2237–46. ity under Adverse Effects of Aspirin, p.21). N CH3
2. Bannwarth B, Berenbaum F. Clinical pharmacology of lumira- In another study2 intranasal lysine aspirin did not show signifi-
coxib, a second-generation cyclooxygenase 2 selective inhibitor.
Expert Opin Invest Drugs 2005; 14: 521–33. cant clinical benefit in preventing the recurrence of nasal polyps
3. Rordorf CM, et al. Clinical pharmacology of lumiracoxib: a se- when compared with placebo. However, significant improve- Cl
lective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet 2005; ment at a microscopic level was noted.
44: 1247–66. 1. Nucera E, et al. Effects of lysine-acetylsalicylate (LAS) treat- Pharmacopoeias. In BP(Vet).
4. Schnitzer TJ, et al. Lumiracoxib in the treatment of osteoarthri- ment in nasal polyposis: two controlled long term prospective BP(Vet) 2008 (Meclofenamic Acid). A white or almost white,
tis, rheumatoid arthritis and acute postoperative dental pain: re- follow up studies. Thorax 2000; 55 (suppl 2): S75–78.
sults of three dose-response studies. Curr Med Res Opin 2005; crystalline powder. Practically insoluble in water; slightly solu-
2. Parikh AA, Scadding GK. Intranasal lysine-aspirin in aspirin-
21: 151–61. sensitive nasal polyposis: a controlled trial. Laryngoscope 2005;
ble in alcohol and in chloroform; sparingly soluble in ether; sol-
5. Berenbaum F, et al. Efficacy of lumiracoxib in osteoarthritis: a 115: 1385–90. uble in dimethylformamide and in 1M sodium hydroxide.
review of nine studies. J Int Med Res 2005; 33: 21–41.
6. Sheldon E, et al. Efficacy and tolerability of lumiracoxib in the Preparations
treatment of osteoarthritis of the knee: a 13-week, randomized, Meclofenamate Sodium (BANM, USAN, rINNM)
Proprietary Preparations (details are given in Part 3)
double-blind comparison with celecoxib and placebo. Clin Ther Méclofénamate de Sodium; Meclofenamato sódico; Natrii
2005; 27: 64–77. Arg.: Aspirina; Corplus†; Decitriol; Yectaspirin; Belg.: Aspegic; Cardegic;
Cz.: Aspegic†; Dolorosan†; Kardegic; Fr.: Aspegic; Cardiosolupsan; Kar- Meclofenamas.
7. Fleischmann R, et al. Lumiracoxib is effective in the treatment degic; Ger.: Aspisol†; Gr.: Aspicalm; Egicalm; Egicalm Cardio; Hung.: As-
of osteoarthritis of the knee: a prospective randomized 13-week pegic; Kardegic; Kardiren†; Israel: Lysoprin†; Ital.: Aspegic; Aspidol†; Car-
Натрий Меклофенамат
study versus placebo and celecoxib. Clin Rheumatol 2006; 25: direne; Flectadol; Malaysia: Aspegic†; Mex.: Coraspir; Kardegic; Neth.: C 14 H 10 Cl 2 NNaO 2,H 2 O = 336.1.
42–53. Aspegic; Cardegic; Pol.: Laspal; Port.: Aspegic; Inesprin; Intraspir; Kardegic; C AS — 6385-02-0.
Preparations Lisaspin; Tiplac†; Spain: ASL; Inyesprin; Lysinotol†; Solusprin†; Switz.: Al-
cacyl instantanee; Aspegic; Kardegic; Venez.: Asalis†. Pharmacopoeias. In US.
Proprietary Preparations (details are given in Part 3) USP 31 (Meclofenamate Sodium). A white to creamy white,
Arg.: Prexige; Austral.: Prexige†; Braz.: Prexige; Chile: Prexige; Hung.: Multi-ingredient: Belg.: Migpriv; Chile: Dolotol 12; Cz.: Migpriv†;
Denm.: Migpriv†; Fin.: Migpriv; Fr.: Aspegic Codeine†; Migpriv; Gr.: odourless to almost odourless, crystalline powder. Freely soluble
Prexige; Indon.: Prexige; NZ: Prexige; Port.: Frexocel†; Hirzia†; UK: Prex- in water, the solution sometimes being somewhat turbid due to
ige†. Premig; Hung.: Migpriv; Ital.: Migpriv; Migraprim; Mex.: Antigram; Neth.:
Migrafin; Norw.: Migpriv†; Pol.: Migpriv; Spain: Fluxal†; Swed.: Migpriv; partial hydrolysis and absorption of carbon dioxide; the solution
Switz.: Migpriv; UK: Migramax. is clear above pH 15. Slightly soluble in chloroform; practically
insoluble in ether; soluble in methyl alcohol. Store in airtight
Lysine Aspirin containers. Protect from light.
Acetilsalicilato de lisina; Aspirin DL-Lysine; Lysiiniasetyylisalisylaatti; Magnesium Salicylate Adverse Effects, Treatment, and Precautions
Lysinacetylsalicylat; Lysine Acetylsalicylate; DL-Lysine Acetylsali- Salicilato magnésico. As for NSAIDs in general, p.96.
cylate; Lysinum Acetylsalicylicum.
Магния Салицилат Incidence of adverse effects. The commonest adverse effect
Лизин-Аспирин in 2500 patients given meclofenamate sodium was gastrointesti-
C 14 H 10 MgO 6,4H 2 O = 370.6.
C 15 H 22N 2 O 6 = 326.3. nal disturbance.1 Diarrhoea occurred in 11.2% of patients in dou-
C AS — 18917-89-0 (anhydrous magnesium salicylate);
C AS — 62952-06-1. 18917-95-8 (magnesium salicylate tetrahydrate). ble-blind studies and 32.8% of patients in long-term studies (up
to 3 years). Ulcers were detected in 22 patients during therapy
and skin rashes occurred in 4% of patients. Transient increases in
COOH serum aminotransferases and BUN occurred in some patients.
O
O CH3 H 2N COOH 1. Preston SN. Safety of sodium meclofenamate (Meclomen™).
O- HO Curr Ther Res 1978; 23 (suppl 4S): S107–12.

O NH2 Mg2+ Effects on the blood. Case reports of agranulocytosis1 and

-
O thrombocytopenia2 associated with meclofenamate therapy.
OH 1. Wishner AJ, Milburn PB. Meclofenamate sodium-induced
Pharmacopoeias. In Fr. O agranulocytosis and suppression of erythropoiesis. J Am Acad
Dermatol 1985; 13: 1052–3.
Adverse Effects, Treatment, and Precautions 2. Rodriguez J. Thrombocytopenia associated with meclofenamate.
As for Aspirin, p.20. Anaphylactic shock has been reported in Pharmacopoeias. In Chin. and US. Drug Intell Clin Pharm 1981; 15: 999.
patients given lysine aspirin by injection. USP 31 (Magnesium Salicylate). A white, odourless, efflorescent,
Lysine aspirin, like aspirin, should not generally be given to chil- crystalline powder. Soluble in water and in alcohol; slightly sol- Interactions
uble in ether; freely soluble in methyl alcohol. Store in airtight For interactions associated with NSAIDs, see p.99.
dren because of the risk of Reye’s syndrome.
containers. Pharmacokinetics
Hypersensitivity. For a suggestion that lysine aspirin might be
Adverse Effects, Treatment, and Precautions Meclofenamate sodium is readily absorbed when given orally.
more suitable than aspirin for the diagnosis of sensitivity to
As for Aspirin, p.20. Magnesium salicylate should also be used Peak plasma concentrations occur about 0.5 to 2 hours after in-
NSAIDs, see under Hypersensitivity on p.21.
with caution in renal impairment because of the risk of hyper- gestion. Meclofenamate is over 99% bound to plasma proteins.
Interactions magnesaemia. The plasma elimination half-life of meclofenamate sodium is
For interactions associated with aspirin, see p.23. about 2 to 4 hours. It is metabolised by oxidation, hydroxylation,
The use of aspirin and other acetylated salicylates is generally dehalogenation, and conjugation with glucuronic acid and ex-
Uses and Administration not recommended for children because of the risk of Reye’s syn-
Lysine aspirin has analgesic, anti-inflammatory, and antipyretic creted in urine mainly as glucuronide conjugates of the metabo-
drome, unless specifically indicated. Some licensed drug infor- lites. About 20 to 30% is recovered in the faeces. One of the
actions similar to those of aspirin (see p.23). When given, lysine mation extends this precaution to magnesium salicylate.
aspirin dissociates into lysine and aspirin; aspirin is then hydro- metabolites, a 3-hydroxymethyl compound, is reported to be ac-
lysed to salicylic acid. Lysine aspirin 900 mg is equivalent to Interactions tive although to a lesser extent than the parent drug.
about 500 mg of aspirin. For interactions associated with salicylates, see Aspirin, p.23. ◊ References.
Lysine aspirin is used in the treatment of pain, fever, and rheu- Uses and Administration 1. Koup JR, et al. A single and multiple dose pharmacokinetic and
matic disorders. It is given in oral doses equivalent to 0.5 to 1 g Magnesium salicylate has analgesic, anti-inflammatory, and metabolism study of meclofenamate sodium. Biopharm Drug
of aspirin, repeated every 4 hours as needed up to a maximum of antipyretic actions similar to those of aspirin (see p.23). Anhy- Dispos 1990; 11: 1–15.
3 g of aspirin daily (2 g daily in the elderly) for pain and fever. drous magnesium salicylate 1 g is equivalent to about 1.2 g of Uses and Administration
The dose for rheumatic disorders is equivalent to 3 to 6 g of as- aspirin. It is used in the treatment of pain and fever and has been Meclofenamic acid, an anthranilic acid derivative similar to
pirin daily in 3 or 4 divided doses. Lysine aspirin is also given used in the management of inflammatory conditions such as os- mefenamic acid (below), is an NSAID (p.99). It is given orally
intramuscularly or intravenously in similar doses; the maximum teoarthritis, rheumatoid arthritis, and other arthritides. Usual oral as the sodium salt in musculoskeletal and joint disorders such as
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
80 Analgesics Anti-inflammatory Drugs and Antipyretics
osteoarthritis and rheumatoid arthritis, in mild to moderate pain, 2. Burns A, Young RE. Mefenamic acid induced leucopenia in the In the UK, the usual oral dose is 500 mg three times
and in dysmenorrhoea and menorrhagia. elderly. Lancet 1984; ii: 46.
3. Handa SI, Freestone S. Mefenamic acid-induced neutropenia daily. US licensed product information recommends
Doses of meclofenamate sodium are expressed in terms of the and renal failure in elderly females with hypothyroidism. Post- an initial dose of 500 mg followed by 250 mg every 6
equivalent amount of meclofenamic acid. Meclofenamic acid grad Med J 1990; 66: 557–9.
100 mg is equivalent to about 113.5 mg of meclofenamate sodi- 4. Muroi K, et al. Treatment of drug-induced agranulocytosis with
hours as needed. In addition, in the USA, when
um. In arthritic conditions it is given in doses equivalent to 200 granulocyte-colony stimulating factor. Lancet 1989; ii: 55. mefenamic acid is used in the treatment of mild to
to 400 mg daily; daily doses are usually given in 3 or 4 divided Effects on the gastrointestinal tract. Reversible steator- moderate pain in adults and adolescents aged 14 years
doses. For relief of mild to moderate pain doses are 50 to 100 mg rhoea has occurred1 with mefenamic acid; it may also provoke and over, it is also recommended that it should not be
every 4 to 6 hours; the daily dose should not exceed 400 mg. The colitis in patients without a history of this condition.2 given for longer than 7 days at a time.
dose in the treatment of dysmenorrhoea and menorrhagia is 1. Marks JS, Gleeson MH. Steatorrhoea complicating therapy with
100 mg three times daily for up to 6 days during menstruation. mefenamic acid. BMJ 1975; 4: 442. For doses of mefenamic acid in children, see below.
Meclofenamic acid has been given as a rectal suppository and is 2. Ravi S, et al. Colitis caused by non-steroidal anti-inflammatory Administration in children. In the UK, licensed product in-
also used in veterinary medicine. drugs. Postgrad Med J 1986; 62: 773–6.
formation states that mefenamic acid may be used in children for
Preparations Effects on the kidneys. Nonoliguric renal failure has occurred the treatment of Still’s disease (see Juvenile Idiopathic Arthritis,
in elderly patients who had had diarrhoea and vomiting while p.10) and fever; however, the BNFC does not recommend
USP 31: Meclofenamate Sodium Capsules. taking mefenamic acid and had continued to take the drug. It is mefenamic acid for juvenile idiopathic arthritis, nor for postop-
Proprietary Preparations (details are given in Part 3) normally recommended that mefenamic acid be stopped in the erative or mild to moderate pain. A suggested oral dose of
Chile: Meclomen; Ital.: Lenidolor; Meclodol†; Movens; Spain: Meclom- event of diarrhoea and it was suggested that in these patients the mefenamic acid for children over 6 months of age is 25 mg/kg
en†.
gastrointestinal toxicity had led to fluid and electrolyte depletion, daily in divided doses. Treatment in children should be given for
thus predisposing these patients to mefenamic acid’s nephrotox- no longer than 7 days unless they are receiving mefenamic acid
icity.1 There has been a subsequent report2 of nonoliguric renal for juvenile idiopathic arthritis.
failure in elderly patients given mefenamic acid for musculoskel-
Mefenamic Acid (BAN, USAN, rINN) etal pain. Preparations
Acide méfénamique; Ácido mefenámico; Acidum mefenamicum; 1. Taha A, et al. Non-oliguric renal failure during treatment with BP 2008: Mefenamic Acid Capsules; Mefenamic Acid Tablets;
mefenamic acid in elderly patients: a continuing problem. BMJ USP 31: Mefenamic Acid Capsules.
CI-473; CN-35355; INF-3355; Kwas mefenamowy; Kyselina 1985; 291: 661–2. Proprietary Preparations (details are given in Part 3)
mefenamová;_ Mefenaamihappo; Mefenamik Asit; Mefenaminsav; 2. Grant DJ, MacConnachie AM. Mefenamic acid is more danger- Arg.: Ponstil; Austral.: Mefic; Ponstan; Austria: Parkemed; Braz.: Ponstan;
Mefenamo ru gštis; Mefenamsyra. N-(2,3-Xylyl)anthranilic acid. ous than most. BMJ 1995; 311: 392. Pontin†; Canad.: Ponstan†; Chile: Algex; Algifemin; Dolcin†; Flipal; Sicadol;
Мефенамовая Кислота Tanston; Templadol; Fin.: Ponstan; Fr.: Ponstyl; Ger.: Parkemed†; Ponalar†;
Effects on the skin. Bullous pemphigoid, together with Gr.: Acinic; Aidol; Ponstan; Vidan; Hong Kong: Dyspen†; Hamitan; Hostan;
C 15 H 15 NO 2 = 241.3. haemolytic anaemia and diarrhoea,1 and fixed drug eruptions2-4 Medicap; Mefa; Mefamic; Mefic; Namic; Napan; Pekaso; Ponstan; Pontacid;
C AS — 61-68-7. have been associated with the use of mefenamic acid. Addition- Sefmic; Hung.: Ponmel; India: Dysmen-500†; Ponstan; Indon.: Analspec;
ally, Stevens-Johnson syndrome, together with cholestatic hepa- Asam; Asimat; Benostan; Cetalmic; Corstanal; Datan; Dolfenal; Dolos; Dys-
ATC — M01AG01. titis and haemolytic anaemia, in one patient has been attributed tan; Femisic; Fensik; Gitaramin; Lapistan; Licostan; Mectan; Mefast; Mefinal;
ATC Vet — QM01AG01. Mefinter; Mefix; Menin; Molasic; Nichostan; Opistan; Ponalar; Poncofen;
to mefenamic acid.5 It is generally recommended that mefenam- Pondex; Ponsamic; Ponstan; Ponstelax; Stanalin; Stanza; Stelpon; Topgesic;
ic acid should be withdrawn if skin reactions develop. Tropistan; Irl.: Mefac; Ponalgic; Ponmel; Ponstan; Ital.: Lysalgo; Malaysia:
1. Shepherd AN, et al. Mefenamic acid-induced bullous pemphig- Beafemic; Mefen†; Mefic; Namic; Napan; Pongesic†; Ponstan; Pontalon;
COOH CH3 oid. Postgrad Med J 1986; 62: 67–8. Mex.: Artriden; Namifen; Ponstan; NZ: Ponstan; Philipp.: Acidan; Afligec;
H 2. Wilson CL, Otter A. Fixed drug eruption associated with Analcid; Aprostal; Atmose; Calibral; Dolfenal; Dolmetine; Dolsten; Escan-
N CH3 mefenamic acid. BMJ 1986; 293: 1243. dar; Eurostan; Finox; Gardan; Gisfen; Hispen; Inflasic; Istan; Kramon; Laffed;
Mecid A; Mefenax; Metaflam; Neostan; Penomor; Ponser; Ponstan; Pontas-
3. Long CC, et al. Fixed drug eruption to mefenamic acid: a report er; Ralgec; Revalan; Selmac; Senflam; Spegic; Suprazen; Tynostan; Vamgesic;
of three cases. Br J Dermatol 1992; 126: 409–11. Vandifen; Zanovic; ZapAn; Zestan; Pol.: Mefacit; Port.: Ponstan; S.Afr.:
4. Rallis E. ‘Dalmatian dog’-like skin eruption (two cases of multi- Fenamin; Ponac; Ponstan; Ponstel; Singapore: Beafemic; Mefacap†; Mefe-
focal fixed drug eruption induced by mefenamic acid). J Eur nix; Ponstan†; Pontalon; Pontyl†; Spain: Coslan; Switz.: mefe-basan†;
Acad Dermatol Venereol 2005; 19: 753–5. Mefenacide; Melur; Mephadolor; Ponstan; Spiralgine; Thai.: Conamic;
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. 5. Chan JCN, et al. A case of Stevens-Johnson syndrome, choles- Dolfen; Dolfenal†; Dyspen†; Femen; Fenamic; Gandin; Manic; Manomic;
Ph. Eur. 6.2 (Mefenamic Acid). A white to almost white, micro- tatic hepatitis and haemolytic anaemia associated with use of Masafen; Mednil; Mefa; Mefen; Mefenan; Namic; Painnox; Panamic; Pefam-
mefenamic acid. Drug Safety 1991; 6: 230–4. ic†; Pondnadysmen; Ponnesia; Ponstan; Prostan; Pynamic; Sefmic; Vestan;
crystalline powder. Practically insoluble in water; slightly solu-
Turk.: Ponstan; Rolan; UK: Dysman†; Ponstan; USA: Ponstel; Venez.: Pon-
ble in alcohol and in dichloromethane; dissolves in dilute solu- Overdosage. Mefenamic acid overdose has been associated stan.
tions of alkali hydroxides. with CNS toxicity, especially with convulsions.1 Coma2,3 has Multi-ingredient: India: Cyclo-Meff; Dysmen; Dysmen Forte; Meftal
USP 31 (Mefenamic Acid). A white to off-white, crystalline also been reported. Forte; Spasmonil Forte; Spasmonil Plus; Tranfib MF; Ze-Spas; Thai.:
powder. Practically insoluble in water; slightly soluble in alcohol 1. Court H, Volans GN. Poisoning after overdose with non-steroi- Difemic; Mainnox; Med-Anspasmic†.
and in methyl alcohol; sparingly soluble in chloroform; soluble dal anti-inflammatory drugs. Adverse Drug React Acute Poison-
in solutions of alkali hydroxides. Store in airtight containers. Pro- ing Rev 1984; 3: 1–21.
2. Gössinger H, et al. Coma in mefenamic acid poisoning. Lancet
tect from light. 1982; ii: 384. Meloxicam (BAN, USAN, rINN)
3. Hendrickse MT. Mefenamic acid overdose mimicking brainstem
Meloksikaami; Meloksikam; Méloxicam; Meloxicamum; Mel-
Adverse Effects, Treatment, and Precau- stroke. Lancet 1988; ii: 1019.
oxikam; UH-AC-62; UH-AC-62XX. 4-Hydroxy-2-methyl-N-(5-
tions Pancreatitis. A report of pancreatitis associated with methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-di-
As for NSAIDs in general, p.96. mefenamic acid.1
oxide.
1. van Walraven AA, et al. Pancreatitis caused by mefenamic acid.
Treatment should be stopped if diarrhoea and rashes Can Med Assoc J 1982; 126: 894. Мелоксикам
occur. Other effects reported include drowsiness, and Porphyria. Mefenamic acid is considered to be unsafe in pa- C 14 H 13N 3 O 4 S 2 = 351.4.
effects on the blood such as thrombocytopenia, occa- tients with porphyria although there is conflicting experimental C AS — 71125-38-7.
sionally haemolytic anaemia, and rarely aplastic anae- evidence of porphyrinogenicity. ATC — M01AC06.
ATC Vet — QM01AC06.
mia. Convulsions may occur on overdosage.
Mefenamic acid is contra-indicated in patients with in- Interactions
flammatory bowel disease. Licensed product informa- For interactions associated with NSAIDs, see p.99. OH O N
tion recommends that blood counts and liver and renal CH3
function should be monitored during long-term thera-
Pharmacokinetics N S
Mefenamic acid is absorbed from the gastrointestinal H
py. Drowsiness may affect the performance of skilled N
tract. Peak plasma concentrations occur about 2 to 4 S
tasks. CH3
hours after ingestion. The plasma elimination half-life
Mefenamic acid may give a false positive in some tests is reported to be about 2 to 4 hours. Mefenamic acid is O O
for the presence of bile in the urine. more than 90% bound to plasma proteins. It is distrib-
Breast feeding. No adverse effects have been seen in breast- uted into breast milk. Mefenamic acid is metabolised Pharmacopoeias. In Br., Chin., and US.
fed infants whose mothers were given mefenamic acid, and the BP 2008 (Meloxicam). A pale yellow powder. Practically insol-
by the cytochrome P450 isoenzyme CYP2C9 to 3-hy- uble in water; very slightly soluble in alcohol and in methyl alco-
American Academy of Pediatrics considers1 that it is therefore droxymethyl mefenamic acid, which may then be oxi-
usually compatible with breast feeding. The BNF also considers hol; slightly soluble in acetone; soluble in dimethylformamide.
that the amount of mefenamic acid distributed into breast milk is dised to 3-carboxymefenamic acid. Over 50% of a USP 31 (Meloxicam). A pale yellow powder. Practically insolu-
too small to be harmful to a breast-fed infant. An early study2 dose may be recovered in the urine, as unchanged drug ble in water; very slightly soluble in alcohol and in methyl alco-
confirms that the distribution of mefenamic acid into breast milk or, mainly, as conjugates of mefenamic acid and its hol; slightly soluble in acetone; soluble in dimethylformamide.
is minimal. However, licensed product information contra-indi- metabolites. Adverse Effects and Treatment
cates the use of mefenamic acid in nursing mothers. As for NSAIDs in general, p.96.
1. American Academy of Pediatrics. The transfer of drugs and oth-
er chemicals into human milk. Pediatrics 2001; 108: 776–89. Uses and Administration Incidence of adverse effects. Between September 1996,
Correction. ibid.; 1029. Also available at: Mefenamic acid, an anthranilic acid derivative, is an when meloxicam was first marketed in the UK, and mid-June
http://aappolicy.aappublications .org/cgi/ content/full/
NSAID (p.99), although its anti-inflammatory proper- 1998 the UK CSM had received a total of 773 reports of 1339
pediatrics%3b108/3/776 (accessed 08/11/07) suspected adverse reactions for meloxicam.1 Of all the reactions
2. Buchanan RA, et al. The breast milk excretion of mefenamic ac- ties are considered to be minor. 41% were gastrointestinal and of these 18% involved gastroin-
id. Curr Ther Res 1968; 10: 592–6.
It is used in mild to moderate pain including headache, testinal perforation, ulceration and/or bleeding; the mean age of
Effects on the blood. References to haematological reactions dental pain, postoperative and postpartum pain, and the patients involved was 64 years. Although most patients re-
in patients taking mefenamic acid including haemolytic anae- covered after withdrawal of meloxicam and/or treatment, 5 died.
dysmenorrhoea, in musculoskeletal and joint disorders
mia,1 leucopenia,2 neutropenia,3 and agranulocytosis.4 A total of 193 reactions involved the skin, the most common be-
1. Scott GL, et al. Autoimmune haemolytic anaemia and mefenam-
such as osteoarthritis and rheumatoid arthritis, and in ing pruritus, rash, and urticaria. There were also reports of an-
ic acid therapy. BMJ 1968; 3: 534–5. menorrhagia. gioedema (25), photosensitivity (12), and bullous dermatoses,
 Mefenamic Acid/Meptazinol Hydrochloride 81
including erythema multiforme and Stevens-Johnson syndrome life of about 20 hours. It is extensively metabolised, mainly by Preparations
(5). No patients died from skin reactions and most recovered af- oxidation to its major metabolite, 5′-carboxymeloxicam. In vitro BP 2008: Meloxicam Tablets;
ter meloxicam was withdrawn. Other frequently reported reac- studies suggest that the cytochrome P450 isoenzyme CYP2C9 USP 31: Meloxicam Oral Suspension; Meloxicam Tablets.
tions were neurological (mostly headache), cardiovascular plays an important role in the metabolism of meloxicam with Proprietary Preparations (details are given in Part 3)
(oedema and palpitations), dizziness, flushing, and fatigue. A CYP3A4 involved to a lesser degree. Meloxicam, in the form of Arg.: Bronax; Dominadol; Flexidol; Flexium; Loxitenk; Meloxid†; Mera-
prescription event monitoring study has also analysed events re- metabolites, is excreted in similar amounts in the urine and in the piran†; Mextran; Miogesil†; Miolox; Mobic; Skudal†; Telaroid; Tenaron; Aus-
ported with meloxicam use.2 In a cohort of 19 087 patients who faeces; less than 5% of a dose is excreted unchanged. The vol- tral.: Mobic; Movalis; Moxicam; Austria: Melodyn; Meloxistad; Metosan;
had received meloxicam some time between December 1996 ume of distribution is increased in renal failure. Movalis; Belg.: Docmeloxi; Mobic; Braz.: Alivian; Artritec†; Bioflac; Dia-
tec†; Dormelox; Flamatec; Inicox; Leutrol; Lonaflam†; Loxam; Loxiflan; Me-
and March 1997, 203 patients had had 252 events considered to locox; Melonan†; Melonax†; Melotec; Meloxigran; Meloxil; Mevamox; Mo-
be suspected adverse reactions. The majority of reactions were ◊ References. vacox†; Movatec; Movoxicam; Canad.: Mobicox; Chile: Anposel; Ecax;
not serious or were labelled adverse effects of meloxicam. Rare, 1. Narjes H, et al. Pharmacokinetics and tolerability of meloxicam Hyflex; Isox; Melic; Melodol; Mexan; Mexilal; Mibloc FT; Mobex; Sition;
serious suspected adverse reactions included 2 reports of throm- after i.m. administration. Br J Clin Pharmacol 1996; 41: 135–9. Tenaron; Zix†; Cz.: Artrilom; Duplicam; Galoxiway; Melobax; Melocox;
Melovis; Meloxistad; Movalis; Recoxa; Denm.: Mobic; Fin.: Latonid; Mobic;
bocytopenia and 1 each of interstitial nephritis and idiosyncratic 2. Türck D, et al. Clinical pharmacokinetics of meloxicam. Arzne- Fr.: Mobic; Ger.: Mobec; Gr.: Arsitec; Arthrox; Auroxicam; Brosiral; Doc-
liver abnormality. The most frequent gastrointestinal event was imittelforschung 1997; 47: 253–8. tinon; Examel; Farmelox; Flumidon; Iamaxicam; Iaten; Iconal; Infomel; Loxi-
dyspepsia; other more serious gastrointestinal events occurring 3. Davies NM, Skjodt NM. Clinical pharmacokinetics of meloxi- tan; Mecalox; Medoxicam; Melice; Melocalm; Melock; Melocox; Melodin;
during meloxicam exposure included upper gastrointestinal cam: a cyclooxygenase-2 preferential nonsteroidal anti-inflam- Meloprol; Melorilif; Melotec; Melotop; Meloxil; Meloxitor; Meomel; Mo-
matory drug. Clin Pharmacokinet 1999; 36: 115–26. vatec; Movaxin; Moxalid; Notpel; Partial; Philipon-S; Rentilox; Reumotec;
bleeding (33 reports) and peptic ulcer (19 reports). However it Reumotherm; Sanetron; Saniflam; Starmelox; Supercad; Transantor; Tro-
was considered that the incidence of gastrointestinal disturbance 4. Meineke I, Türck D. Population pharmacokinetic analysis of pofin; Valoxin; Vexicam; Zametrixal; Zerelin; Hong Kong: Melflam; Melox;
was low in the absence of gastrointestinal risk factors. Adverse meloxicam in rheumatoid arthritis patients. Br J Clin Pharmacol Mobic; Hung.: Camelox; Melodyn; Melogen; Meloxan; Meloxep; Movalis;
drug reactions reported during the first year of marketing of mel- 2003; 55: 32–8. Moxicam; Noflamen; India: Mel-OD; Melflam; Melstar†; Indon.: Artrilox;
5. Burgos-Vargas R, et al. Pharmacokinetics of meloxicam in pa- Flamoxi; Loxinic; Mecox; Meloxin; Mevilox; Mexpharm; Mobiflex; Movi-
oxicam to the Swedish Medical Products Agency suggested a Cox; Movix; Moxam; Moxic; Nulox; Ostelox; Velcox; X-Cam; Irl.: Areloger;
similar safety profile to other NSAIDs.3 Of the 15 reports, 6 were tients with juvenile rheumatoid arthritis. J Clin Pharmacol 2004;
44: 866–72. Melcam; Mobic; Mobiglan; Movox; Ital.: Leutrol; Mobic; Jpn: Mobic; Ma-
for gastrointestinal disturbances and 5 involved skin reactions. laysia: Mel-OD; Melocam; Melox; Mobic; Rafree; Mex.: Aflamid; Anfla-
1. CSM/MCA. Meloxicam (Mobic): gastrointestinal and skin reac- tox†; Anpre; Auricam; Dolocam; Exel; Flexiver; Flexol; Lexpram; Loxam;
Renal impairment. For reference to the pharmacokinetics of Loxibach; Loxibest; Masflex†; Mavicam; Maxoflam; Meflen; Melarthryl; Mel-
tions. Current Problems 1998; 24: 13. Also available at: http:// meloxicam in renal impairment, see under Precautions, above.
w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ ican; Melosteral; Menflixil; Mobicox; Promotion; Reosan; Retoflam; Neth.:
FILE&dDocName=CON2023231&RevisionSelectionMethod= Movalis; Movicox; Norw.: Mobic; NZ: Mobic; Philipp.: Melora; Mobic;
LatestReleased (accessed 08/11/07)
Uses and Administration Pol.: Aglan; Aspicam; Lormed; Meloksam; Melokssia; Meloxic; MeloxiLek;
Meloxicam, an oxicam derivative, is an NSAID (p.99). It is re- Meloxistad; Movalis; Port.: Marlex; Melpor; Movalis; Ziloxican†; Rus.: Lem
2. Martin RM, et al. The incidence of adverse events and risk fac- (Лем); Melokan (Мелокан); Melox (Мелокс); Mirlox (Мирлокс); Movalis
tors for upper gastrointestinal disorders associated with meloxi- ported to be a selective inhibitor of cyclo-oxygenase-2 (COX-2).
(Мовалис); Movasin (Мовасин); S.Afr.: Coxflam; Flexocam; Loxiflam; Mel-
cam use amongst 19 087 patients in general practice in England: Meloxicam is used in the management of rheumatoid arthritis, flam; Mobic; Singapore: Melox; Mobic; Spain: Aliviodol; Movalis; Parocin;
cohort study. Br J Clin Pharmacol 2000; 50: 35–42. for the short-term symptomatic treatment of acute exacerbations Uticox; Swed.: Latonid†; Mobic; Switz.: Mobicox; Zilutrol†; Thai.: Mel-
3. Anonymous. Meloxicam safety similar to other NSAIDs. WHO of osteoarthritis, and for the symptomatic treatment of ankylos- cam; Melobic; Melox; Mobic; Turk.: Exen; Melox; Mobic; Zeloxim; UK: Mo-
Drug Information 1998; 12: 147. bic; USA: Mobic; Venez.: Biomelox; Calmox†; Mecox†; Melonax; Melovax;
ing spondylitis. It may also be used in the treatment of juvenile
Effects on the gastrointestinal tract. It is generally accept- Mobic; Mowin†; Taucaron.
idiopathic arthritis.
ed that inhibition of cyclo-oxygenase-1 (COX-1) plays a role in Multi-ingredient: Arg.: Flexidol Relax; Mextran Flex; India: Melodol;
In the treatment of rheumatoid arthritis and ankylosing spondyli- Mex.: Dolocam Plus; Dolocartigen; Dorsal; Flexamol; Nuro-B; Retoflam F.
the adverse gastrointestinal effects of NSAIDs, and that selective
tis, meloxicam is given in a usual oral dose of 15 mg daily as a
inhibition of the other isoform, COX-2, by NSAIDs such as mel-
single dose. Those with an increased risk of adverse reactions
oxicam may cause less gastrotoxicity than that seen with the non-
should be started on 7.5 mg daily. A dose of 7.5 mg daily is rec-
selective inhibition of traditional NSAIDs. However, there has
been little convincing evidence that the risk of severe gastrointes-
ommended for long-term treatment in the elderly. In the treat- Meptazinol Hydrochloride
ment of acute exacerbations of osteoarthritis the usual oral daily
tinal events is lower with meloxicam than with other NSAIDs at (BANM, USAN, rINNM)
dose of meloxicam is 7.5 mg, increased if necessary to a maxi-
equi-effective doses.1 Two large multicentre studies2,3 have re-
mum of 15 mg daily given as a single dose. Hidrocloruro de meptazinol; IL-22811 (meptazinol); Meptazinol,
ported a lower incidence of gastrointestinal adverse effects with
meloxicam than with non-selective cyclo-oxygenase inhibitors For dosage details in children see below. Chlorhydrate de; Meptazinoli Hydrochloridum; Wy-22811
(diclofenac2 or piroxicam3) but in one of these2 the dose of mel- (meptazinol). 3-(3-Ethyl-1-methylperhydroazepin-3-yl)phenol
Meloxicam may be given by rectal suppository in doses similar
oxicam given also appeared to be less effective than the reference hydrochloride.
to those used orally but use should be limited to the shortest time
drug. A more recent systematic review4 also found a lower risk possible. Мептазинола Гидрохлорид
of serious gastrointestinal toxicity with meloxicam 7.5 mg daily C 15 H 23 NO,HCl = 269.8.
when compared with diclofenac (100 or 150 mg daily), naproxen For the dose of meloxicam in patients with renal impairment, see
(500 mg twice daily), or piroxicam (20 mg daily); however, below. C AS — 54340-58-8 (meptazinol); 59263-76-2 (meptazi-
when given at a dose of 15 mg daily, the risk of toxicity with nol hydrochloride); 34154-59-1 ( ± -meptazinol hydrochlo-
meloxicam was significantly lower only when compared with Administration in children. In the USA, meloxicam is used ride).
piroxicam. in the treatment of juvenile idiopathic arthritis in children aged 2
y ea r s a n d o v e r. T h e r e c o m m e n d e d o r a l d o s e i s
Individual case reports of gastrointestinal toxicity with meloxi- 125 micrograms/kg once daily, up to a maximum of 7.5 mg dai-
cam included one of ischaemic colitis associated with high-dose CH3
ly. In the UK, licensed product information states that meloxicam
(15 mg daily) meloxicam treatment.5 should not be used in children aged under 15 years; however, the
1. Anonymous. Meloxicam—a safer NSAID? Drug Ther Bull N
1998; 36: 62–4.
BNFC has suggested the following oral doses, according to
2. Hawkey C, et al. Gastrointestinal tolerability of meloxicam com- body-weight, in those aged 12 to 18 years who are intolerant of
other NSAIDs: OH
pared to diclofenac in osteoarthritis patients. Br J Rheumatol
1998; 37: 937–45.
• less than 50 kg: 7.5 mg once daily CH3
3. Dequeker J, et al. Improvement in gastrointestinal tolerability of
the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, • over 50 kg: 15 mg once daily (meptazinol)
compared with piroxicam: results of the safety and efficacy
large-scale evaluation of COX-inhibiting therapies (SELECT) Administration in renal impairment. Meloxicam is nor-
trial in osteoarthritis. Br J Rheumatol 1998; 37: 946–51. mally contra-indicated in patients with severe renal impairment. Pharmacopoeias. In Br.
4. Singh G, et al. Risk of serious upper gastrointestinal and cardio- BP 2008 (Meptazinol Hydrochloride). A white or almost white
vascular thromboembolic complications with meloxicam. Am J However, in dialysed patients, meloxicam may be given in a
Med 2004; 117: 100–106. dose of 7.5 mg daily by mouth or by rectal suppository. No dose powder. Very soluble in water and in methyl alcohol; freely sol-
5. Garcia B, et al. Ischaemic colitis in a patient taking meloxicam. reduction is required in those with mild to moderate renal impair- uble in alcohol; very slightly soluble in acetone; dissolves in di-
Lancet 2001; 357: 690. ment (creatinine clearance of greater than 25 mL/min). lute solutions of alkali hydroxides. Store at a temperature not ex-
Precautions ceeding 25°.
Musculoskeletal and joint disorders. Meloxicam is used in
As for NSAIDs in general, p.98.
the treatment of osteoarthritis (see p.11), rheumatoid arthritis Dependence and Withdrawal
Meloxicam should be avoided in severe hepatic impairment, in (see p.11) including juvenile idiopathic arthritis (p.10), and anky-
bleeding disorders, and in patients with renal failure unless re- losing spondylitis (see Spondyloarthropathies, p.13). However, As for Opioid Analgesics, p.101.
ceiving dialysis. Rectal use should be avoided in patients with a
history of proctitis, haemorrhoids, or rectal bleeding.
in the UK, the use of meloxicam and other selective cyclo-oxy- ◊ In assessing the dependence potential of meptazinol, a WHO
genase-2 (COX-2) inhibitors is limited to those patients with expert committee1 noted in 1989 that abrupt discontinuation of
Renal impairment. The pharmacokinetics of meloxicam were good cardiovascular health and at high risk of developing serious chronic meptazinol use precipitated only slight withdrawal signs
not substantially altered in patients with a creatinine clearance gastrointestinal problems if given a non-selective NSAID (see in animals and that meptazinol did not suppress opioid with-
(CC) of 41 to 60 mL/minute compared with those with normal p.97). drawal signs and symptoms in humans dependent on morphine.
renal function.1 In those with a CC of 20 to 40 mL/minute, total References. Abuse had not been reported. They considered that the likelihood
plasma-meloxicam concentrations were lower but meloxicam of abuse was moderate and that international control was not
free fractions were higher. Such free meloxicam concentrations 1. Lemmel EM, et al. Efficacy and safety of meloxicam in patients warranted at that time.
with rheumatoid arthritis. J Rheumatol 1997; 24: 282–90.
were similar to the other groups. On the basis of these results, it 1. WHO. WHO expert committee on drug dependence: twenty-
was suggested that it was not necessary to reduce meloxicam 2. Yocum D, et al. Safety and efficacy of meloxicam in the treat- fifth report. WHO Tech Rep Ser 775 1989. Also available at:
doses in patients with a CC greater than 20 mL/minute. ment of osteoarthritis: a 12-week, double-blind, multiple-dose, http://libdoc.who.int/trs/WHO_TRS_775.pdf (accessed 26/06/08)
placebo-controlled trial. The Meloxicam Osteoarthritis Investi-
1. Boulton-Jones JM, et al. Meloxicam pharmacokinetics in renal gators. Arch Intern Med 2000; 160: 2947–54.
impairment. Br J Clin Pharmacol 1997; 43: 35–40.
3. Combe B, et al. Comparison of intramuscular and oral meloxi- Adverse Effects, Treatment, and Precau-
Interactions cam in rheumatoid arthritis patients. Inflamm Res 2001; 50 (sup- tions
For interactions associated with NSAIDs, see p.99. pl 1): S10–16. As for Opioid Analgesics in general, p.102.
Colestyramine increases the clearance and decreases the half-life 4. Fleischmann R, et al. Meloxicam. Expert Opin Pharmacother
of meloxicam. 2002; 3: 1501–12. Gastrointestinal adverse effects are commonly report-
ed with meptazinol and include abdominal pain, con-
Pharmacokinetics Veterinary use. For the suggestion that meloxicam should be
stipation, dyspepsia, diarrhoea, and nausea and vomit-
Meloxicam is well absorbed after oral or rectal doses with peak used as an alternative to diclofenac in cattle in South Asia (to
plasma concentrations reached in up to 6 hours. It is 99% bound reduce toxicity to vultures who may consume their carcasses), ing. Meptazinol is claimed to have a low incidence of
to plasma proteins. Meloxicam has a plasma-elimination half- see under Precautions of Diclofenac, p.45 respiratory depression; nonetheless, UK licensed prod-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
82 Analgesics Anti-inflammatory Drugs and Antipyretics
uct information states that it should not be used in pa- 3.39 and 1.94 hours, respectively after single oral doses1 and 2.93 Methadone Hydrochloride
and 2.06 hours, respectively after intravenous doses.2
(BANM, pINNM) ⊗
tients with acute respiratory depression. There have
been occasional reports of psychiatric disorders such as 1. Norbury HM, et al. Pharmacokinetics of meptazinol after single
and multiple oral administration to elderly patients. Eur J Clin Amidine Hydrochloride; Amidone Hydrochloride; Hidrocloruro
hallucinations, confusion, and depression. As meptazi- Pharmacol 1984; 27: 223–6.
nol has both antagonist and agonist properties its ef- 2. Murray GR, et al. Pharmacokinetics of meptazinol after
de amidina; Hidrocloruro de metadona; Metadon Hidroklorür;
parenteral administration in the elderly. Eur J Clin Pharmacol Metadon-hidroklorid; Metadonhydroklorid; Metadonihydroklori-
fects may be only partially reversed by naloxone, but 1987; 31: 733–6. di; Metadono hidrochloridas; Metadonu chlorowodorek; Metha-
use of the latter is still recommended in overdosage. don hydrochlorid; Méthadone, chlorhydrate de; (±)-Methadone
Hepatic impairment. Oral bioavailability of meptazinol
Meptazinol has the potential to precipitate withdrawal appeared to be enhanced in patients with liver disease. After Hydrochloride; Methadoni hydrochloridum; Phenadone. (±)-6-
symptoms if given to patients who are physically de- a single oral dose of meptazinol mean peak plasma Dimethylamino-4,4-diphenylheptan-3-one hydrochloride.
pendent on opioids. concentrations were 184 nanograms/mL, 131 nanograms/mL, Метадона Гидрохлорид
and 53 nanograms/mL in cirrhotic patients, patients with non- C 21 H 27NO,HCl = 345.9.
Abuse. See under Dependence and Withdrawal, above. cirrhotic liver disease, and patients with normal liver function, C AS — 76-99-3 (methadone); 297-88-1 ( ± methadone);
respectively, although there was no evidence of accumulation af-
Effects on the respiratory system. Meptazinol is said to 1095-90-5 (methadone hydrochloride); 125-56-4 ( ± meth-
ter chronic dosing.1 There were no significant differences in plas-
have a relatively low potential for respiratory depression and in ma clearance after an intravenous dose. Reduced oral doses of adone hydrochloride).
healthy subjects was reported to produce substantially less respi- meptazinol might be advisable in cirrhotic patients. ATC — N07BC02.
ratory depression than morphine or pentazocine at usual analge- ATC Vet — QN07BC02.
1. Birnie GG, et al. Enhanced oral bioavailability of meptazinol in
sic doses.1 However, respiratory depression does occur in anaes- cirrhosis. Gut 1987; 28: 248–54.
thetised patients given meptazinol2 and the effects on respiration
may be similar to those of morphine3,4 or pethidine.5,6 Compen- Pregnancy. In women given an intramuscular injection of 100 CH3
satory mechanisms may come into play after repeated doses of to 150 mg during labour, meptazinol was found to cross the pla- O CH3
meptazinol but the intravenous use of meptazinol during anaes- centa readily but was rapidly eliminated from the neonate.1 This
thesia should be viewed with as much caution as with any other contrasted with pethidine which was known to be excreted very N
opioid.6 slowly from neonates. As in the adult, elimination of meptazinol CH3
Respiratory arrest occurred after an overdose of 50 meptazinol by the neonate appeared to take place mainly by conjugation
with glucuronic acid.2 A half-life of 3.4 hours, similar to that in CH3
200-mg tablets and a quarter of a bottle of whisky.7 Full recovery
eventually followed supportive measures although spontaneous adults, has been reported in the neonate,3 in contrast to 22.7 hours
respiration was not re-established by naloxone intravenously to a for pethidine in neonates.
cumulative total dose of 10 mg. Disposition of meptazinol appears not to be significantly affected
1. Jordan C, et al. A comparison of the respiratory effects of
by pregnancy. Mean half-lives of 1.36 and 1.68 hours were re- (methadone)
meptazinol, pentazocine and morphine. Br J Anaesth 1979; 51: ported in pregnant and non-pregnant women, respectively,4 com-
497–502. pared with 2.06 hours in men.
2. Hardy PAJ. Meptazinol and respiratory depression. Lancet 1983; 1. Franklin RA, et al. Preliminary studies on the disposition of NOTE. The following terms have been used as ‘street names’ (see
ii: 576. meptazinol in the neonate. Br J Clin Pharmacol 1981; 12: p.vi) or slang names for various forms of methadone:
3. Frater RAS, et al. Analgesia-induced respiratory depression: 88–90. Amidone; Balloons; Breeze; Burdock; Buzz bomb; Dollies;
comparison of meptazinol and morphine in the postoperative pe- 2. Dowell PS, et al. Routes of meptazinol conjugation in the ne- Dolls; Done; Doses; Fizzies; Juice; Jungle juice; Junk; Meta;
riod. Br J Anaesth 1989; 63: 260–5. onate. Br J Clin Pharmacol 1982; 14: 748–9. Mud; Phy; Phyamps; Tootsie roll.
4. Verborgh C, Camu F. Post-surgical pain relief with zero-order 3. Jackson MBA, Robson PJ. Preliminary clinical and pharmacok- Pharmacopoeias. In Chin., Eur. (see p.vii), and US.
intravenous infusions of meptazinol and morphine: a double- inetic experiences in the newborn when meptazinol is compared Ph. Eur. 6.2 (Methadone Hydrochloride). A white or almost
blind placebo-controlled evaluation of their effects on ventila- with pethidine as an obstetric analgesic. Postgrad Med J 1983;
tion. Eur J Clin Pharmacol 1990; 38: 437–42. 59 (suppl 1): 47–51. white, crystalline powder. Soluble in water; freely soluble in al-
5. Wilkinson DJ, et al. Meptazinol—a cause of respiratory depres- 4. Murray GR, et al. The disposition of meptazinol after single and cohol. Protect from light.
sion in general anaesthesia. Br J Anaesth 1985; 57: 1077–84. multiple intravenous administration to pregnant and non-preg- USP 31 (Methadone Hydrochloride). Odourless colourless
6. Lee A, Drummond GB. Ventilatory effects of meptazinol and nant women. Eur J Clin Pharmacol 1989; 36: 273–7. crystals or white crystalline powder. Soluble in water; freely sol-
pethidine in anaesthetised patients. Br J Anaesth 1987; 59: uble in alcohol and in chloroform; practically insoluble in ether
1127–33. Uses and Administration and in glycerol. pH of a 1% solution in water is between 4.5 and
7. Davison AG, et al. Meptazinol overdose producing near fatal res- Meptazinol is a mixed opioid agonist and antagonist 6.5. Store in airtight containers at a temperature of 25°, excur-
piratory depression. Hum Toxicol 1987; 6: 331. sions permitted between 15° and 30°. Protect from light.
with partial opioid agonist activity at the μ1 opioid re-
ceptor (see p.104); it also has cholinergic activity. Incompatibility. There appears to be adequate evidence that
Interactions stable solutions containing methadone hydrochloride and hy-
For interactions associated with opioid analgesics, see Meptazinol is used in the treatment of moderate to se- droxybenzoate esters can be formulated but the risk of precipita-
p.103. vere pain. It has a shorter duration of action than mor- tion exists if syrup preserved with hydroxybenzoates is used to
phine. extemporaneously prepare a methadone mixture 1 mg/mL to the
Plasma concentrations of meptazinol may be increased DTF formula.1 An oral formulation of methadone hydrochloride
by ritonavir and use together should be avoided (see Meptazinol hydrochloride is given orally or by intra- 5 mg/mL containing methyl hydroxybenzoate 0.1% as preserva-
also p.103). muscular or intravenous injection; doses are expressed tive rather than chloroform has been reported stable for at least 4
in terms of the base. Meptazinol hydrochloride months at room temperature.2
Pharmacokinetics 115.6 mg is equivalent to about 100 mg of meptazinol. 1. PSGB Lab Report P/80/1 1980.
2. Ching MS, et al. Stability of methadone mixture with methyl hy-
After oral doses of meptazinol peak plasma concentra- For the short-term treatment of moderate pain meptazi- droxybenzoate as a preservative. Aust J Hosp Pharm 1989; 19:
tions have been achieved within 0.5 to 2 hours, but bio- nol is given in an oral dose of 200 mg every 3 to 6 159–61.

availability is low since it undergoes extensive first- hours, as required. The intramuscular dose is 75 to
100 mg given every 2 to 4 hours, as required; for ob- Dependence and Withdrawal
pass metabolism. Systemic availability is improved af- As for Opioid Analgesics, p.101.
ter rectal doses. Peak plasma concentrations have been stetric pain a dose of 2 mg/kg (100 to 150 mg) may be
achieved 30 minutes after rectal or intramuscular use. used. Meptazinol is also given by slow intravenous in- Methadone withdrawal symptoms are similar to, but
Plasma protein binding has averaged only about 27%. jection in doses of 50 to 100 mg every 2 to 4 hours, as more prolonged than, those produced by morphine or
Elimination half-lives of about 2 hours have been re- required. diamorphine. They develop more slowly and do not
ported. Meptazinol is extensively metabolised in the Administration. EPIDURAL ROUTE. Epidural meptazinol
usually appear until 3 to 4 days after the last dose.
liver and is excreted mainly in the urine as the glucuro- 90 mg for postoperative pain was reported to be superior to an Methadone is used for substitution therapy in the man-
intramuscular dose of 90 mg.1 However, in another study2 a agement of opioid dependence (see Uses and Admin-
nide conjugate. Less than 10% of a dose has been re- 30-mg dose was ineffective and associated with an unaccept-
covered from the faeces. Meptazinol crosses the pla- istration, below) including neonatal abstinence syn-
able incidence of adverse effects. A 60-mg dose was also
centa. found to be ineffective because of its short duration of action.3 drome (see Administration in Children, below).
◊ References. UK licensed product information states that the injectable formu-
lation is not suitable for epidural or intrathecal use. Adverse Effects and Treatment
1. Franklin RA, et al. Studies on the metabolism of meptazinol, a As for Opioid Analgesics in general, p.102.
new analgesic drug. Br J Clin Pharmacol 1976; 3: 497–502. 1. Verborgh C, et al. Meptazinol for postoperative pain relief in
man: comparison of extradural and im administration. Br J Methadone has a more prolonged effect than morphine
2. Franklin RA, et al. Studies on the absorption and disposition of Anaesth 1987; 59: 1134–9.
meptazinol following rectal administration. Br J Clin Pharmacol
2. Francis RI, Lockhart AS. Epidural meptazinol. Anaesthesia
and readily accumulates with repeated doses. It may
1977; 4: 163–7.
1986; 41: 88–9. have a relatively greater respiratory depressant effect
3. Davies G, et al. Pharmacokinetics of meptazinol in man follow-
ing repeated intramuscular administration. Eur J Clin Pharma- 3. Birks RJS, Marsh DRG. Epidural meptazinol. Anaesthesia 1986; than morphine and, although reported to be less sedat-
41: 883.
col 1982; 23: 535–8. ing, repeated doses of methadone may result in marked
4. Norbury HM, et al. Pharmacokinetics of the new analgesic, Administration in hepatic impairment. See under Phar- sedation. QT prolongation and torsade de pointes have
meptazinol, after oral and intravenous administration to volun- macokinetics, above for a suggestion that doses may need to be
teers. Eur J Clin Pharmacol 1983; 25: 77–80. been reported rarely with methadone use, particularly
reduced in patients with cirrhosis.
5. Murray GR, et al. The systemic availability of meptazinol in man at doses above 100 mg daily. After gross overdosage
after oral and rectal doses. Eur J Clin Pharmacol 1989; 36: Preparations symptoms are similar to those of morphine poisoning.
279–82.
BP 2008: Meptazinol Injection; Meptazinol Tablets. Pulmonary oedema after overdosage is a common
The elderly. A lower clearance and longer elimination half-life cause of fatalities among addicts.
Proprietary Preparations (details are given in Part 3)
has been reported for meptazinol in elderly patients, but dosage
reduction was not considered warranted on pharmacokinetic Austria: Meptidol†; Ger.: Meptid; Irl.: Meptid; UK: Meptid. Methadone causes pain at injection sites; subcutaneous
grounds. Mean half-lives in elderly and young subjects were injection causes local tissue irritation and induration.
 Methadone Hydrochloride 83
Effects on the cardiovascular system. Methadone prolongs therapy. This has been attributed to the difficulty in determining Pregnancy. Methadone is not recommended for use in labour
the QT interval and has rarely been associated with torsade de a safe and effective starting dose of methadone and unreliable because its prolonged duration of action increases the risk of ne-
pointes. In a retrospective case series,1 17 patients on high-dose accounts of a patient’s recent drug use. onatal respiratory depression.
methadone (mean daily dose of 397 mg) developed torsade de 1. Harding-Pink D. Opioid toxicity: methadone: one person’s Neonatal abstinence syndrome and low birth-weight are imme-
pointes; of these, 14 had potential risk factors for arrhythmia and maintenance dose is another’s poison. Lancet 1993; 341: 665–6. diate problems in infants born to women receiving methadone
6 had had their dose increased within the last month. In another 2. Aronow R, et al. Childhood poisoning: an unfortunate conse-
quence of methadone availability. JAMA 1972; 219: 321–4. for the management of opioid addiction; increased still-birth
study2 torsade de pointes developed in 5 patients taking metha- 3. Zador DA, Sunjic SD. Methadone-related deaths and mortality rates have also been noted.1-3 In the neonatal period moderate to
done (mean daily dose 268 mg); however, they all had other con- rate during induction into methadone maintenance, New South severe opioid abstinence syndrome occurred in 75% of infants in
tributing risk factors. Other studies3,4 did not find instances of Wales, 1996. Drug Alcohol Rev 2002; 21: 131–6. a study,2 as well as reduced head circumference and raised systo-
torsade de pointes and the increase in QT interval was considered 4. Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid lic blood pressure. At follow-up over 18 months these children
clinically insignificant; in one study,4 the mean daily dose of exposure in toddlers. J Emerg Med 2005; 29: 77–84. had a higher incidence of otitis media, of reduced head circum-
methadone was 110 mg and some patients also had risk factors 5. Caplehorn JRM, Drummer OH. Mortality associated with New
South Wales methadone programs in 1994: lives lost and saved. ference, and of abnormal eye findings when compared with
for arrhythmia. Med J Aust 1999; 170: 104–9. drug-free controls. Neurobehavioural abnormalities and lower
For a report of QT interval prolongation in an infant born to a 6. Buster MCA, et al. An increase in overdose mortality during the scores on mental and motor developmental indices were thought
mother on maintenance methadone therapy for opioid addiction, first 2 weeks after entering or re-entering methadone treatment to be possible predictors of later learning and behavioural prob-
see Pregnancy, below. in Amsterdam. Addiction 2002; 97: 993–1001. lems. In a later study,4 the use of methadone alone during preg-
In a small case-controlled study of sudden cardiac deaths,5 the nancy as part of a maintenance program was claimed to increase
prevalence of underlying cardiac disease or structural abnormal- Precautions the risk of prematurity twofold, of intra-uterine growth retarda-
ities was lower in the 22 cases with evidence of therapeutic meth- As for Opioid Analgesics in general, p.103. tion fourfold, and of microcephaly threefold when compared
adone levels when compared with the 106 cases without evi- Methadone should be given with caution to patients at with a normal population. In addition, in those mothers who con-
dence of methadone use. The authors considered that the low tinued to abuse other drugs, as well as receive methadone, the
prevalence of cardiac risk factors in the methadone group sug- risk of developing prolongation of the QT interval in- risks of these events were further increased. However, an earlier
gested a role for methadone itself in the pathogenesis of sudden cluding those with cardiac or hepatic disease, with hy- study5 has reported that methadone or diamorphine had no spe-
death in this group. pokalaemia or other electrolyte imbalance, or with a cific effect on intra-uterine and postnatal growth.
1. Krantz MJ, et al. Torsade de pointes associated with very-high- family history of sudden death. It should also be used The relationship between maternal methadone dose and the inci-
dose methadone. Ann Intern Med 2002; 137: 501–4. dence and severity of neonatal abstinence syndrome is unclear.
2. Sticherling C, et al. Methadone-induced torsade de pointes tach- with caution in patients who are taking other potential-
Although a retrospective study6 found a correlation in some
ycardias. Swiss Med Wkly 2005; 135: 282–5. ly arrhythmogenic drugs, drugs likely to cause electro- pregnancies, others7,8 did not and there was no evidence of an
3. Martell BA, et al. The impact of methadone induction on cardiac lyte imbalance, or drugs that inhibit the cytochrome
conduction in opiate users. Ann Intern Med 2003; 139: 154–5. increased incidence of neonatal withdrawal symptoms even with
4. Cruciani RA, et al. Measurement of QTc in patients receiving P450 isoenzyme CYP3A4 (see under Interactions, be- high maternal doses of 100 mg or more daily.8
chronic methadone therapy. J Pain Symptom Manage 2005; 29: low). ECG monitoring is recommended before starting A small retrospective study9 comparing the use of methadone
385–91. during pregnancy for the treatment of chronic pain with use in
5. Chugh SS, et al. A community-based evaluation of sudden death methadone treatment in these patients, with a further
associated with therapeutic levels of methadone. Am J Med test at dose stabilisation. ECG monitoring is also rec- maintenance therapy for opioid addiction found a lower inci-
2008; 121: 66–71. dence of neonatal abstinence syndrome and better growth pa-
ommended before and at 7 days after dose titration rameters in infants born to the former group of mothers; howev-
Effects on the endocrine system. Hypoadrenalism has been above 100 mg daily in patients without recognised risk er, a higher rate of slight prematurity was also found in this group
found in chronic methadone addicts. Findings consistent with
deficient ACTH production and subsequent secondary hypoad- factors. of infants. The authors suggested that lower maternal doses and
shorter durations of treatment may account for the favourable
renalism have been reported1 although there is also evidence2 of Administration. Methadone has a long half-life and accumu- findings, in addition to better maternal health, nutrition, and so-
methadone-induced primary adrenal cortical hypofunction. lation may occur with repeated doses, especially in elderly or de- cio-economic status.
Hyperprolactinaemia and galactorrhoea have also been report- bilitated patients. An 81-year-old woman given methadone 5 mg
ed.3 See also Effects on Sexual Function, below. three times daily orally for 2 days became deeply unconscious Clinically significant prolongation of the QT interval has been
but awoke immediately when given naloxone 400 micrograms reported10 in an infant born to a mother taking methadone 50 mg
1. Dackis CA, et al. Methadone induced hypoadrenalism. Lancet
1982; ii: 1167. intravenously.1 daily for maintenance therapy; the infant had mild withdrawal
2. Pullan PT, et al. Methadone-induced hypoadrenalism. Lancet symptoms and follow-up at 2 months of age was normal.
Sudden death in 10 diamorphine addicts occurred between 2 and
1983; i: 714. 1. Blinick G, et al. Methadone maintenance, pregnancy, and prog-
3. Bennett J, Whale R. Galactorrhoea may be associated with meth-
6 days after starting a methadone maintenance programme.2 The eny. JAMA 1973; 225: 477–9.
adone use. BMJ 2006; 332: 1071. mean prescribed dose of methadone at the time of death had been 2. Rosen TS, Johnson HL. Children of methadone-maintained
about 60 mg. There was evidence of chronic persistent hepatitis mothers: follow-up to 18 months of age. J Pediatr 1982; 101:
Effects on the nervous system. Choreic movements oc- in all cases and liver disease could have reduced methadone 192–6.
curred in a 25-year-old man on long-term methadone mainte- clearance resulting in higher than expected blood concentrations. 3. Kalter H, Warkany J. Congenital malformations. N Engl J Med
nance treatment of 45 to 60 mg daily for diamorphine addiction.1 Liver function tests and urine testing for the presence of drugs 1983; 308: 491–7.
Similar adverse effects were seen in a 41-year-old woman taking 4. Arlettaz R, et al. Methadone maintenance program in pregnancy
before entry into methadone maintenance programmes, and low- in a Swiss perinatal center (II): neonatal outcome and social re-
5 mg methadone four times daily for complex regional pain syn- er starting doses, might decrease the likelihood of such deaths. sources. Acta Obstet Gynecol Scand 2005; 84: 145–50.
drome.2 In both cases, symptoms resolved when methadone was Like dextropropoxyphene, methadone has membrane stabilising 5. Lifschitz MH, et al. Fetal and postnatal growth of children born
stopped. activity and can block nerve conduction, and it was suggested3 to narcotic-dependent women. J Pediatr 1983; 102: 686–91.
1. Wasserman S, Yahr MD. Choreic movements induced by the use that the sudden deaths were mainly due to accumulation of meth- 6. Dashe JS et al. Relationship between maternal methadone dos-
of methadone. Arch Neurol 1980; 37: 727–8. age and neonatal withdrawal. Obstet Gynecol 2002; 100:
2. Clark JD, Elliott J. A case of a methadone-induced movement
adone over several days resulting in complications such as cardi- 1244–9.
disorder. Clin J Pain 2001; 17: 375–7. ac arrhythmias or cardiovascular collapse (above). See also 7. Berghella V, et al. Maternal methadone dose and neonatal with-
Overdosage, above. drawal. Am J Obstet Gynecol 2003; 189: 312–17.
Effects on the respiratory system. Sleep apnoea has been 8. McCarthy JJ, et al. High-dose methadone maintenance in preg-
For the effects of hepatic and renal impairment on the disposition
reported1,2 in patients on stable methadone maintenance treat- nancy: maternal and neonatal outcomes. Am J Obstet Gynecol
of methadone, see under Pharmacokinetics, below. 2005; 193: 606–10.
ment.
1. Symonds P. Methadone and the elderly. BMJ 1977; i: 512. 9. Sharpe C, Kuschel C. Outcomes of infants born to mothers re-
1. Teichtahl H, et al. Sleep-disordered breathing in stable metha- 2. Drummer OH, et al. Deaths of heroin addicts starting on a meth-
done programme patients: a pilot study. Addiction 2001; 96: ceiving methadone for pain management in pregnancy. Arch Dis
adone maintenance programme. Lancet 1990; 335: 108. Child Fetal Neonatal Ed 2004; 89: F33–F36.
395–403. 3. Wu C, Henry JA. Deaths of heroin addicts starting on methadone
2. Wang D, et al. Central sleep apnea in stable methadone mainte- 10. Hussain T, Ewer AK. Maternal methadone may cause arrhyth-
maintenance. Lancet 1990; 335: 424. mias in neonates. Acta Paediatr 2007; 96: 768–9.
nance treatment patients. Chest 2005; 128: 1348–56.
Breast feeding. The American Academy of Pediatrics consid-
Effects on sexual function. Sexual performance was im- Interactions
ers that the use of methadone in breast-feeding mothers is usually
paired in 29 male diamorphine addicts receiving methadone compatible with breast feeding.1 The BNF also permits breast
maintenance therapy.1 The function of secondary sex organs was For interactions associated with opioid analgesics, see
feeding by mothers on methadone maintenance although the p.103.
markedly suppressed when compared with untreated diamor-
dose should be as low as possible and the infant monitored to
phine addicts or controls and serum-testosterone concentrations avoid sedation. Others have suggested that the amount of meth- Methadone is metabolised in the liver mainly via the
were 43% lower in those on methadone. However, in a more re-
cent study2 in 92 opioid addicts also receiving methadone main-
adone in breast milk is unlikely to have any pharmacological ef- cytochrome P450 isoenzyme CYP3A4; the isoen-
fect on the infant.2-8 However, in the past, there has been a report zymes CYP2B6, CYP2D6, CYP2C9, CYP2C19, and
tenance, rates of sexual dysfunction (erectile, libido, and orgasm of the death of a 5-week-old breast-fed infant whose mother was
dysfunction) were found to be similar to that of the general pop-
on methadone maintenance.9
CYP1A2 are also thought to be involved. Consequent-
ulation. Rates of dysfunction between patients just started on ly, use with other drugs that induce or inhibit these
1. American Academy of Pediatrics. The transfer of drugs and oth-
methadone and those on methadone for at least 60 days were not er chemicals into human milk. Pediatrics 2001; 108: 776–89. isoenzymes may result in changes in plasma concen-
significantly different although new patients generally had lower Correction. ibid.; 1029. Also available at:
rates. Mean plasma levels of testosterone and prolactin were h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
trations of methadone and, possibly adverse effects.
within normal ranges and although 8 individuals had low testo- pediatrics%3b108/3/776 (accessed 26/06/08) There is a risk of cardiac events in patients receiving
sterone levels, only 1 case of dysfunction was reported in this 2. Blinick G, et al. Methadone assays in pregnant women and prog- methadone who are also taking drugs that affect cardi-
group. eny. Am J Obstet Gynecol 1975; 121: 617–21.
3. Wojnar-Horton RE, et al. Methadone distribution and excretion ac conduction or electrolyte balance.
1. Cicero TJ, et al. Function of the male sex organs in heroin and into breast milk of clients in a methadone maintenance pro-
methadone users. N Engl J Med 1975; 292: 882–7. gramme. Br J Clin Pharmacol 1997; 44: 543–7. ◊ Drugs that acidify or alkalinise the urine may have an effect on
2. Brown R, et al. Methadone maintenance and male sexual dys- 4. Geraghty B, et al. Methadone levels in breast milk. J Hum Lact methadone pharmacokinetics since body clearance is increased
function. J Addict Dis 2005; 24: 91–106. 1997; 13: 227–30. at acidic pH and decreased at alkaline pH.1
Overdosage. Most cases of methadone poisoning occur in per- 5. McCarthy JJ, Posey BL. Methadone levels in human milk. J 1. Nilsson M-I, et al. Effect of urinary pH on the disposition of
Hum Lact 2000; 16: 115–20.
sons not on maintenance,1-4 particularly children or family mem- 6. Begg EJ, et al. Distribution of R- and S-methadone into human
methadone in man. Eur J Clin Pharmacol 1982; 22: 337–42.
bers of maintenance patients.1 Methadone is highly toxic to any- milk during multiple, medium to high oral dosing. Br J Clin Antibacterials. Withdrawal symptoms have been reported in
one who is not tolerant to opioids; 50 to 100 mg can be life- Pharmacol 2001; 52: 681–5. patients maintained on methadone when they were given the en-
threatening in non-tolerant adults and 10 mg can be fatal in a 7. Jansson LM, et al. Methadone maintenance and breastfeeding in zyme inducer rifampicin.1-3 Conversely, the use of ciprofloxacin,
young child.1 Furthermore, life-threatening toxicity from oral the neonatal period. Pediatrics 2008; 121: 106–14.
which inhibits CYP1A2 and CYP3A4, has resulted in signs of
doses as low as 5 mg has been reported in children.2,4 8. Jansson LM, et al. Methadone maintenance and long-term lacta-
tion. Breastfeed Med 2008; 3: 34–7. methadone toxicity.4
Various groups5,6 have found that the risk of death from metha- 9. Smialek JE, et al. Methadone deaths in children. JAMA 1977; 1. Kreek MJ, et al. Rifampin-induced methadone withdrawal. N
done toxicity is greatest during the first 2 weeks of maintenance 238: 2516–17. Engl J Med 1976; 294: 1104–6.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
84 Analgesics Anti-inflammatory Drugs and Antipyretics
2. Bending MR, Skacel PO. Rifampicin and methadone withdraw- authors commented that such effects may occur in patients with with severe chronic liver disease. However, plasma concentra-
al. Lancet 1977; i: 1211. reduced opioid tolerance, particularly when starting methadone tions were not increased in such patients.
3. Raistrick D, et al. Methadone maintenance and tuberculosis treatment.
treatment. BMJ 1996; 313: 925–6. 1. Moore RA, et al. Opiate metabolism and excretion. Baillieres
4. Herrlin K, et al. Methadone, ciprofloxacin, and adverse drug re- 1. Benmebarek M, et al. Effects of grapefruit juice on the pharma- Clin Anaesthesiol 1987; 1: 829–58.
actions. Lancet 2000; 356: 2069–70. cokinetics of the enantiomers of methadone. Clin Pharmacol 2. Novick DM, et al. Methadone disposition in patients with chron-
Ther 2004; 76: 55–63. ic liver disease. Clin Pharmacol Ther 1981; 30: 353–62.
Antidepressants. SSRIs such as fluoxetine 1 and
fluvoxamine1,2 may enhance the effects of some opioid analge- Pregnancy. Plasma concentrations of methadone were reduced
sics; such interactions may lead to methadone toxicity. St John’s Pharmacokinetics in methadone-maintained pregnant women, probably due to en-
wort reduced the plasma-methadone concentration to dose ratios Methadone hydrochloride is readily absorbed from the hanced metabolism.1,2 It was suggested that the dose of metha-
by 47% in 4 patients on methadone maintenance therapy for opi- gastrointestinal tract and from subcutaneous or intra- done might need to be increased in such patients.
oid addiction; 2 patients reported symptoms suggestive of a with- 1. Pond SM, et al. Altered methadone pharmacokinetics in metha-
muscular injections. It is widely distributed in the tis- done-maintained pregnant women. J Pharmacol Exp Ther 1985;
drawal syndrome.3
sues, diffuses across the placenta, and is distributed 233: 1–6.
1. Eap CB, et al. Fluvoxamine and fluoxetine do not interact in the
into breast milk. It is extensively protein bound. Meth- 2. Wolff K, et al. Changes to methadone clearance during pregnan-
same way with the metabolism of the enantiomers of methadone.
cy. Eur J Clin Pharmacol 2005; 61: 763–8.
J Clin Psychopharmacol 1997; 17: 113–17. adone is metabolised in the liver, mainly by N-demeth-
2. Bertschy G, et al. Probable metabolic interaction between meth- Renal impairment. The urinary excretion of methadone was
adone and fluvoxamine in addict patients. Ther Drug Monit ylation and cyclisation, and the metabolites are excret-
reduced in renal failure,1 but plasma concentrations were within
1994; 16: 42–5. ed in the bile and urine. Metabolism is primarily the usual range and faecal excretion accounted for the majority
3. Eich-Höchli D, et al. Methadone maintenance treatment and St. catalysed by CYP3A4, although other cytochrome
John’s Wort: a case report. Pharmacopsychiatry 2003; 36: 35–7. of the dose. Very little methadone was removed by peritoneal
P450 isoenzymes also play a role (see Interactions, dialysis or haemodialysis.
Antiepileptics. Opioid withdrawal symptoms have been re-
ported in patients maintained on methadone when they were giv- above). It has a prolonged half-life and is subject to ac- 1. Kreek MJ, et al. Methadone use in patients with chronic renal
disease. Drug Alcohol Depend 1980; 5: 197–205.
en carbamazepine,1,2 phenobarbital,3 or phenytoin.4,5 Converse- cumulation.
ly, methadone-induced respiratory depression developed in a ◊ In reviews of the pharmacokinetics of methadone1-5 particular
patient on carbamazepine, gabapentin, and methadone for neuro- Uses and Administration
reference has been made to its long elimination half-life, accu- Methadone hydrochloride, a diphenylheptane deriva-
pathic pain, after carbamazepine was stopped.6
mulation after repeated doses, and wide interindividual varia-
1. Bell J, et al. The use of serum methadone levels in patients re-
tions. tive, is an opioid analgesic (p.104) that is primarily a μ
ceiving methadone maintenance. Clin Pharmacol Ther 1988; 43: opioid agonist. Single doses of methadone have a less
623–9. Methadone is rapidly absorbed after oral doses and has high oral
2. Saxon AJ, et al. Valproic acid, unlike other anticonvulsants, has bioavailability. Peak plasma concentrations have been reported 1 marked sedative action than single doses of morphine.
no effects on methadone metabolism: two cases. J Clin Psychia- to 5 hours after a single tablet by mouth. It undergoes considera- Methadone is a racemic mixture and levomethadone
try 1989; 50: 228–9.
3. Liu S-J, Wang RIH. Case report of barbiturate-induced enhance-
ble tissue distribution and protein binding is reported to be 60 to (p.77) is the active isomer.
ment of methadone metabolism and withdrawal syndrome. Am J 90% with α1-acid glycoprotein being the main binding protein in
Psychiatry 1984; 141: 1287–8. plasma. Metabolism to the major metabolite 2-ethylidine-1,5- Methadone hydrochloride is used in the treatment of
4. Finelli PF. Phenytoin and methadone tolerance. N Engl J Med dimethyl-3,3-diphenylpyrrolidine and the minor metabolite 2- moderate to severe pain; it may be of use for those pa-
1976; 294: 227. ethyl-3,3-diphenyl-5-methylpyrrolidine, both of them inactive, tients who experience excitation or exacerbation of
5. Tong TG, et al. Phenytoin-induced methadone withdrawal. Ann occurs in the liver. These metabolites are excreted in the faeces
Intern Med 1981; 94: 349–51. pain with morphine. Methadone is also used in the
and urine with unchanged methadone. Other metabolites, includ-
6. Benítez-Rosario MA, et al. Methadone-induced respiratory de-
ing methadol and normethadol, have also been described. The
management of opioid dependence. It has a depressant
pression after discontinuing carbamazepine administration. J
Pain Symptom Manage 2006; 32: 99–100. liver may also serve as a major storage site of unchanged metha- action on the cough centre and has been used as a
Antifungals. Use of methadone with fluconazole has been done which is taken up, bound non-specifically by the liver, and cough suppressant in terminal illness, although the
reported1 to increase serum concentrations of methadone al- released again mainly unchanged. Urinary excretion of metha- BNF discourages this use because of the risks of accu-
though the authors considered that for patients being treated for done is pH-dependent, the lower the pH the greater the clearance. mulation.
opioid dependence the interaction was unlikely to require adjust- In addition to marked interindividual variations there are differ-
ences in the pharmacokinetics of methadone after single or mul- For pain relief starting oral doses of methadone hydro-
ment of the methadone dose. However, respiratory depression
has been reported2 after intravenous doses of fluconazole were tiple doses. Elimination half-lives vary considerably (a range of chloride may range from 2.5 to 10 mg given every 6 to
given to a 60-year-old man also taking oral methadone for pain 15 to 60 hours has been quoted) and may be much longer than 8 hours or longer and thereafter adjusted as necessary.
relief in advanced gastric cancer. Although a randomised place- the 18 hours reported following a single dose. Careful adjust- Methadone may also be given parenterally. In the UK,
bo-controlled study3 found that giving voriconazole to patients ment of dosage is necessary with repeated doses. the subcutaneous and intramuscular routes are licensed
on methadone maintenance therapy for opioid addiction was Most studies have been in addicts. Plasma concentrations have with the intramuscular route being recommended for
generally safe and well tolerated, the authors recommended been found to vary widely during methadone maintenance ther-
monitoring and possible dose reduction of methadone when the apy with large differences between patients and wide fluctua- prolonged use; US licensed product information states
2 drugs are used together. Similar recommendations are also giv- tions in individual patients. These variations in kinetics have also that the intravenous, intramuscular, and subcutaneous
en in the licensed product information for voriconazole. been seen in cancer patients. routes may be used although it gives doses for the in-
1. Cobb MN, et al. The effect of fluconazole on the clinical phar- 1. Säwe J. High-dose morphine and methadone in cancer patients: travenous route only. Initial dose ranges for parenteral
macokinetics of methadone. Clin Pharmacol Ther 1998; 63: clinical pharmacokinetic considerations of oral treatment. Clin
655–62. Pharmacokinet 1986; 11: 87–106.
routes are similar to those used orally; however, if
2. Tarumi Y, et al. Methadone and fluconazole: respiratory depres- 2. Moore RA, et al. Opiate metabolism and excretion. Baillieres transferring between oral and parenteral methadone,
sion by drug interaction. J Pain Symptom Manage 2002; 23:
148–53.
Clin Anaesthesiol 1987; 1: 829–58. US product information states that the initial conver-
3. Liu P, et al. Pharmacokinetic interaction between voriconazole 3. Eap CB, et al. Interindividual variability of the clinical pharma- sion dose should be based on the guide that 10 mg of
and methadone at steady state in patients on methadone therapy. cokinetics of methadone: implications for the treatment of opioid
Antimicrob Agents Chemother 2007; 51: 110–18. dependence. Clin Pharmacokinet 2002; 41: 1153–93. oral methadone is equivalent to about 5 mg of
4. Ferrari A, et al. Methadone—metabolism, pharmacokinetics and parenteral methadone. The analgesic effect of metha-
Antivirals. The potential for interaction between antiretrovirals interactions. Pharmacol Res 2004; 50: 551–9.
and methadone has been reviewed.1 Available evidence for HIV- 5. Lugo RA, et al. Pharmacokinetics of methadone. J Pain Palliat
done begins about 10 to 20 minutes after parenteral in-
protease inhibitors suggests that atazanavir, indinavir, and, pos- Care Pharmacother 2005; 19: 13–24. jection and about 30 to 60 minutes after oral doses, the
sibly, saquinavir alone have no effect on plasma concentrations Administration. Methadone is considerably more lipid-solu- effect of a single dose usually lasting about 4 hours. As
of methadone; amprenavir, nelfinavir, ritonavir, and ritonavir- ble than morphine. A study of plasma concentrations and analge- accumulation occurs with repeated doses, the effects
boosted saquinavir may reduce plasma-methadone concentra- sia after intramuscular injection indicated that more rapid and become more prolonged. Consequently, to avoid the
tions but the effect is unlikely to be clinically significant. Lopina- greater relief of pain might be achieved if lipid-soluble opioid
vir-ritonavir may also reduce methadone concentrations and, al- risk of opioid overdose, it is recommended that in pro-
analgesics were injected into the deltoid rather than the gluteal
though most studies found the interaction to be insignificant, one muscle; there was no significant difference in absorption of mor-
longed use methadone should not be given more than
study reported opioid withdrawal symptoms in some patients. phine from the two sites.1 twice daily.
Unpublished data [also referred to in the licensed product infor-
mation] on tipranavir (boosted with ritonavir) in healthy, opioid- Other routes investigated in pharmacokinetic studies include Methadone is used as part of the treatment of opioid
naive subjects suggest that it may decrease plasma-methadone; continuous intravenous infusion2 and continuous epidural infu- dependence, although prolonged use of methadone it-
licensed product information for tipranavir recommends that pa- sion.3 Rectal administration4 has also been studied. self may result in dependence. Initially, methadone hy-
tients are monitored for symptoms of opioid withdrawal. 1. Grabinski PY, et al. Plasma levels and analgesia following del- drochloride is given in doses sufficient to suppress
toid and gluteal injections of methadone and morphine. J Clin
The NNRTIs nevirapine and efavirenz have both been reported Pharmacol 1983; 23: 48–55. signs of opioid withdrawal but avoid toxicity; the BNF
to reduce plasma-methadone levels and withdrawal symptoms
have occurred when they were given to patients receiving meth-
2. Denson DD, et al. Pharmacokinetics of continuous intravenous and US licensed product information recommended a
infusion of methadone in the early post-burn period. J Clin Phar-
adone. Conversely, delavirdine may increase methadone concen- macol 1990; 30: 70–5. starting dose of 10 to 40 mg daily. Subsequent dose ad-
trations although the effect is unlikely to be clinically significant. 3. Shir Y, et al. Plasma concentrations of methadone during postop- justments should be made cautiously because of the
Methadone possibly increases plasma concentrations of the erative patient-controlled extradural analgesia. Br J Anaesth risks of accumulation; the BNF suggests adjusting the
NRTI zidovudine (see p.915). 1990; 65: 204–9.
4. Dale O, et al. Bioavailabilities of rectal and oral methadone in dose in steps of 10 mg to a maximum weekly increase
1. Bruce RD, et al. Pharmacokinetic drug interactions between opi-
oid agonist therapy and antiretroviral medications: implications healthy subjects. Br J Clin Pharmacol 2004; 58: 156–62. of 30 mg. Once the dose has been stabilised, patients
and management for clinical practice. J Acquir Immune Defic Hepatic impairment. Overall hepatic dysfunction does not may choose to receive prolonged therapy with a care-
Syndr 2006; 41: 563–72.
seem unduly to disrupt methadone metabolism1 and it has been fully selected methadone dose for each individual;
Gastrointestinal drugs. Histamine H2-antagonists such as ci- suggested2 that maintenance dosage of methadone need not be most patients in such maintenance programmes are sta-
metidine (see p.103) may enhance the effects of some opioid an- changed in stable chronic liver disease, although abrupt changes
algesics; such interactions may lead to methadone toxicity.
bilised on once-daily doses of 60 to 120 mg. Alterna-
in hepatic status might result in substantial alterations in metha-
done disposition requiring dosage adjustments. tively, detoxification may be appropriate with the dose
Grapefruit juice. Grapefruit juice, an inhibitor of the cyto-
chrome P450 isoenzyme CYP3A4, has been shown to modestly In a study of patients on methadone maintenance therapy2 appar-
of methadone being gradually decreased until total
increase the bioavailability of methadone;1 although no symp- ent terminal half-life of methadone was prolonged from a mean withdrawal is achieved. Methadone is usually given
toms of methadone toxicity were seen in the studied patients, the of 18.8 hours in those with healthy livers to 35.5 hours in patients orally for the treatment of dependence although
 Methadone Hydrochloride/Methyl Salicylate 85
parenteral routes may be used, particularly when oral ing of its pharmacokinetics and of equianalgesic doses may ad- Preparations
therapy is not possible; the doses stated above may be dress early concerns about the risk of cumulative toxicity associ- Proprietary Preparations (details are given in Part 3)
ated with prolonged use. However, its long terminal half-life Ital.: Doloderm.
given orally or parenterally. In the UK, oral treatment makes it less suitable for the treatment of breakthrough pain.
is commonly given as a mixture containing 1 mg/mL Methadone has been given by the oral, rectal, and parenteral
of methadone hydrochloride. routes.
Methyl Gentisate
For details of doses in children, see below. References.
1. Ayonrinde OT, Bridge DT. The rediscovery of methadone for Gentisato de metilo. 2,5-Dihydroxybenzoic acid methyl ester.
For the control of intractable cough associated with cancer pain management. Med J Aust 2000; 173: 536–40. C 8 H 8 O 4 = 168.1.
terminal lung cancer, methadone hydrochloride is usu- 2. Bruera E, Sweeney C. Methadone use in cancer patients with C AS — 2150-46-1.
ally given in the form of a linctus in a dose of 1 to 2 mg pain: a review. J Palliat Med 2002; 5: 127–38.
3. Bruera E, et al. Methadone versus morphine as a first-line strong
every 4 to 6 hours, but reduced to twice daily on pro- opioid for cancer pain: a randomized, double-blind study. J Clin
longed use. Oncol 2004; 22: 185–92. HO H3C
4. Moryl N, et al. Methadone in the treatment of pain and terminal
Administration. Although duration of action after single doses delirum [sic] in advanced cancer patients. Palliat Support Care
O
of methadone is similar to that of morphine, it increases consid- 2005; 3: 311–17.
erably with multiple dosing of methadone because of the long 5. Mannino R, et al. Methadone for cancer-related neuropathic
pain: a review of the literature. J Opioid Manag 2006; 2: 269–76. O
elimination half-life (see under Pharmacokinetics, above). The 6. Nicholson AB. Methadone for cancer pain. Available in The Co-
minimum effective dose of methadone can be difficult to titrate chrane Database of Systematic Reviews; Issue 4. Chichester: OH
for the individual patient. A fixed 10-mg oral dose with a flexible John Wiley; 2007 (accessed 26/06/08).
patient-controlled dosage interval has been used in patients with Opioid dependence. The treatment of opioid dependence is Profile
chronic cancer pain.1 Dosage not more frequently than every 4 discussed on p.101. In the UK, oral liquid preparations of meth- Methyl gentisate has been used topically for the relief of muscu-
hours during the first 3 to 5 days, followed by a fixed dose every adone hydrochloride 1 mg/mL are widely used for this purpose. loskeletal and joint pain.
8 to 12 hours depending on the patient’s requirements, was ad- It is important to note that these preparations are 2.5 times
vised. Preparations
stronger than Methadone Linctus (BP 2008), and although some Proprietary Preparations (details are given in Part 3)
A suggested initial dose for patients who need to switch from are licensed for analgesia in severe pain, many are licensed for
oral morphine to methadone because of poor pain control is one Multi-ingredient: Ital.: Reumacort.
the treatment of opioid dependence only. Methadone Oral Solu-
tenth of the total daily dose of morphine, but not greater than tion (1 mg/mL) (BP 2008) is available as a ready-to-use solution
100 mg, given at intervals determined by the patient, typically or may be prepared from Methadone Hydrochloride Oral Con-
every 8 hours.2 centrate. However, most commercially available preparations in Methyl Nicotinate (USAN)
When switching from oral to parenteral use it was suggested3 the UK still follow an earlier formula formerly listed in the Drug Méthyle, nicotinate de; Methyli Nicotinas; Methylis nicotinas; Me-
that the dose of methadone should be halved and adjusted there- Tariff Formulary (DTF):
after as necessary. thyl-nikotinát; Metilo nikotinatas; Metylnikotinat; Metyylinikoti-
Methadone Mixture 1 mg/mL naatti; Nicotinato de metilo. Methyl pyridine-3-carboxylate.
Evidence of the prolonged effect of methadone was methadone hydrochloride 10 mg
demonstrated when a single intravenous bolus dose of 20 mg C 7 H 7 NO 2 = 137.1.
Green S and Tartrazine Solution (BP 1980) 0.02 mL C AS — 93-60-7.
resulted in postoperative analgesia lasting about 25 hours.4 An
Compound Tartrazine Solution (BP 1980) 0.08 mL
initial 2-hour loading intravenous infusion of methadone 100
to 200 micrograms/kg per hour to provide rapid analgesia syrup, unpreserved 5 mL
chloroform water, double-strength to 10 mL. N
followed by infusion at a lower maintenance rate of 10 to
20 micrograms/kg per hour for continuous pain relief has been Some commercially available forms of DTF Methadone Mixture
used in burn patients.5 Methadone has also been given by contin- 1 mg/mL use a preservative system based on hydroxybenzoate OCH3
uous subcutaneous infusion for severe cancer pain6,7 although esters rather than chloroform; however, syrup preserved with hy-
this route has been associated with local tissue irritation and droxybenzoate esters may be unsuitable for extemporaneous dis-
induration. Epidural methadone has been used successfully in pensing (see under Incompatibility, above). O
doses of up to 5 mg for analgesia in association with bupi- References.
vacaine.8,9 Intermittent and continuous epidural infusion of 1. Ghodse AH, et al. Comparison of oral preparations of heroin and
Pharmacopoeias. In Eur. (see p.vii).
methadone has also been tried10 in postoperative analgesia. methadone to stabilise opiate misusers as inpatients. BMJ 1990; Ph. Eur. 6.2 (Methyl Nicotinate). A white or almost white pow-
A small case series11 found topical methadone powder to be ef- 300: 719–20. der. M.p. 40° to 42°. Very soluble in water, in alcohol, and in
fective for pain relief of open, exudative wounds.
2. Wolff K, et al. Measuring compliance in methadone maintenance dichloromethane. Protect from light.
patients: use of a pharmacologic indicator to "estimate" metha-
1. Säwe J, et al. Patient-controlled dose regimen of methadone for done plasma levels. Clin Pharmacol Ther 1991; 50: 199–207. Profile
chronic cancer pain. BMJ 1981; 282: 771–3. 3. Wilson P, et al. Methadone maintenance in general practice: pa- Methyl nicotinate is used in topical preparations as a rubefacient.
2. Morley JS, et al. Methadone in pain uncontrolled by morphine. tients, workload, and outcomes. BMJ 1994; 309: 641–4.
Lancet 1993; 342: 1243. 4. Farrell M, et al. Methadone maintenance treatment in opiate de- Preparations
3. Säwe J. High-dose morphine and methadone in cancer patients: pendence: a review. BMJ 1994; 309: 997–1001. Proprietary Preparations (details are given in Part 3)
clinical pharmacokinetic considerations of oral treatment. Clin 5. Henry JA. Methadone: where are we now? Hosp Med 1999; 60: UK: Pickles Chilblain Cream.
Pharmacokinet 1986; 11: 87–106. 161–4.
4. Gourlay GK, et al. Methadone produces prolonged postopera- Multi-ingredient: Arg.: Infrarub†; Medex Rub; Austral.: Deep Heat;
6. Faggiano F, et al. Methadone maintenance at different dosages Austria: Berggeist; Belg.: Algipan; Emerxil; Percutalgine; Rado-Spray†; Ca-
tive analgesia. BMJ 1982; 284: 630–1.
for opioid dependence. Available in The Cochrane Database of nad.: Arthricare for Women Multi-Action†; Arthricare Triple Medicated†;
5. Denson DD, et al. Pharmacokinetics of continuous intravenous
infusion of methadone in the early post-burn period. J Clin Systematic Reviews; Issue 3. Chichester: John Wiley; 2003 (ac- Midalgan†; Chile: Frixio; Konirub; Mentobalsam; Fr.: Algipan; Capsic; Cliptol
Pharmacol 1990; 30: 70–5. cessed 28/08/08). Sport†; Decontractyl; Gel Rubefiant; Percutalgine; Sedartryl†; Ger.: Dolo-
6. Mathew P, Storey P. Subcutaneous methadone in terminally ill 7. Mattick RP, et al. Methadone maintenance therapy versus no neuro†; Forapin E†; Kytta-Balsam f; Rheuma Bad; Spondylon; Tetesept
patients: manageable local toxicity. J Pain Symptom Manage opioid replacement therapy for opioid dependence. Available in Badekonzentrat Rheuma Bad†; Gr.: Faragel-Forte; India: Algipan; Flamar;
1999; 18: 49–52. The Cochrane Database of Systematic Reviews; Issue 2. Chich- Medicreme; Relaxyl; Indon.: Remakrim; Irl.: Algipan; Israel: Deep Heat
7. Makin MK, Morley JS. Subcutaneous methadone in terminally- ester: John Wiley; 2003 (accessed 26/06/08). Spray; Ital.: Altadrine; Balsamo Sifcamina; Relaxar; Sedalpan; Neth.: Cre-
ill patients. J Pain Symptom Manage 2000; 19: 237–8. 8. Amato L, et al. Methadone at tapered doses for the management mor capsici comp; Cremor Capsici compositus; Kruidvat Spierbalsem; Pol.:
8. Drenger B, et al. Extradural bupivacaine and methadone for ex- of opioid withdrawal. Available in The Cochrane Database of Deep Heat; Port.: Midalgan†; S.Afr.: Deep Heat Spray; Infrarub; Sloan’s
tracorporeal shock-wave lithotripsy. Br J Anaesth 1989; 62: Systematic Reviews; Issue 3. Chichester: John Wiley; 2005 (ac- Heat Rub; Singapore: Deep Heating Spray†; Spain: Doctofril Antiinfla-
82–6. cessed 26/06/08). mat; Doctomitil†; Radio Salil; Switz.: Kytta Baume; Midalgan; Radalgin;
9. Martin CS, et al. Extradural methadone and bupivacaine in la- 9. NICE. Methadone and buprenorphine for the management of Thai.: Percutalgine†; UK: Cremalgin; Deep Heat Spray; Dubam; Fiery Jack;
bour. Br J Anaesth 1990; 65: 330–2. opioid dependence: Technology Appraisal Guidance 114 (issued Radian-B Red Oils; Ralgex; Ralgex Heat Spray (low-odour); Red Oil; Trans-
10. Prieto-Alvarez P, et al. Continuous epidural infusion of racemic January 2007). Available at: http://www.nice.org.uk/nicemedia/ vasin Heat Spray; USA: Arthricare Odor Free; Arthricare Triple Medicated;
methadone results in effective postoperative analgesia and low pdf/TA114Niceguidance.pdf (accessed 26/06/08) Musterole.
plasma concentrations. Can J Anaesth 2002; 49: 25–31.
11. Gallagher RE, et al. Analgesic effects of topical methadone: a Preparations
report of four cases. Clin J Pain 2005; 21: 190–2. BP 2008: Methadone Injection; Methadone Linctus; Methadone Oral So-
Administration in children. Methadone is not licensed for lution (1 mg per mL); Methadone Tablets; Methyl Salicylate
use in children. However, it has been tried1 intravenously in chil- USP 31: Methadone Hydrochloride Injection; Methadone Hydrochloride Methyl Sal.; Méthyle, salicylate de; Methyli Salicylas; Methylis sali-
Oral Concentrate; Methadone Hydrochloride Oral Solution; Methadone
dren aged 3 to 7 years to prevent postoperative pain; a dose of Hydrochloride Tablets; Methadone Hydrochloride Tablets for Oral Suspen- cylas; Methyl-salicylát; Metilsalicilatas; Metilsalisilat; Metil-szalicilát;
200 micrograms/kg was given perioperatively followed postop- sion. Metylsalicylat; Metylu salicylan; Metyylisalisylaatti; Salicilato de
eratively by 50 micrograms/kg every 10 minutes until the patient Proprietary Preparations (details are given in Part 3) metilo. Methyl 2-hydroxybenzoate.
was both comfortable and adequately alert. Methadone has also Arg.: Gobbidona; Austral.: Biodone†; Physeptone; Austria: Heptadon; Метилсалицилат
been tried2 orally for the treatment of severe pain in hospitalised Belg.: Mephenon; Braz.: Metadon; Mytedom; Canad.: Metadol; Chile:
C 8 H 8 O 3 = 152.1.
children; daily doses ranged from 200 to 600 micrograms/kg for Amidona†; Fin.: Dolmed; Hong Kong: Physeptone†; Hung.: Depridol;
Metadon; Irl.: Phymet DTF; Physeptone†; Pinadone DTF; Israel: Adolan; C AS — 119-36-8.
up to 6 weeks. Ital.: Eptadone; Malaysia: Aseptone; Neth.: Symoron; NZ: Biodone;
Methadone is used for the management of neonatal abstinence Methatabs; Pallidone; S.Afr.: Physeptone; Singapore: Physeptone†; Spain:
syndrome (p.102). The BNFC suggests an initial oral dose of Metasedin; Switz.: Ketalgine; UK: Eptadone; Martindale Methadone Mix- O
ture DTF; Methadose; Physeptone; Synastone; USA: Diskets; Dolophine;
100 micrograms/kg increased by 50 micrograms/kg every 6 Methadose.
hours until symptoms are controlled; once stabilised, the total
daily dose is given in 2 divided doses for maintenance. When OCH3
withdrawing methadone, the dose should be reduced over 7 to 10
days. Methyl Butetisalicylate OH
1. Berde CB, et al. Comparison of morphine and methadone for Butetisalicilato de metilo; Methyl Diethylacetylsalicylate. Methyl
prevention of postoperative pain in 3- to 7-year-old children. J O-(2-ethylbutyryl)salicylate.
Pediatr 1991; 119: 136–41. NOTE. Methyl salicylate and methyl salicylate liniment have been
2. Shir Y, et al. Oral methadone for the treatment of severe pain in C 14 H 18 O 4 = 250.3. known previously as oil of wintergreen, wintergreen, and winter-
hospitalized children: a report of five cases. Clin J Pain 1998; Profile green oil. Wintergreen oil has also been known as sweet birch oil.
14: 350–3. Methyl butetisalicylate is a salicylic acid derivative that has been Pharmacopoeias. In Eur. (see p.vii), Jpn, and Viet. Also in US-
Cancer pain. Methadone is used as an alternative to morphine used similarly to methyl salicylate (p.85) as a rubefacient for the NF.
in the treatment of severe cancer pain (p.5). A better understand- relief of musculoskeletal, joint, and soft-tissue pain. Ph. Eur. 6.2 (Methyl Salicylate). A colourless or slightly yellow
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
86 Analgesics Anti-inflammatory Drugs and Antipyretics
liquid. Very slightly soluble in water; miscible with alcohol, and of pain in musculoskeletal, joint, and soft-tissue disorders. It is
with fatty and essential oils. Protect from light. also used for minor peripheral vascular disorders such as chil-
USNF 26 (Methyl Salicylate). It is produced synthetically or is blains and as an ingredient in inhalations for the symptomatic F
obtained from the leaves of Gaultheria procumbens (Ericaceae) relief of upper respiratory-tract disorders.
[wintergreen] or from the bark of Betula lenta (Betulaceae) Wintergreen oil is also used in aromatherapy. F
[sweet or black birch]. The source of the methyl salicylate must
be indicated on the label. Preparations F
A colourless, yellowish, or reddish liquid having the characteris- BP 2008: Kaolin Poultice; Methyl Salicylate Liniment; Methyl Salicylate Oint- NH N O
tic odour of wintergreen. Slightly soluble in water; soluble in al- ment; Surgical Spirit.
N O
cohol and in glacial acetic acid. Store in airtight containers. Proprietary Preparations (details are given in Part 3)
Storage. Certain plastic containers, such as those made from Arg.: Aspi-Rub†; Rati Salil Gel; Austral.: Linsal†; Canad.: Deep Heating;
Chile: Parche Calorub; Ger.: Hewedolor N; India: Dolocide Plus; Mex.: O
polystyrene, are unsuitable for liniments or ointments containing Balsamo Nordin; Friccion Don Juan; Tolan; S.Afr.: Thermo-Rub; Thai.: My-
methyl salicylate. gesal; UK: Numark Muscle Rub; USA: Argesic†; Exocaine†; Gordogesic;
Adverse Effects, Treatment, and Precautions
Venez.: Novofric†; Ultrafil†. Profile
Multi-ingredient: numerous preparations are listed in Part 3. Morniflumate, the morpholinoethyl ester of niflumic acid (p.95),
Salicylate intoxication can occur after ingestion or topical appli-
is an NSAID (p.96). It has been used in inflammatory conditions
cation of methyl salicylate (see Overdosage, below).
in doses of 700 mg given twice daily by mouth or rectally as sup-
Overdosage. Ingestion of methyl salicylate poses the threat of positories.
severe, rapid-onset salicylate poisoning because of its liquid con- Mofebutazone (rINN) Preparations
centrated form and lipid solubility.1 It is readily absorbed from Mofebutatsoni; Mofebutazon; Mofebutazona; Mofébutazone;
the gastrointestinal tract and most is rapidly hydrolysed to free Proprietary Preparations (details are given in Part 3)
Mofebutazonum; Monobutazone; Monophenylbutazone. 4- Fr.: Nifluril; Ital.: Flomax; Flumarin; Morniflu; Niflam; Spain: Niflactol.
salicylate. The symptoms, which may appear within 2 hours of
ingestion, are similar to those of salicylate poisoning in general Butyl-1-phenylpyrazolidine-3,5-dione.
(see Adverse Effects of Aspirin, p.20), although methyl sali- Мофебутазон
cylate is expected to be more toxic because of its lipid solubility.
There have been reports of fatalities after ingestion of as little as
C 13 H 16N 2 O 2 = 232.3. Morphine (BAN) ⊗
C AS — 2210-63-1.
4 mL in a child and 6 mL in an adult, although the adult lethal ATC — M01AA02; M02AA02. Morfiini; Morfin; Morfina; Morphinum. 7,8-Didehydro-4,5-epoxy-
dose is estimated to be 30 mL.1 Topical Chinese herbal medici- 17-methylmorphinan-3,6-diol.
ATC Vet — QM01AA02; QM02AA02.
nal preparations may contain methyl salicylate in variable Морфин
amounts, and salicylate poisoning has been reported in a 40-year- C 17 H 19NO 3 = 285.3.
old man after a total body application of such a preparation.2 Sal-
icylate poisoning has also been reported in a woman who had O C AS — 57-27-2 (anhydrous morphine); 6009-81-0 (mor-
attempted suicide by ingesting Red Flower Oil, a topical Chinese phine monohydrate).
herbal oil.3 The authors also noted that some patients took small ATC — N02AA01.
amounts of this preparation orally in an attempt to enhance its N ATC Vet — QN02AA01.
analgesic effects. H3C N
1. Chan TYK. Potential dangers from topical preparations contain-
O H
ing methyl salicylate. Hum Exp Toxicol 1996; 15: 747–50. HO
2. Bell AJ, Duggin G. Acute methyl salicylate toxicity complicat-
ing herbal skin treatment for psoriasis. Emerg Med (Fremantle)
Profile
2002; 14: 188–90. Mofebutazone, a derivative of phenylbutazone (p.117), is an
3. Chan TH, et al. Severe salicylate poisoning associated with the NSAID (p.96). It has been used in the management of muscu-
intake of Chinese medicinal oil (‘Red Flower Oil’). Aust N Z J loskeletal and joint disorders. The sodium salt has been given by O H
Med 1995; 25: 57. intramuscular injection.
NCH3
Percutaneous absorption. Like other salicylates, methyl sal- Preparations
icylate may be absorbed through intact skin.1 Percutaneous ab-
sorption is enhanced by exercise, heat, occlusion, or disruption of Proprietary Preparations (details are given in Part 3)
HO
the integrity of the skin. The amount absorbed will also be in- Ger.: Mofesal N†.
creased by application to large areas of skin. NOTE. The following terms have been used as ‘street names’ (see
Results from a study in healthy subjects showed that a consider- p.vi) or slang names for various forms of morphine:
able amount of salicylic acid may be absorbed through the skin Mofezolac (rINN) Adolf; Block; China White; Cube; Dreamer; Drug store dope;
after topical application of products containing methyl sali- Drugstore dope; Emsel; First line; German boy; God’s drug; Go-
cylate.2 Both the rate and extent of absorption increased after re- Mofézolac; Mofezolaco; Mofezolacum; N-22. 3,4-Bis(p-methoxy- ma; Hard stuff; Hospital Heroin; Hows; Hydrogen Bomb; M;
peated application; the bioavailability of the ointment prepara- phenyl)-5-isoxazoleacetic acid. Miss Emma; Mister blue; Mojo; Monf; Monkey; Morf; Morfs;
tion used in the study increased from 15% after the second dose Мофезолак Morfa; Morphia; Morphina; Morpho; Morphy; Mr. Blue; M.S.;
to 22% after the third to eighth dose. The authors recommend MS; Mud; Murphy; Nasty; Nazi; Sweet Jesus; Sweet Morpheus;
C 19 H 17NO 5 = 339.3. Tar; Unkie; White Stuff.
that topical analgesic preparations containing methyl salicylate C AS — 78967-07-4.
or other salicylates should be used with caution in patients at in-
creased risk of developing salicylate adverse effects (see Precau- Morphine Hydrochloride (BANM) ⊗
tions of Aspirin, p.22). Morfiinihydrokloridi; Morfin Hidroklorür; Morfina, hidrocloruro
Results from another study3 showing high tissue to plasma ratios H 3C de; Morfin-hidroklorid; Morfin-hydrochlorid trihydrát; Morfinhy-
O
after topical application of a methyl salicylate formulation sug- droklorid; Morfino hidrochloridas; Morfiny chlorowodorek; Mor-
gest that direct penetration and not recirculation in the blood is phine, chlorhydrate de; Morphini hydrochloridum; Morphini Hy-
responsible for the salicylate concentrations found. The results drochloridum Trihydricum; Morphinii Chloridum; Morphinum
also showed that methyl salicylate is extensively metabolised to Chloratum.
salicylic acid in the dermal and subcutaneous tissues after topical
application. Морфина Гидрохлорид
O
However, for a study suggesting limited absorption from a patch C 17 H 19NO 3 ,HCl,3H 2 O = 375.8.
CH3 C AS — 52-26-6 (anhydrous morphine hydrochloride);
preparation containing camphor, menthol, and methyl salicylate, N 6055-06-7 (morphine hydrochloride trihydrate).
see Menthol, p.2340.
1. Chan TYK. Potential dangers from topical preparations contain- O Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and Viet.
ing methyl salicylate. Hum Exp Toxicol 1996; 15: 747–50. Ph. Eur. 6.2 (Morphine Hydrochloride). Colourless, silky nee-
2. Morra P, et al. Serum concentrations of salicylic acid following dles, cubical masses or a white or almost white, crystalline pow-
topical applied salicylate derivatives. Ann Pharmacother 1996; HO der. It is efflorescent in a dry atmosphere. Soluble in water;
30: 935–40. slightly soluble in alcohol; practically insoluble in toluene. Pro-
3. Cross SE, et al. Is there tissue penetration after application of O
topical salicylate formulations? Lancet 1997; 350: 636.
tect from light.
Interactions Profile Incompatibility. See under Morphine Sulfate, below.
Absorption of methyl salicylate through the skin can occur after Mofezolac is an NSAID (p.96) given orally in the management
excessive topical application (see above), and interactions would of pain and musculoskeletal and joint disorders. Morphine Sulfate ⊗
be expected to be as for other salicylates (see Interactions of As- Preparations Morfiinisulfaatti; Morfin Sülfat; Morfina, sulfato de; Morfino sulfa-
pirin, p.23). tas; Morfinsulfat; Morfin-sulfát pentahydrát; Morfin-szulfát; Mor-
Proprietary Preparations (details are given in Part 3)
Anticoagulants. Potentiation of warfarin anticoagulation has Jpn: Disopain.
finy siarczan; Morphine, sulfate de; Morphine Sulphate (BANM);
been reported1-3 after topical application of methyl salicylate Morphini sulfas; Morphini Sulfas Pentahydricus.
preparations. Морфина Сульфат
1. Littleton F. Warfarin and topical salicylates. JAMA 1990; 263: (C 17 H 19 NO 3 ) 2 ,H 2 SO 4 ,5H 2 O = 758.8.
2888. Morniflumate (USAN, rINN) C AS — 64-31-3 (anhydrous morphine sulfate); 6211-15-
2. Tam LS, et al. Warfarin interactions with Chinese traditional 0 (morphine sulfate pentahydrate).
medicines: danshen and methyl salicylate medicated oil. Aust N Morniflumato; Morniflumatum; UP-164. 2-Morpholinoethyl 2-
Z J Med 1995; 25: 258. (α,α,α-trifluoro-m-toluidino)nicotinate. Pharmacopoeias. In Chin., Eur. (see p.vii), Int., and US.
3. Joss JD, LeBlond RF. Potentiation of warfarin anticoagulation Ph. Eur. 6.2 (Morphine Sulphate). A white or almost white,
associated with topical methyl salicylate. Ann Pharmacother Морнифлумат
crystalline powder. Soluble in water; very slightly soluble in al-
2000; 34: 729–33. C 19 H 20F 3 N 3 O 3 = 395.4. cohol; practically insoluble in toluene. Protect from light.
Uses and Administration C AS — 65847-85-0. USP 31 (Morphine Sulfate). White, feathery, silky crystals,
Methyl salicylate is a salicylic acid derivative that is irritant to the ATC — M01AX22. cubical masses of crystals, or a white crystalline powder. Is
skin and is used topically in rubefacient preparations for the relief ATC Vet — QM01AX22. odourless and when exposed to air it gradually loses water of hy-
 Mofebutazone/Morphine 87
dration. It darkens on prolonged exposure to light. Soluble 1 in concentration of morphine sulfate when stored at 4° or 23° for Effects on the nervous system. Myoclonus, often associated
16 of water and 1 in 1 of water at 80°; soluble 1 in 570 of alcohol 7 days, whether or not they were protected from light. Solu- with hyperalgesia, has been reported in patients with advanced
and 1 in 240 of alcohol at 60°; insoluble in chloroform and in tions prepared from commercially available injection or from malignant disease treated with morphine.1-5 It appears to be
ether. Store in airtight containers at a temperature up to 40° as powder, in 0.9% sodium chloride or 5% glucose, and stored uncommon with typical oral doses of morphine and is more often
permitted by the manufacturer. Protect from light. in PVC bags or glass bottles did not differ in stability from associated with high intravenous and spinal doses. Neuroexcita-
one another. In a further study2 10 mg/mL or 5 mg/mL solu- tory metabolites of morphine are often implicated in the develop-
Incompatibility. Incompatibility data for morphine has been tions of morphine sulfate in glucose or sodium chloride and ment of myoclonus;2,4,5 however, other possible mechanisms
extensively studied1,2 and may depend on many factors such as stored in portable infusion pump cassettes retained more than such as drug interactions cannot be ruled out.4-6
the formulation used, and order and ratio of mixing; however, 95% of their initial concentration when kept at 23° for 30
most studies are usually only short term and contain few details It has been reported that myoclonus induced by morphine can be
days. A 0.9% solution of sodium chloride containing mor- successfully controlled using a benzodiazepine such as mida-
on mixing the same drugs in a variety of different situations. phine sulfate 2 mg/mL was stable for 6 weeks when stored in zolam.7 Indeed, some researchers8 consider benzodiazepines to
Morphine salts are sensitive to changes in pH and morphine is polypropylene syringes at ambient temperatures in the light be the drugs of choice: clonazepam, diazepam, and lorazepam
liable to be precipitated out of solution in an alkaline environ- or dark but a similar solution which also contained 0.1% so- were most frequently used. Dantrolene5,8 and gabapentin9 have
ment. Compounds incompatible with morphine salts include dium metabisulfite lost 15% of its potency during the same also been tried.
aminophylline and sodium salts of barbiturates and phenytoin. period.3 Stability of such a solution with or without sodium 1. Potter JM, et al. Myoclonus associated with treatment with high
Other incompatibilities, sometimes attributed to particular for- metabisulfite was considered to be unacceptable when stored doses of morphine: the role of supplemental drugs. BMJ 1989;
mulations, have included: in glass syringes in the dark.4 299: 150–3.
• Aciclovir sodium—precipitate noted 2 hours after admixture A more recent review5 (which included some of the above stud- 2. Glare PA, et al. Normorphine, a neurotoxic metabolite? Lancet
with morphine sulfate solution3 ies) has concluded that the degradation of morphine solutions is
1990; 335: 725–6.
3. De Conno F, et al. Hyperalgesia and myoclonus with intrathecal
• Chlorpromazine hydrochloride injection—precipitation was not affected by oxygen, light, diluent type, salt form, or morphine infusion of high-dose morphine. Pain 1992; 47: 337–9.
considered to be due to chlorocresol present in the morphine concentration when stored under normal conditions; it was con- 4. Sjøgren P, et al. Hyperalgesia and myoclonus in terminal cancer
sulfate injection4 sidered that morphine solutions could be stored for at least 3 patients treated with continuous intravenous morphine. Pain
• Doxorubicin—addition of morphine sulfate 1 mg/mL to months without stability problems. 1993; 55: 93–7.
d o xo ru b i c i n h yd r oc h lo r i de l i p o s o m a l i n j e c t i o n 1. Vecchio M, et al. The stability of morphine intravenous infusion 5. Mercadante S. Pathophysiology and treatment of opioid-related
solutions. Can J Hosp Pharm 1988; 41: 5–9, 43. myoclonus in cancer patients. Pain 1998; 74: 5–9.
400 micrograms/mL in dextrose 5% resulted in turbidity 6. Quinn N. Myoclonus associated with high doses of morphine.
changes5 2. Walker SE, et al. Hydromorphone and morphine stability in port-
BMJ 1989; 299: 683–4.
able infusion pump cassettes and minibags. Can J Hosp Pharm
• Fluorouracil—immediate precipitate formed after admixture 1988; 41: 177–82. 7. Holdsworth MT, et al. Continuous midazolam infusion for the
of fluorouracil 1 or 16 mg/mL with morphine sulfate management of morphine-induced myoclonus. Ann Pharmaco-
3. Grassby PF. The stability of morphine sulphate in 0.9 per cent
1 mg/mL in dextrose 5% or sodium chloride 0.9%6 ther 1995; 29: 25–9.
sodium chloride stored in plastic syringes. Pharm J 1991; 248:
HS24–HS25. 8. Ferris DJ. Controlling myoclonus after high-dosage morphine
• Furosemide—precipitate noted 1 hour after admixture with infusions. Am J Health-Syst Pharm 1999; 56: 1009–10.
morphine sulfate solution3 4. Grassby PF, Hutchings L. Factors affecting the physical and
chemical stability of morphine sulphate solutions stored in sy- 9. Mercadante S, et al. Gabapentin for opioid-related myoclonus in
• Haloperidol—immediate precipitation seen after admixture of ringes. Int J Pharm Pract 1993; 2: 39–43. cancer patients. Support Care Cancer 2001; 9: 205–6.
haloperidol and morphine sulfate solution7 5. Vermeire A, Remon JP. Stability and compatibility of morphine.
• Heparin sodium—incompatibility has been reported from Int J Pharm 1999; 187: 17–51. Precautions
straightforward additive studies.1 Another study8 indicated ORAL PREPARATIONS. Studies1,2 have shown that for optimum As for Opioid Analgesics in general, p.103.
that morphine sulfate and heparin sodium were only incom- stability of morphine content, Kaolin and Morphine Mixture
patible at morphine sulfate concentrations greater than Biliary-tract disorders. See under Precautions of Opioid An-
(BP) needed to be stored in well-filled glass containers. algesics, p.103.
5 mg/mL and that this incompatibility could be prevented by 1. Helliwell K, Game P. Stability of morphine in kaolin and mor-
using 0.9% sodium chloride solution as the admixture diluent phine mixture BP. Pharm J 1981; 227: 128–9. Breast feeding. Measurable blood concentrations of morphine
rather than water 2. Helliwell K, Jennings P. Kaolin and morphine mixture BP: ef- have been detected in 2 breast-fed infants whose mothers re-
• Pethidine hydrochloride—incompatibility has been noted af- fects of containers on the stability of morphine. Pharm J 1984; ceived oral or intrathecal morphine during and after their preg-
232: 682. nancies; however, no adverse effects were reported in either of
ter admixture with morphine sulfate1,9
• Prochlorperazine edisilate—immediate precipitation was at- TOPICAL PREPARATIONS. When mixed with about 8 g of Intra- these infants.1,2 In a group of 7 women given patient-controlled
tributed to phenol in the morphine sulfate injection site gel (Smith & Nephew Healthcare, UK) morphine sulfate, analgesia with intravenous morphine after caesarean delivery,
formulation10,11 in a concentration of 1.25 mg/mL, remained chemically sta- the concentrations of morphine and its metabolite morphine-6
ble over a 28-day period stored at 4° or at room temperature, glucuronide in the colostrum were found to be very small.3 Al-
• Promethazine hydrochloride—cloudiness was reported to de-
irrespective of light exposure.1 However, unless prepared un- though no infants were breast fed during the study, it was consid-
velop when 12.5 mg of promethazine hydrochloride was
der sterile conditions, the mixture should be used within 7 ered that the effects of maternal morphine on breast-fed infants
drawn into a syringe containing morphine sulfate 8 mg.12
days because of the risk of microbial contamination once the would be negligible.3 The American Academy of Pediatrics4
Others9 have noted no incompatibility
gel has been opened. also states that the use of morphine is usually compatible with
• Ranitidine hydrochloride—crystal needles and/or sticky spots breast feeding.
1. Zeppetella G, et al. Stability of morphine sulphate and diamor-
observed in admixtures of morphine hydrochloride and raniti- phine hydrochloride in Intrasite gel . Palliat Med 2005; 19: 1. Robieux I, et al. Morphine excretion in breast milk and resultant
dine hydrochloride in various ratios stored at different 131–6. exposure of a nursing infant. J Toxicol Clin Toxicol 1990; 28:
temperatures13 365–70.
• Tetracyclines—colour change from pale yellow to light green Morphine Tartrate (BANM) ⊗ 2. Oberlander TF, et al. Prenatal and breast milk morphine expo-
sure following maternal intrathecal morphine treatment. J Hum
occurred when solutions of minocycline hydrochloride or tet-
Morfina, tartrato de. Lact 2000; 16: 137–42.
racycline hydrochloride were mixed with morphine sulfate in 3. Baka N-E, et al. Colostrum morphine concentrations during
5% glucose injection14 Морфина Тартрат postcesarean intravenous patient-controlled analgesia. Anesth
1. Patel JA, Phillips GL. A guide to physical compatibility of in- (C 17 H 19 NO 3 ) 2 ,C 4 H 6 O 6 ,3H 2 O = 774.8. Analg 2002; 94: 184–7.
travenous drug admixtures. Am J Hosp Pharm 1966; 23: C AS — 302-31-8 (anhydrous morphine tartrate); 6032- 4. American Academy of Pediatrics. The transfer of drugs and oth-
409–11. 59-3 (morphine tartrate trihydrate). er chemicals into human milk. Pediatrics 2001; 108: 776–89.
2. Vermeire A, Remon JP. Stability and compatibility of morphine. Correction. ibid.; 1029. Also available at:
Int J Pharm 1999; 187: 17–51. Incompatibility. See under Morphine Sulfate, above. h t tp : / /a a p po l i c y. a a pp u b l ica ti o n s .o rg/ c g i / c o nt e n t / f u ll /
3. Pugh CB, et al. Visual compatibility of morphine sulphate and pediatrics%3b108/3/776 (accessed 26/06/08)
meperidine hydrochloride with other injectable drugs during
simulated Y-site injection. Am J Hosp Pharm 1991; 48: 123–5. Dependence and Withdrawal Hepatic impairment. In view of its hepatic metabolism, cau-
4. Crapper JB. Mixing chlorpromazine and morphine. BMJ 1975; As for Opioid Analgesics, p.101. tion is generally advised when giving morphine to patients with
i: 33. hepatic impairment (but see under Pharmacokinetics, below).
5. Trissel LA, et al. Compatibility of doxorubicin hydrochloride Dependence associated with morphine and closely re- The BNF advises that use should be avoided or the dose reduced
liposome injection with selected other drugs during simulated
Y-site administration. Am J Health-Syst Pharm 1997; 54:
lated μ-agonists appears to result in more severe with- because of the risk of precipitating a coma, although it is also
2708–13. drawal symptoms than that associated with κ-receptor noted that many patients with hepatic impairment tolerate mor-
6. Xu QA, et al. Stability and compatibility of fluorouracil with agonists. With morphine, withdrawal symptoms usual- phine well. Others have considered that severe hepatic impair-
morphine sulfate and hydromorphone hydrochloride. Ann Phar- ment may affect morphine metabolism but less severe impair-
macother 1996; 30: 756–61. ly begin within a few hours, reach a peak within 36 to ment does not.1
7. LeBelle MJ, et al. Compatibility of morphine and midazolam or 72 hours, and then gradually subside.
haloperidol in parenteral admixtures. Can J Hosp Pharm 1995; The mean elimination half-life of morphine in 12 patients with
48: 155–60. Morphine is used for substitution therapy in the man- cirrhosis was almost twice that in 10 healthy subjects after ad-
8. Baker DE, et al. Compatibility of heparin sodium and morphine ministration of a modified-release oral morphine preparation
sulfate. Am J Hosp Pharm 1985; 42: 1352–5. agement of neonatal abstinence syndrome (see Admin-
9. Parker WA. Physical compatibilities of preanesthetic medica- istration in Children, below). (MST-Continus; Napp, UK) and peak serum concentrations were
tions. Can J Hosp Pharm 1976; 29: 91–2. almost three times as high.2 Patients with cirrhosis had a greater
10. Stevenson JG, Patriarca C. Incompatibility of morphine sulfate degree of sedation but none developed encephalopathy. It was
and prochlorperazine edisylate in syringes. Am J Hosp Pharm Adverse Effects and Treatment recommended that the dose for modified-release preparations
1985; 42: 2651. As for Opioid Analgesics in general, p.102. should be reduced and that it be given less often when patients
11. Zuber DEL. Compatibility of morphine sulfate injection and have cirrhosis.
prochlorperazine edisylate injection. Am J Hosp Pharm 1987; ◊ References.
44: 67. In a later study3 15 patients with liver cancer were given the same
1. Cherny N, et al. Strategies to manage the adverse effects of oral
12. Fleischer NM. Promethazine hydrochloride—morphine sulfate
morphine: an evidence-based report. J Clin Oncol 2001; 19: oral morphine preparation and compared with 10 healthy sub-
incompatibility. Am J Hosp Pharm 1973; 30: 665. jects from the previous study; the area under the serum concen-
13. Vermeire A, et al. A new method to obtain and present complete 2542–54.
information on the compatibility: study of its validity for eight
tration-time curve of morphine was increased three- to fourfold
Effects on the cardiovascular system. For a reference to the in those with cancer. The elimination half-life of morphine was
binary mixtures of morphine with drugs frequently used in pal-
liative care. Palliat Med 2002; 16: 417–24. effects of morphine on histamine release compared with some also prolonged in patients with primary cancer when compared
14. Nieves-Cordero AL, et al. Compatibility of narcotic analgesic other opioids, see under Pethidine, p.114. with healthy subjects and those with secondary metastatic dis-
solutions with various antibiotics during simulated Y-site injec- ease. Adverse effects were more frequent in the primary cancer
tion. Am J Hosp Pharm 1985; 42: 1108–9. Effects on the muscles. Severe rectovaginal spasms that oc-
curred in a patient given intrathecal morphine1 were successfully group and included 2 cases of respiratory depression; the authors
Stability. INTRAVENOUS PREPARATIONS. Solutions of morphine controlled with midazolam. commented that altered blood-brain transportation may have
sulfate for intravenous infusion appear to be relatively stable. 1. Littrell RA, et al. Muscle spasms associated with intrathecal been partly responsible for such effects.
In a study 1 solutions containing 40 micrograms/mL and morphine therapy: treatment with midazolam. Clin Pharm 1992; 1. Twycross R, Wilcock A. Palliative Care Formulary. 3rd ed. Not-
400 micrograms/mL retained more than 90% of their initial 11: 57–9. tingham, Palliativedrugs.com Ltd, 2007: 274.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
88 Analgesics Anti-inflammatory Drugs and Antipyretics
2. Kotb HIM, et al. Pharmacokinetics of controlled release mor- release morphine1 and antagonism of the effects of morphine on 14. McQuay HJ, et al. Oral morphine in cancer pain: influences on
phine (MST) in patients with liver cirrhosis. Br J Anaesth 1997; gastric emptying by intravenous metoclopramide.2 morphine and metabolite concentration. Clin Pharmacol Ther
79: 804–6. 1990; 48: 236–44.
1. Manara AR, et al. The effect of metoclopramide on the absorp- 15. Hanna MH, et al. Disposition of morphine-6-glucuronide and
3. Kotb HIM, et al. Pharmacokinetics of controlled release mor- tion of oral controlled release morphine. Br J Clin Pharmacol
phine (MST) in patients with liver carcinoma. Br J Anaesth morphine in healthy volunteers. Br J Anaesth 1991; 66: 103–7.
1988; 25: 518–21. 16. Portenoy RK, et al. The metabolite morphine-6-glucuronide
2005; 94: 95–9. 2. McNeill MJ, et al. Effect of iv metoclopramide on gastric emp- contributes to the analgesia produced by morphine infusion in
Phaeochromocytoma. Morphine and some other opioids can tying after opioid premedication. Br J Anaesth 1990; 64: 450–2. patients with pain and normal renal function. Clin Pharmacol
induce the release of endogenous histamine and thereby stimu- Tricyclic antidepressants. Both clomipramine and am- Ther 1992; 51: 422–31.
17. Thompson PI, et al. Respiratory depression following morphine
late catecholamine release making them unsuitable for use in pa- itriptyline significantly increased the plasma availability of mor- and morphine-6-glucuronide in normal subjects. Br J Clin Phar-
tients with phaeochromocytoma. For further details, see p.103. phine when given to cancer patients taking oral morphine solu- macol 1995; 40: 145–52.
tion.1 It was noted however that the potentiation of the analgesic 18. Lötsch J, Geisslinger G. Morphine-6-glucuronide: an analgesic
Renal impairment. Severe and prolonged respiratory depres- of the future? Clin Pharmacokinet 2001; 40: 485–99.
effects of morphine by these drugs might not be confined to in-
sion has occurred in patients with renal impairment given mor- 19. Wittwer E, Kern SE. Role of morphine’s metabolites in analge-
creased bioavailability of morphine; the dose of tricyclic to use
phine. Toxicity in 3 such patients was attributed to the accumu- sia: concepts and controversies. AAPS J 2006; 8: E348–E352.
with morphine in the treatment of cancer pain should be decided
lation of the active metabolite morphine-6-glucuronide.1 Plasma 20. van Dorp ELA, et al. Morphine-6-glucuronide: morphine’s suc-
by clinical evaluation rather than by pharmacokinetic data. cessor for postoperative pain relief? Anesth Analg 2006; 102:
concentrations of this metabolite were found2 to be ten times 1789–97.
1. Ventafridda V, et al. Antidepressants increase bioavailability of
higher than normal in a 7-year-old girl with haemolytic uraemic morphine in cancer patients. Lancet 1987; i: 1204. 21. Lugo RA, Kern SE. Clinical pharmacokinetics of morphine. J
syndrome given morphine intravenously although the half-life of Pain Palliat Care Pharmacother 2003; 16 (4): 5–18.
morphine was also prolonged. Plasma concentrations of mor- 22. Smith MT, et al. Morphine-3-glucuronide—a potent antagonist
phine-6-glucuronide were also reported3 to be persistently in- Pharmacokinetics of morphine analgesia. Life Sci 1990; 47: 579–85.
Morphine salts are well absorbed from the gastrointes- 23. Morley JS, et al. Paradoxical pain. Lancet 1992; 340: 1045.
creased 19 days after stopping morphine by intravenous infusion 24. Morley JS, et al. Methadone in pain uncontrolled by morphine.
in a 17-year-old girl with normal renal function. The authors of tinal tract but have poor oral bioavailability since they Lancet 1993; 342: 1243.
the report suggested that alterations in bowel flora after antibac- undergo extensive first-pass metabolism in the liver
terial therapy or inhibition of morphine-3-glucuronide glucuro- Administration. There have been many studies on the phar-
and gut. After subcutaneous or intramuscular injection macokinetics of morphine given by various routes and methods.
nidation by lorazepam might be responsible. It has also been
reported4 that accumulation of morphine can occur in renal fail- morphine is readily absorbed into the blood. The These include the buccal route (see below), modified-release oral
majority of a dose of morphine is conjugated with glu- preparations,1,2 the rectal route,3,4 the topical route,5 the pulmo-
ure, although to a lesser extent than accumulation of metabolites
nary route,6,7 continuous subcutaneous compared with intrave-
(see also under Pharmacokinetics, below). curonic acid in the liver and gut to produce morphine- nous infusion,8 and the intraspinal route.9-13
1. Osborne RJ, et al. Morphine intoxication in renal failure: the role 3-glucuronide and morphine-6-glucuronide. The latter Slow dural transfer of morphine and its prolonged presence in
of morphine-6-glucuronide. BMJ 1986; 292: 1548–9.
2. Hasselström J, et al. Long lasting respiratory depression induced
is considered to contribute to the analgesic effect of the CSF appear to correlate with its slow onset and long duration
by morphine-6-glucuronide? Br J Clin Pharmacol 1989; 27: morphine, especially with repeated oral doses. Mor- of action by epidural and intrathecal injection.14 More lipid-sol-
515–18. phine-3-glucuronide on the other hand can antagonise uble opioids, such as diamorphine and pethidine, enter and leave
3. Calleja MA, et al. Persistently increased morphine-6-glucuro-
the analgesic action and might be responsible for the the CSF more rapidly than morphine.
nide concentrations. Br J Anaesth 1990; 64: 649. The pharmacokinetics of morphine given by 5 different routes—
4. Osborne R, et al. The pharmacokinetics of morphine and mor- paradoxical pain seen in some patients given mor- intravenous bolus injection and oral, sublingual, buccal, and
phine glucuronides in kidney failure. Clin Pharmacol Ther 1993; phine. Other active metabolites include normorphine,
54: 158–67. modified-release buccal tablets—were studied15 with particular
codeine, and morphine ethereal sulfate. Enterohepatic reference to morphine-6-glucuronide, the active metabolite. This
circulation probably occurs. Morphine is distributed metabolite occurred in large quantities after intravenous doses
Interactions and plasma concentrations rapidly exceeded those of morphine.
For interactions associated with opioid analgesics, see throughout the body but mainly in the kidneys, liver,
After oral doses morphine-6-glucuronide and morphine-3-glu-
p.103. lungs, and spleen, with lower concentrations in the curonide were present in quantities similar to those seen after in-
brain and muscles. Morphine crosses the blood-brain travenous morphine; morphine concentrations in plasma were
US licensed product information for some once-daily barrier less readily than more lipid-soluble opioids very low and the mean morphine-6-glucuronide to morphine
modified-release preparations of morphine sulfate such as diamorphine, but it has been detected in the area under the curve ratio was 9.7 to 1. There was delayed ab-
states that patients must not ingest alcohol, including CSF as have its highly polar metabolites morphine-3- sorption with attenuation and delay of peak morphine and metab-
alcohol-containing medicines, at the same time due to olite plasma concentrations after sublingual or buccal dosage.
glucuronide and morphine-6-glucuronide. Morphine Compared with oral doses, concentrations of morphine were
the risk of rapid release and absorption of a potentially diffuses across the placenta and traces also appear in
fatal dose of morphine; in-vitro studies showed that al- higher and those of its glucuronides lower when morphine was
breast milk and sweat. About 35% is protein bound. given rectally,16 suggesting avoidance of first-pass metabolism.
cohol accelerated the release of morphine. Mean plasma elimination half-lives of about 2 hours Morphine was not absorbed systemically when applied topically
◊ For references to myoclonus associated with morphine and the for morphine and 2.4 to 6.7 hours for morphine-3-glu- to ulcers although some absorption may occur when a large sur-
concurrent use of other drugs, see Effects on the Nervous System face area is involved.5
curonide have been reported.
under Adverse Effects, above. 1. Pinnock CA, et al. Absorption of controlled release morphine
Up to 10% of a dose of morphine may eventually be sulphate in the immediate postoperative period. Br J Anaesth
Antibacterials. There is some evidence1 that the potent en- excreted, as conjugates, through the bile into the 1986; 58: 868–71.
zyme inducer rifampicin can reduce the serum concentration of 2. Savarese JJ, et al. Steady-state pharmacokinetics of controlled
morphine and decrease its analgesic effect; induction of the en- faeces. The remainder is excreted in the urine, mainly release oral morphine sulphate in healthy subjects. Clin Phar-
as conjugates. About 90% of total morphine is excreted macokinet 1986; 11: 505–10.
zymes responsible for conversion of morphine to the active glu- 3. Moolenaar F, et al. Drastic improvement in the rectal absorption
curonide metabolite did not seem to occur. in 24 hours with traces in urine for 48 hours or more. profile of morphine in man. Eur J Clin Pharmacol 1985; 29:
1. Fromm MF, et al. Loss of analgesic effect of morphine due to 119–21.
coadministration of rifampin. Pain 1997; 72: 261–7.
◊ Much has been published on the metabolism and disposition of 4. Cole L, et al. Further development of a morphine hydrogel sup-
morphine and its relevance to the clinical use of morphine, in pository. Br J Clin Pharmacol 1990; 30: 781–6.
Benzodiazepines. An additive sedative effect is to be expected particular the analgesic effect of repeated oral doses and the rel- 5. Ribeiro MDC, et al. The bioavailability of morphine applied
between opioid analgesics and benzodiazepines and has been re- ative potency of oral to parenteral doses. There has been uncer- topically to cutaneous ulcers. J Pain Symptom Manage 2004;
27: 434–9.
ported with morphine and midazolam.1 tainty as to the contributions in man of first-pass metabolism in 6. Ward ME, et al. Morphine pharmacokinetics after pulmonary
For reference to a suggestion that lorazepam may inhibit mor- the liver and gut,1-4 the possible role of renal metabolism,2,3,5,6 administration from a novel aerosol delivery system. Clin Phar-
phine-3-glucuronide glucuronidation, see Renal Impairment un- the analgesic activity and clinical importance of the metabolite macol Ther 1997; 62: 596–609.
der Precautions, above. morphine-6-glucuronide,2,7-21 and enterohepatic circulation.2,9 7. Masood AR, Thomas SHL. Systemic absorption of nebulized
There has also been interest in the effects of the metabolite mor- morphine compared with oral morphine in healthy subjects. Br
1. Tverskoy M, et al. Midazolam-morphine sedative interaction in J Clin Pharmacol 1996; 41: 250–2.
patients. Anesth Analg 1989; 68: 282–5. phine-3-glucuronide.21-24 8. Waldmann CS, et al. Serum morphine levels: a comparison be-
1. Hanks GW, Aherne GW. Morphine metabolism: does the renal tween continuous subcutaneous infusion and continuous intra-
Cisapride. Plasma concentrations of morphine have been in- hypothesis hold water? Lancet 1985; i: 221–2. venous infusion in postoperative patients. Anaesthesia 1984;
creased by oral cisapride.1 2. Hanks GW, et al. Explanation for potency of repeated oral doses 39: 768–71.
1. Rowbotham DJ, et al. Effect of cisapride on morphine absorption of morphine? Lancet 1987; ii: 723–5. 9. Gustafsson LL, et al. Disposition of morphine in cerebrospinal
after oral administration of sustained-release morphine. Br J 3. Bodenham A, et al. Extrahepatic morphine metabolism in man fluid after epidural administration. Lancet 1982; i: 796.
Anaesth 1991; 67: 421–5. during the anhepatic phase of orthotopic liver transplantation. 10. Moore A, et al. Spinal fluid kinetics of morphine and heroin.
Br J Anaesth 1989; 63: 380–4. Clin Pharmacol Ther 1984; 35: 40–5.
Histamine H2-antagonists. See under Opioid Analgesics, 4. Moore RA, et al. Opiate metabolism and excretion. Baillieres 11. Max MB, et al. Epidural and intrathecal opiates: cerebrospinal
p.103. Clin Anaesthesiol 1987; 1: 829–58. fluid and plasma profiles in patients with chronic cancer pain.
5. McQuay H, Moore A. Metabolism of narcotics. BMJ 1984; 288: Clin Pharmacol Ther 1985; 38: 631–41.
Local anaesthetics. Prior use of epidural chloroprocaine, 237. 12. Nordberg G, et al. Extradural morphine: influence of adrenaline
6. Moore A, et al. Morphine kinetics during and after renal trans- admixture. Br J Anaesth 1986; 58: 598–604.
when compared with lidocaine, has been reported to reduce the plantation. Clin Pharmacol Ther 1984; 35: 641–5. 13. Ionescu TI, et al. The pharmacokinetics of intradural morphine
duration1 and efficacy2 of epidural morphine analgesia. Howev- 7. McQuay HJ, et al. Potency of oral morphine. Lancet 1987; ii: in major abdominal surgery. Clin Pharmacokinet 1988; 14:
er, a later study3 found no such effects; the authors suggested that 1458–9. 178–86.
findings from the previous 2 studies were due to breakthrough 8. Hanks GW, et al. Enterohepatic circulation of morphine. Lancet 14. Morgan M. The rational use of intrathecal and extradural opio-
pain caused by the early resolution of chloroprocaine anaesthesia 1988; i: 469. ids. Br J Anaesth 1989; 63: 165–88.
9. Osborne R, et al. Analgesic activity of morphine-6-glucuronide. 15. Osborne R, et al. Morphine and metabolite behavior after differ-
occurring before the maximum onset of morphine analgesia. Lancet 1988; i: 828. ent routes of morphine administration: demonstration of the im-
1. Eisenach JC, et al. Effect of prior anesthetic solution on epidural 10. Hanks GW, Wand PJ. Enterohepatic circulation of opioid drugs: portance of the active metabolite morphine-6-glucuronide. Clin
morphine analgesia. Anesth Analg 1991; 73: 119–23. is it clinically relevant in the treatment of cancer patients? Clin Pharmacol Ther 1990; 47: 12–19.
2. Karambelkar DJ, Ramanathan S. 2-Chloroprocaine antagonism Pharmacokinet 1989; 17: 65–8. 16. Babul N, Darke AC. Disposition of morphine and its glucuro-
of epidural morphine analgesia. Acta Anaesthesiol Scand 1997; 11. Paul D, et al. Pharmacological characterization of morphine-6β- nide metabolites after oral and rectal administration: evidence
41: 774–8. glucuronide, a very potent morphine metabolite. J Pharmacol of route specificity. Clin Pharmacol Ther 1993; 54: 286–92.
Exp Ther 1989; 251: 477–83.
3. Hess PE, et al. Chloroprocaine may not affect epidural morphine 12. Hanna MH, et al. Analgesic efficacy and CSF pharmacokinetics BUCCAL ROUTE. Conflicting results from studies on buccal
for postcesarean delivery analgesia. J Clin Anesth 2006; 18: of intrathecal morphine-6-glucuronide: comparison with mor- morphine may reflect differences in formulation1 and hence
29–33. phine. Br J Anaesth 1990; 64: 547–50. absorption. Some2 reported equivalent analgesia with buccal
Metoclopramide. Reports on the effects of metoclopramide 13. Osborne R, et al. Morphine and metabolite behavior after differ- and intramuscular morphine although others3 found marked
ent routes of morphine administration: demonstration of the im-
on morphine have included an increased rate of onset and degree portance of the active metabolite morphine-6-glucuronide. Clin interindividual variability with mean peak serum concentra-
of sedation when oral metoclopramide was given with modified- Pharmacol Ther 1990; 47: 12–19. tions of morphine some eight times lower after a buccal tablet
 Morphine 89
than after an intramuscular injection and occurring a mean of group, apparent volume of distribution at steady state was about dial infarction, and surgery. In addition to relieving
4 hours later. Morphine sulfate in aqueous solution has been half that of the young group and plasma clearance was reduced. pain, morphine also alleviates the anxiety associated
reported to be moderately well absorbed from the buccal mu- 1. Owen JA, et al. Age-related morphine kinetics. Clin Pharmacol
cosa.4 Absolute bioavailability for morphine was estimated to Ther 1983; 34: 364–8. with severe pain and it is useful as a hypnotic where
be 23.8% after an oral solution, 22.4% after a modified-re- Hepatic impairment. The liver is a major site of morphine sleeplessness is due to pain. It is also used in the man-
lease oral tablet (MST Continus; Napp, UK), and 20.2% after metabolism and therefore hepatic impairment could be expected agement of neonatal abstinence syndrome (see Admin-
a modified-release buccal tablet, with maximum plasma-mor- to affect elimination (see under Precautions, above). There is istration in Children, below).
phine concentrations at 45 minutes, 2.5 hours, and 6 hours some evidence that in cirrhosis glucuronidation might be rela-
respectively; mean ratios of area under the plasma concentra- Morphine reduces intestinal motility but its role, if any,
tively spared compared with other metabolic processes and that
tion-time curve for morphine-6-glucuronide to morphine in some extrahepatic metabolism may occur. Several studies have in the symptomatic treatment of diarrhoea is very lim-
plasma were 11:1 after buccal and oral morphine compared served to illustrate these points: ited. It also relieves dyspnoea associated with various
with 2:1 for intravenous morphine.5 There was considerable • Hepatic extraction of morphine was impaired in cirrhotic pa- conditions, including that due to pulmonary oedema
inter-subject variation in plasma concentrations of the mor- tients, but less than expected1
phine metabolites, morphine-3-glucuronide and morphine-6-
resulting from left ventricular failure. It is an effective
• Morphine metabolism was minimal during the anhepatic cough suppressant, but codeine is usually preferred as
glucuronide after buccal doses of morphine as a modified-re-
phase of liver transplantation, but increased markedly when there is less risk of dependence; morphine may howev-
lease formulation,6 and lack of pain relief was subsequently
the new liver was reperfused2
reported with this buccal formulation.7 Poor absorption of er be necessary to control intractable cough associated
morphine from modified-release buccal tablets when com- • Morphine metabolism was virtually complete after liver trans-
plantation with only 4.5% unchanged morphine being excret- with terminal lung cancer. Morphine has been used
pared with intramuscular injection was also reported;8 bitter-
ness of the tablets, leading to their premature removal, and ed in the urine 24 hours after administration3 pre-operatively as an adjunct to anaesthesia for pain re-
poor dissolution may have contributed. • Morphine elimination was reduced when hepatic blood flow lief and to allay anxiety. It has also been used in high
1. Calvey TN, Williams NE. Pharmacokinetics of buccal morphine.
was impaired4 doses as a general anaesthetic in specialised procedures
Br J Anaesth 1990; 64: 256. 1. Crotty B, et al. Hepatic extraction of morphine is impaired in
cirrhosis. Eur J Clin Pharmacol 1989; 36: 501–6. such as open-heart surgery.
2. Bell MDD, et al. Buccal morphine—a new route for analgesia?
2. Bodenham A, et al. Extrahepatic morphine metabolism in man Morphine is usually administered as the sulfate, al-
Lancet 1985; i: 71–3.
during the anhepatic phase of orthotopic liver transplantation. Br
3. Fisher AP, et al. Serum morphine concentrations after buccal and J Anaesth 1989; 63: 380–4. though the hydrochloride and the tartrate are used in
intramuscular morphine administration. Br J Clin Pharmacol 3. Shelly MP, et al. Pharmacokinetics of morphine in patients fol- similar doses. Doses are expressed as the salts. Dosage
1987; 24: 685–7. lowing orthotopic liver transplantation. Br J Anaesth 1989; 63:
4. Al-Sayed-Omar O, et al. Influence of pH on the buccal absorp- 375–9. routes include the oral, subcutaneous, intramuscular,
tion of morphine sulphate and its major metabolite, morphine-3- 4. Manara AR, et al. Morphine elimination and liver blood flow: a intravenous, intraspinal, and rectal routes. Subcutane-
glucuronide. J Pharm Pharmacol 1987; 39: 934–5. study in patients undergoing distal splenorenal shunt. Br J Hosp
5. Hoskin PJ, et al. The bioavailability and pharmacokinetics of Med 1989; 42: 148 (abstract).
ous injections are considered unsuitable for oedema-
morphine after intravenous, oral and buccal administration in tous patients. Parenteral doses may be intermittent
healthy volunteers. Br J Clin Pharmacol 1989; 27: 499–505. Renal impairment. Only a small amount of morphine is ex-
creted unchanged in the urine. There are conflicting reports of injections or continuous or intermittent infusions ad-
6. Manara AR, et al. Pharmacokinetics of morphine following ad-
ministration by the buccal route. Br J Anaesth 1989; 62: morphine accumulation in patients with renal impairment; some justed according to individual analgesic requirements.
498–502. for,1,2 others against.3-5 It does seem clear though that morphine Doses should generally be reduced in the elderly or de-
7. Manara AR, et al. Analgesic efficacy of perioperative buccal metabolites accumulate in such patients5-9 including those on
morphine. Br J Anaesth 1990; 64: 551–5. peritoneal dialysis;10 the half-life of the active metabolite mor-
bilitated or in patients with hepatic or renal impairment
8. Simpson KH, et al. An investigation of premedication with mor- phine-6-glucuronide was reported to be prolonged and its clear- (see also under Precautions, above).
phine given by the buccal or intramuscular route. Br J Clin Phar- ance reduced when morphine-6-glucuronide was given to pa-
macol 1989; 27: 377–80.
For pain:
tients with renal impairment.11 Opioid intoxication12 and a
Children. The pharmacokinetics of morphine in children are prolonged opioid effect13 in patients with renal failure has been • Oral doses are usually in the range of 5 to 20 mg
generally considered similar to those in adults;1-3 in both an elim- associated with morphine-6-glucuronide (see also under Precau- every 4 hours and may be given as an aqueous solu-
ination half-life of about 2 hours has been reported after intrave- tions, above). tion of the hydrochloride or sulfate, as modified-
nous administration of morphine. In neonates, however, clear- 1. Ball M, et al. Renal failure and the use of morphine in intensive release granules or tablets, or as tablets. With modi-
ance is generally reduced4-7 and pharmacokinetics are more care. Lancet 1985; i: 784–6.
2. Osborne R, et al. The pharmacokinetics of morphine and mor- fied-release preparations the 24-hour dose is usually
variable.8-10 Studies7,11 have found significantly higher plasma phine glucuronides in kidney failure. Clin Pharmacol Ther
concentrations of morphine and a significantly lower morphine- given as a single dose or in 2 divided doses; in the
1993; 54: 158–67.
6-glucuronide to morphine ratio in neonates when compared 3. Säwe J, et al. Kinetics of morphine in patients with renal failure. USA, a modified-release preparation (MS Contin,
with older infants and children; however, the morphine-6-glu- Lancet 1985; ii: 211. Purdue) that allows dosing every 8 or 12 hours is
curonide to morphine-3-glucuronide ratio remains constant irre- 4. Woolner DF, et al. Renal failure does not impair the metabolism
of morphine. Br J Clin Pharmacol 1986; 22: 55–9. also available. With all modified-release prepara-
spective of age.7 Elimination half-lives of 6.7 and 10 hours have 5. Chauvin M, et al. Morphine pharmacokinetics in renal failure.
been reported in term and preterm infants, respectively after a
tions, additional doses of a conventional formulation
Anesthesiology 1987; 66: 327–31.
single intravenous dose of morphine, with nearly 80% of the 6. Säwe J, Odar-Cederlöf I. Kinetics of morphine in patients with may be needed if breakthrough pain occurs. As with
dose remaining unbound.10 The reduced clearance, which is de- renal failure. Eur J Clin Pharmacol 1987; 32: 377–82. the other routes, high oral doses may be required for
7. Wolff J, et al. Influence of renal function on the elimination of
pendent on gestational age and birth weight,12,13 and higher mor- morphine and morphine glucuronides. Eur J Clin Pharmacol effective analgesia in palliative care.
phine concentrations are probably due to reduced metabolism in 1988; 34: 353–7.
neonates as well as immature renal function: the capacity to con- 8. Sear JW, et al. Studies on morphine disposition: influence of • Morphine is sometimes given rectally generally as
jugate morphine by glucuronidation is reduced in preterm in- renal failure on the kinetics of morphine and its metabolites. Br suppositories in doses of 10 to 30 mg every 4 hours.
J Anaesth 1989; 62: 28–32.
fants,6,8,9 and some premature neonates may lack the capacity 9. Peterson GM, et al. Plasma levels of morphine and morphine Oral modified-release preparations have also been
entirely.9 glucuronides in the treatment of cancer pain: relationship to re- used rectally although such use is unlicensed in the
1. Dahlström B, et al. Morphine kinetics in children. Clin Pharma- nal function and route of administration. Eur J Clin Pharmacol
col Ther 1979; 26: 354–65. 1990; 38: 121–4. UK and is generally not recommended except, pos-
2. Stanski DR, et al. Kinetics of high-dose intravenous morphine 10. Pauli-Magnus C, et al. Pharmacokinetics of morphine and its sibly, in some emergency situations.
in cardiac surgery patients. Clin Pharmacol Ther 1976; 19: glucuronides following intravenous administration of morphine
752–6. in patients undergoing continuous ambulatory peritoneal dialy- • The usual dose by subcutaneous or intramuscular
sis. Nephrol Dial Transplant 1999; 14: 903–9. injection is 10 mg every 4 hours but may range from
3. Olkkola KT, et al. Clinical pharmacokinetics and pharmacody- 11. Hanna MH, et al. Morphine-6-glucuronide disposition in renal
namics of opioid analgesics in infants and children. Clin Phar- impairment. Br J Anaesth 1993; 70: 511–14. 5 to 20 mg.
macokinet 1995; 5: 385–404. 12. Osborne RJ, et al. Morphine intoxication in renal failure: the
4. Koren G, et al. Postoperative morphine infusion in newborn in- role of morphine-6-glucuronide. BMJ 1986; 292: 1548–9. • Doses of up to 15 mg have been given by slow intra-
fants: assessment of disposition characteristics and safety. J 13. Bodd E, et al. Morphine-6-glucuronide might mediate the pro- venous injection, sometimes as a loading dose for
Pediatr 1985; 107: 963–7. longed opioid effect of morphine in acute renal failure. Hum
5. Lynn AM, Slattery JT. Morphine pharmacokinetics in early in- Exp Toxicol 1990; 9: 317–21. continuous or patient-controlled infusion. For con-
fancy. Anesthesiology 1987; 66: 136–9. tinuous intravenous administration maintenance
6. Choonara IA, et al. Morphine metabolism in children. Br J Clin Uses and Administration doses have generally ranged from 0.8 to 80 mg/hour,
Pharmacol 1989; 28: 599–604.
7. Bouwmeester NJ, et al. Age- and therapy-related effects on Morphine, a phenanthrene derivative, is the main alka- although some patients have required and been giv-
morphine requirements and plasma concentrations of morphine loid of opium (p.105). It is now commonly obtained en much higher doses. Similar doses have been giv-
and its metabolites in postoperative infants. Br J Anaesth 2003;
90: 642–52. from whole opium poppies (Papaver somniferum) en by continuous subcutaneous infusion.
8. Hartley R, et al. Pharmacokinetics of morphine infusion in pre- which are harvested as poppy straw; a concentrate of • For myocardial infarction, the BNF recommends
mature neonates. Arch Dis Child 1993; 69: 55–8.
9. Bhat R, et al. Morphine metabolism in acutely ill preterm new-
poppy straw is known as CPS. that 10 mg may be given by intravenous injection at
born infants. J Pediatr 1992; 120: 795–9. Morphine is an opioid analgesic (p.104) with agonist a rate of 2 mg/minute followed by a further 5 to
10. Bhat R, et al. Pharmacokinetics of a single dose of morphine in
preterm infants during the first week of life. J Pediatr 1990;
activity mainly at μ opioid receptors and perhaps at κ 10 mg if necessary; half this dose should be used in
117: 477–81. and δ receptors. It acts mainly on the CNS and smooth elderly or debilitated patients.
11. Bouwmeester NJ, et al. Postoperative pain in the neonate: age- muscle. Although morphine is mainly a CNS depres- • Intraspinal doses are in the region of 5 mg for an
related differences in morphine requirements and metabolism.
Intensive Care Med 2003; 29: 2009–15. sant it has some central stimulant actions which result initial epidural injection; if pain relief is unsatisfac-
12. Scott CS, et al. Morphine pharmacokinetics and pain assess- in nausea and vomiting and miosis. Morphine general- tory after one hour, further doses of 1 to 2 mg may be
ment in premature newborns. J Pediatr 1999; 135: 423–9. ly increases smooth muscle tone, especially the sphinc-
13. Saarenmaa E, et al. Morphine clearance and effects in newborn given up to a total dose of 10 mg per 24 hours. The
infants in relation to gestational age. Clin Pharmacol Ther ters of the gastrointestinal and biliary tracts. recommended initial dose for continuous epidural
2000; 68: 160–6. Morphine may produce both physical and psychologi- infusion is 2 to 4 mg per 24 hours increased if neces-
The elderly. The pharmacokinetics of morphine were cal dependence (see p.101) and should therefore be sary by further doses of 1 to 2 mg. A modified-re-
compared1 in 7 healthy elderly (60 to 69 years) and 13 healthy used with discrimination. Tolerance may also develop.
young (24 to 28 years) subjects, after a single intravenous injec-
lease formulation of liposomal morphine sulfate for
tion of morphine sulfate 10 mg per 70 kg. Although the terminal Morphine is used for the relief of moderate to severe lumbar epidural use is also available for the treat-
rate of drug disappearance from plasma was faster in the elderly pain, especially that associated with cancer, myocar- ment of pain after major surgery; doses range from
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
90 Analgesics Anti-inflammatory Drugs and Antipyretics
10 to 20 mg, depending on the type of surgery, and 2. Gustafsson LL, Wiesenfeld-Hallin Z. Spinal opioid analgesia: a Guidelines2 for analgesia in children in Accident and Emergency
critical update. Drugs 1988; 35: 597–603. departments in the UK recommend the use of intravenous mor-
should be given before the operation, or after clamp- 3. McQuay HJ. Opioids in chronic pain. Br J Anaesth 1989; 63: phine as an alternative to, or after initial treatment with,
ing of the umbilical cord if used during caesarean 213–26.
intranasal diamorphine for severe pain such as that associated
4. Sylvester RK, et al. The conversion challenge: from intrathecal
section. It is intended for single-use only and no oth- to oral morphine. Am J Hosp Palliat Care 2004; 21: 143–7. with large burns, long bone dislocation, appendicitis, or sickle-
er drugs should be administered into the epidural PATIENT-CONTROLLED ANALGESIA. Morphine is one of the most
cell crisis, but it should be used with caution if there is risk of
space for at least the next 48 hours. depression of airway, breathing, or circulation.
frequently used opioid analgesics for patient-controlled
analgesia (see p.4). Most experience has been with the intra- In the UK, morphine is also used in the management of neonatal
• Intrathecal use of morphine and its salts has tended abstinence syndrome (p.102) under specialist supervision. The
to be less common than epidural. Doses of venous route, but the intramuscular, subcutaneous, oral, pul-
monary, and epidural1 routes have also been used. Reasonable BNFC recommends an initial oral dose of 40 micrograms/kg (in-
200 micrograms to 1 mg have been injected intrath- initial settings recommended for intravenous use have been a crease dose if necessary) every 4 hours until symptoms are con-
ecally on a single occasion. demand dose of 1 to 2 mg of morphine sulfate (or its equiva- trolled; the dosage frequency should be reduced gradually over 6
lent) and a lockout interval of 5 to 10 minutes.2 to 10 days until a dose of 40 micrograms/kg once daily is
For details of doses in children see below. achieved after which the drug should be stopped.
1. Sjöström S, et al. Patient-controlled analgesia with extradural
In acute pulmonary oedema 5 to 10 mg may be given morphine or pethidine. Br J Anaesth 1988; 60: 358–66. 1. Lloyd-Thomas AR. Pain management in paediatric patients. Br
2. Grass JA. Patient-controlled analgesia. Anesth Analg 2005; 101 J Anaesth 1990; 64: 85–104.
by intravenous injection at a rate of 2 mg/minute. (suppl): S44–S61. 2. British Association for Emergency Medicine. Clinical Effective-
For the control of intractable cough associated with ness Committee guideline for the management of pain in chil-
PULMONARY ROUTE. For reference to the use of nebulised mor- dren (2004). Available at: http://www.emergencymed.org.uk/
terminal lung cancer, morphine oral solution is given in phine see Dyspnoea, below. BAEM/CEC/assets/cec_pain_in_children.pdf (accessed
an initial dose of 5 mg every 4 hours. 26/06/08)
TOPICAL ROUTE. Morphine has been applied topically for local
analgesia in oral mucositis1,2 and cutaneous ulceration3-6 in- Cancer pain. Morphine is the opioid of choice for moderate to
Administration. CONTINUOUS INFUSION. Both acute and
cluding epidermolysis bullosa.7 severe cancer pain (p.5); guidelines for its use issued by the Eu-
chronic pain have been controlled satisfactorily by continu- ropean Association for Palliative Care1 include:
1. Cerchietti LC, et al. Effect of topical morphine for mucositis-
ous intravenous or subcutaneous infusions of morphine associated pain following concomitant chemoradiotherapy for
sulfate1-3 but diamorphine hydrochloride or hydromorphone • the optimal route for use is by mouth. For best effect, both
head and neck carcinoma. Cancer 2000; 95: 2230–6. Correction. conventional (for dose titration) and modified-release (for
hydrochloride may be preferred for subcutaneous infusion be- ibid. 2003; 97: 1137.
cause their greater solubility in water allows a smaller dose 2. Cerchietti L. Morphine mouthwashes for painful mucositis. Sup- maintenance) dosage forms are required
volume. Continuous subcutaneous infusions may be preferred port Care Cancer 2007; 15: 115–16. • the simplest method of dose titration is with conventional
to continuous intravenous infusions.4 Continuous subcutane- 3. Twillman RK, et al. Treatment of painful skin ulcers with topical morphine dosage every 4 hours, and the same dose for break-
opioids. J Pain Symptom Manage 1999; 17: 288–92. through pain. This ‘rescue dose’ may be given as often as re-
ous infusion may be less effective than epidural morphine for 4. Krajnik M, et al. Potential uses of topical opioids in palliative
relief of postoperative pain;5 however, it was still considered care–report of 6 cases. Pain 1999; 80: 121–5.
quired, up to hourly. The total daily dose of morphine should
to provide simple and relatively effective analgesia with a low 5. Zeppetella G, et al. Analgesic efficacy of morphine applied top- be reviewed each day and the regular dose adjusted to take
rate of adverse effects. ically to painful ulcers. J Pain Symptom Manage 2003; 25: into account the amount needed for breakthrough pain
555–8. • if pain returns consistently before the next dose is due the reg-
See also Patient-controlled Analgesia, below. 6. Zeppetella G, Ribeiro MDC. Morphine in Intrasite gel applied ular dose should be increased. Conventional formulations do
1. Waldmann CS, et al. Serum morphine levels: a comparison be- topically to painful ulcers. J Pain Symptom Manage 2005; 29:
tween continuous subcutaneous infusion and continuous intrave- 118–19. not generally need to be given more often than every 4 hours,
nous infusion in postoperative patients. Anaesthesia 1984; 39: 7. Watterson G, et al. Peripheral opioids in inflammatory pain. Arch and modified-release products should be given according to
768–71. Dis Child 2004; 89: 679–81. the intended duration of the preparation (usually every 12 or
2. Goudie TA, et al. Continuous subcutaneous infusion of mor- Administration in children. Opioid analgesics are used in 24 hours). Patients stabilised on regular oral morphine require
phine for postoperative pain relief. Anaesthesia 1985; 40:
children in the management of moderate to severe pain (see p.3); continued access to a rescue dose for breakthrough pain
1086–92. • if a conventional formulation of morphine is not available and
3. Stuart GJ, et al. Continuous intravenous morphine infusions for
morphine is the most widely used opioid for severe pain in chil-
dren and is the standard against which other opioids are com- treatment is started with modified-release morphine, changes
terminal pain control: a retrospective review. Drug Intell Clin
Pharm 1986; 20: 968–72. pared. Morphine may be given to children requiring acute to the regular dose should not be made more often than every
4. Drexel H. Long-term continuous subcutaneous and intravenous analgesia as a result of surgery or invasive procedures. It may 48 hours, which means that dose titration will be prolonged
opioid infusions. Lancet 1991; 337: 979. also be given for chronic non-malignant pain and is the opioid of • for patients taking conventional morphine preparations every
5. Hindsholm KB, et al. Continuous subcutaneous infusion of mor- choice for the oral treatment of severe pain in palliative care. Its 4 hours, a double dose at bedtime is effective to prevent pain
phine—an alternative to extradural morphine for postoperative analgesic and sedative properties are useful in the management disturbing sleep
pain relief. Br J Anaesth 1993; 71: 580–2. of children in intensive care (see p.957); morphine is considered • if patients are unable to take morphine orally the preferred al-
INTRA-ARTICULAR ROUTE. Intra-articular injection of morphine to be a more rational choice than fentanyl in settings where long- ternative route is subcutaneous. There is no indication for in-
into the knee at the end of arthroscopy has been reported to term infusions are required. Respiratory depression with mor- tramuscular morphine for cancer pain since subcutaneous
provide some degree of postoperative pain relief;1,2 such pain phine treatment is a risk in all children; however, neonates (and dosage is simpler and less painful
relief may be more pronounced than that produced by the particularly those who are breathing spontaneously) may have an • when converting dosage, the relative potency of oral to subcu-
same dose given intravenously1 or intramuscularly.2 The ef- enhanced susceptibility because of the pharmacokinetic differ- taneous morphine is between about 1:2 and 1:3, so 20 to
fect appears to be due to the action of morphine on peripheral ences of morphine in this age group (see above). 30 mg of oral morphine is equianalgesic to 10 mg by subcuta-
opioid receptors2 although a systemic effect has not been The following initial doses are recommended by the BNFC; dos- neous injection
completely excluded.1 es should thereafter be adjusted according to response: • in patients who need continuous parenteral morphine the pre-
There have been conflicting results on whether addition of mor- • By subcutaneous or intramuscular injection, neonates may be ferred route is by subcutaneous infusion. However, intrave-
phine to intra-articular bupivacaine improves analgesia3,4 and a given 100 micrograms/kg every 6 hours; those aged 1 to 6 nous infusion may be preferred:
systematic review5 concluded that from the few well-controlled months, 100 to 200 micrograms/kg every 6 hours; 6 months to in patients who already have an indwelling intravenous line
studies there was no evidence of an added analgesic effect of 2 years, 100 to 200 micrograms/kg every 4 hours; 2 to 12
in those with generalised oedema
morphine compared with saline alone. years, 200 micrograms/kg every 4 hours; 12 to 18 years, 2.5 to
10 mg every 4 hours if erythema, soreness, or sterile abscess develop during subcu-
Doses of morphine reported to have been injected intra-articular- taneous dosage
ly have ranged from 1 to 10 mg. • By intravenous injection over at least 5 minutes, neonates may
be given 50 micrograms/kg every 6 hours; those aged 1 to 6 in patients with coagulation disorders
1. Gupta A, et al. A systematic review of the peripheral analgesic where peripheral circulation is poor
effects of intraarticular morphine. Anesth Analg 2001; 93:
months, 100 micrograms/kg every 6 hours; 6 months to 12
761–70. years, 100 micrograms/kg every 4 hours; 12 to 18 years, • when converting dosage, the relative potency of oral to intra-
2. Raj N, et al. Comparison of the analgesic efficacy and plasma 2.5 mg every 4 hours venous morphine is also between about 1:2 and 1:3
concentrations of high-dose intra-articular and intramuscular The following doses given by slow intravenous injection are • the buccal, sublingual, and nebulised routes of administration
morphine for knee arthroscopy. Eur J Anaesthesiol 2004; 21: suggested as loading doses for continuous intravenous infu- are not recommended in the absence of evidence for clinical
932–7. sion: neonates may be given 25 to 100 micrograms/kg; those advantage over more usual routes
3. Laurent SC, et al. Addition of morphine to intra-articular bupi- aged 1 to 6 months, 100 to 200 micrograms/kg; 6 months to
vacaine does not improve analgesia after day-case arthroscopy. • a small proportion of patients develop intolerable adverse ef-
Br J Anaesth 1994; 72: 170–3. 12 years, 100 to 200 micrograms/kg; 12 to 18 years, 2.5 to fects with oral morphine (in conjunction with adjuvant non-
4. Heine MF, et al. Intra-articular morphine after arthroscopic knee
10 mg. The loading dose may be followed by an infusion giv- opioid analgesics as appropriate) before achieving adequate
operation. Br J Anaesth 1994; 73: 413–15. en in a dose dependent on the patient’s age: neonates, 5 to pain relief. In such patients a change to an alternative opioid,
5. Rosseland LA. No evidence for analgesic effect of intra-articular 40 micrograms/kg per hour; 1 to 6 months, 10 to or a change in the route should be considered. Although
morphine after knee arthroscopy: a qualitative systematic re- 30 micrograms/kg per hour; 6 months to 18 years, 20 to switching between opioids complicates pain management, ad-
view. Reg Anesth Pain Med 2005; 30: 83–98. 30 micrograms/kg per hour equate pain relief for some may depend on the use of alterna-
INTRANASAL ROUTE. An intranasal formulation of morphine is
• By mouth or rectum, infants aged 1 to 12 months may be giv- tive drugs, the use of intraspinal routes, or non-drug methods
under investigation for the relief of acute pain. en 80 to 200 micrograms/kg every 4 hours; those aged 1 to 2 of pain control
years, 200 to 400 micrograms/kg every 4 hours; 2 to 12 years, Similar recommendations are given in guidelines issued by the
INTRASPINAL ROUTE. Morphine is given epidurally and intrath- 200 to 500 micrograms/kg, to a maximum of 20 mg, every 4 US National Comprehensive Cancer Network.2
ecally to relieve both acute and chronic pain. However, re- hours; 12 to 18 years, 5 to 20 mg every 4 hours. In palliative 1. Hanks GW, et al. Expert Working Group of the Research Net-
views on the role of spinal opioids have generally concluded care, modified-release oral preparations may be used; they are work of the European Association for Palliative Care. Morphine
that they should be reserved for pain not controlled by more given as a single daily dose or in 2 divided doses and alternative opioids in cancer pain: the EAPC recommenda-
conventional routes.1-3 When converting from conventional • By continuous subcutaneous infusion, children aged 1 to 3 tions. Br J Cancer 2001; 84: 587–93.
routes it has been suggested that 1% of the total daily dose months may be given 10 micrograms/kg per hour; those aged 2. National Comprehensive Cancer Network. Clinical practice
could be tried as the daily intrathecal dose and 10% as the guidelines in oncology: adult cancer pain (version 1.2008).
3 months to 18 years, 20 micrograms/kg per hour Available at: http://www.nccn.org/professionals/physician_gls/
epidural dose.3 Conversion from intrathecal to oral dosage Intraspinal doses of morphine that have been tried1 in children PDF/pain.pdf (accessed 26/06/08)
has also been investigated.4 are as follows: Dyspnoea. In the treatment of dyspnoea (p.104), doses of mor-
Intrathecal morphine may be delivered continuously via an im- • Caudal epidural block, 100 micrograms/kg phine tend to be smaller than those used for pain relief. Morphine
planted programmable infusion pump for the long-term manage- • Thoracic or lumbar epidural block, 50 micrograms/kg hydrochloride or sulfate may be given as an oral solution in care-
ment of chronic non-malignant and cancer pain. • Intrathecal doses of 20 or 30 micrograms/kg have provided fully titrated doses, starting at a dose of 5 mg every 4 hours; as
See also Patient-controlled Analgesia, below. satisfactory postoperative pain relief, but respiratory depres- little as 2.5 mg every 4 hours may be sufficient for opioid-naive
1. Anonymous. Spinal opiates revisited. Lancet 1986; i: 655–6. sion occurred in 10 and 25%, respectively patients.1 In acute pulmonary oedema, 5 to 10 mg may be given
 Morphine/Nalbuphine Hydrochloride 91
by slow intravenous injection. In patients already receiving mor- Preparations tion and conjugation. About 80% of a dose is excreted in the
phine for pain relief the following doses have been suggested:2 urine as inactive or conjugated metabolites and less than 1% as
Proprietary Preparations (details are given in Part 3)
• mild dyspnoea: 25 to 50% of usual analgesic dose unchanged 6-MNA.
Israel: Dolical.
• moderate dyspnoea: 50 to 100% of usual analgesic dose ◊ References.
• severe dyspnoea: 100% or more of usual analgesic dose
1. Brier ME, et al. Population pharmacokinetics of the active me-
Patients have also obtained relief from subcutaneous injection.3 tabolite of nabumetone in renal dysfunction. Clin Pharmacol
Although it has been reported that a low dose of nebulised mor- Nabumetone (BAN, USAN, rINN) Ther 1995; 57: 622–7.
phine (mean dose 1.7 mg) improved exercise endurance in pa- 2. Davies NM. Clinical pharmacokinetics of nabumetone: the dawn
BRL-14777; Nabumeton; Nabumetona; Nabumetonas; Nabu-
tients with dyspnoea due to advanced chronic lung disease,4 sev- of selective cyclo-oxygenase-2 inhibition? Clin Pharmacokinet
eral subsequent studies5-7 have failed to obtain significant métone; Nabumetoni; Nabumetonum. 4-(6-Methoxy-2-naph- 1997; 33: 403–16.
improvements with doses up to 40 mg. It is considered that cur- thyl)butan-2-one.
Uses and Administration
rent evidence does not support the use of nebulised morphine for Набуметон Nabumetone is a non-active prodrug whose major metabolite is
breathlessness.1,8-10 Furthermore, bronchospasm can be a prob- an NSAID (p.99) structurally similar to naproxen (p.92). It is
C 15 H 16 O 2 = 228.3.
lem, particularly at high doses, and there is no consensus on the used for the relief of pain and inflammation associated with os-
optimal dose, schedule, or method of dose titration. C AS — 42924-53-8.
teoarthritis and rheumatoid arthritis in a usual oral dose of 1 g
1. Davis CL. ABC of palliative care: breathlessness, cough, and ATC — M01AX01. taken as a single dose in the evening; if necessary 0.5 to 1 g may
other respiratory problems. BMJ 1997; 315: 931–4. ATC Vet — QM01AX01. be given additionally in the morning. It has been recommended
2. Twycross R, Wilcock A. Palliative Care Formulary. 3rd ed.
Nottingham, Palliativedrugs.com Ltd, 2007: 280. that a dose of 1 g daily should not be exceeded in elderly patients
3. Bruera E, et al. Subcutaneous morphine for dyspnea in cancer and that 500 mg daily may be satisfactory in some cases.
patients. Ann Intern Med 1993; 119: 906–7. O
4. Young IH, et al. Effect of low dose nebulised morphine on ex- ◊ References.
ercise endurance in patients with chronic lung disease. Thorax 1. Friedel HA, et al. Nabumetone: a reappraisal of its pharmacolo-
1989; 44: 387–90. CH3 gy and therapeutic use in rheumatic diseases. Drugs 1993; 45:
5. Beauford W, et al. Effects of nebulized morphine sulfate on the
exercise tolerance of the ventilatory limited COPD patients. 131–56.
Chest 1993; 104: 175–8. 2. Proceedings of a symposium: continuing developments with
6. Noseda A, et al. Disabling dyspnoea in patients with advanced H3CO nabumetone: an investigators’ update. Am J Med 1993; 95 (suppl
disease: lack of effect of nebulized morphine. Eur Respir J 2A): 1S–45S.
1997; 10: 1079–83. Pharmacopoeias. In Eur. (see p.vii) and US. 3. Dahl SL. Nabumetone: a "nonacidic" nonsteroidal antiinflam-
7. Jankelson D, et al. Lack of effect of high doses of inhaled mor- matory drug. Ann Pharmacother 1993; 27: 456–63.
phine on exercise endurance in chronic obstructive pulmonary Ph. Eur. 6.2 (Nabumetone). A white or almost white crystalline
disease. Eur Respir J 1997; 10: 2270–4. powder. Practically insoluble in water; freely soluble in acetone; 4. Hedner T, et al. Nabumetone: therapeutic use and safety profile
in the management of osteoarthritis and rheumatoid arthritis.
8. Polosa R, et al. Nebulised morphine for severe interstitial lung slightly soluble in methyl alcohol. Protect from light. Drugs 2004; 64: 2315–43.
disease. Available in The Cochrane Database of Systematic Re- USP 31 (Nabumetone). A white or almost white crystalline
views; Issue 3. Chichester: John Wiley; 2002 (accessed Preparations
26/06/08). powder. Practically insoluble in water; sparingly soluble in alco-
9. Foral PA, et al. Nebulized opioids use in COPD. Chest 2004; hol and in methyl alcohol; freely soluble in acetone. Store in air- BP 2008: Nabumetone Oral Suspension; Nabumetone Tablets;
125: 691–4. tight containers. Protect from light. USP 31: Nabumetone Tablets.
10. Brown SJ, et al. Nebulized morphine for relief of dyspnea due
to chronic lung disease. Ann Pharmacother 2005; 39: 1088–92. Adverse Effects, Treatment, and Precautions Proprietary Preparations (details are given in Part 3)
As for NSAIDs in general, p.96. Nabumetone is contra-indicated Braz.: Relifex†; Canad.: Relafen; Cz.: Relifex; Rodanol S†; Denm.: Relifex;
Preparations Fin.: Relifex; Fr.: Nabucox; Gr.: Akratol; Anfer; Ethyfen†; Flogmed;
in patients with severe hepatic impairment. Mevedal; Nabuton; Naditone; Relifex; Hong Kong: Relifex†; Hung.: Re-
BP 2008: Chloroform and Morphine Tincture; Morphine and Atropine
Injection; Morphine Sulphate Injection; Morphine Suppositories; Morphine lifex; Rodanol S†; India: Nabuflam; Indon.: Goflex; Irl.: Relifex; Religer;
Effects on the gastrointestinal tract. Like other NSAIDs Israel: Nabuco; Relifex; Ital.: Artaxan; Nabuser; Jpn: Relifen; Mex.: Na-
Tablets; Prolonged-release Morphine Tablets;
USP 31: Morphine Sulfate Extended-Release Capsules; Morphine Sulfate nabumetone can produce adverse effects on the gastrointestinal flam; Relifex; Neth.: Mebutan; Norw.: Relifex; Philipp.: Relifex; Pol.:
Injection; Morphine Sulfate Suppositories. tract, although some studies have produced favourable compari- Coxalgan; Coxeton; Nabuton; Relifex; Rodanol S; Port.: Balmox; Elitar;
sons with ibuprofen1 or naproxen.2 A recent review3 noted that Rus.: Rodanol (Роданол); S.Afr.: Relifen; Relisan; Relitone; Spain: Listran;
Proprietary Preparations (details are given in Part 3) Relif; Swed.: Relifex; Switz.: Balmox; Thai.: Aflex; Anfer†; Bumetone;
Arg.: Algedol; Amidiaz; Analmorph; Duramorph; GNO; MST Continus; limited comparative data suggest that nabumetone has a similar Nabone; Nabonet; Naflex; Nametone; No-Ton†; Relifex; Turk.: Relifex;
Neocalmans; Austral.: Anamorph; Kapanol; MS Contin; MS Mono; Ordine; gastrointestinal adverse effect profile to that of selective COX-2 UK: Relifex; USA: Relafen†.
Sevredol; Austria: Compensan; Kapabloc; Kapanol; M-Dolor; Morapid; inhibitors. It has been suggested4 that nabumetone may be a pref-
Mundidol; Substitol; Vendal; Belg.: Docmorfine; Kapanol; MS Contin; MS
Direct; Oramorph; Stellorphinad; Stellorphine; Braz.: Dimorf; Dolo Moff; erential inhibitor of cyclo-oxygenase-2 (COX-2) but the signifi-
MS-Long†; MST Continus†; Canad.: Kadian; M-Eslon; Morphitec†; MOS; cance of this in determining its adverse effects is uncertain.
MS Contin; MSIR; Oramorph†; Statex†; Chile: M-Eslon; Cz.: Doltard†; M-
Eslon; MST Continus; MST Uno†; Oramorph†; Sevredol; Skenan†; Sloval-
1. Roth SH, et al. A controlled study comparing the effects of
nabumetone, ibuprofen, and ibuprofen plus misoprostol on the
Nalbuphine Hydrochloride
gin; Vendal; Denm.: Contalgin; Depolan; Doltard; Fin.: Depolan; Dolcontin;
Fr.: Actiskenan; Kapanol; Moscontin; Oramorph; Sevredol; Skenan; Ger.: upper gastrointestinal tract mucosa. Arch Intern Med 1993; 153: (BANM, USAN, rINNM)
Capros; Kapanol; M-beta; M-Dolor†; M-long; M-Stada; Mogetic†; Morph; 2565–71.
Morphanton; MSI; MSR; MST; Onkomorphin†; Oramorph; Painbreak; 2. Roth SH, et al. A longterm endoscopic evaluation of patients EN-2234A; Hidrocloruro de nalbufina; Nalbufine Hydrochloride;
Sevredol; Hong Kong: M-Eslon; MST Continus; Hung.: M-Eslon; Moretal; with arthritis treated with nabumetone vs naproxen. J Rheumatol Nalbuphine, Chlorhydrate de; Nalbuphini Hydrochloridum. 17-
MST Continus; Sevredol; India: Morcontin; Indon.: MST; Irl.: Morstel†; 1994; 21: 1118–23. Cyclobutylmethyl-7,8-dihydro-14-hydroxy-17-normorphine hy-
MST Continus; MXL; Oramorph; Sevredol; Slo-Morph†; Israel: Kapanol†; 3. Bannwarth B. Safety of the nonselective NSAID nabumetone:
MCR; MIR; Morphex; MSP; Ital.: MS Contin; Oramorph; Skenan†; Ticinan; drochloride; (−)-(5R,6S,14S)-9a-Cyclobutylmethyl-4,5-epoxy-
focus on gastrointestinal tolerability. Drug Safety 2008; 31:
Twice; Jpn: MS Contin; Malaysia: MST Continus; Mex.: Analfin; Dural- 485–503. morphinan-3,6,14-triol hydrochloride.
mor†; Graten; Neth.: Kapanol; MS Contin; Noceptin†; Oramorph; Sevred-
ol; Skenan; Norw.: Dolcontin; NZ: Kapanol; LA Morph; M-Eslon; MST Con- 4. Davies NM. Clinical pharmacokinetics of nabumetone: the dawn Налбуфина Гидрохлорид
tinus†; MST Mono†; RA Morph; Sevredol; Philipp.: M-Dolor; MST of selective cyclo-oxygenase-2 inhibition? Clin Pharmacokinet
Continus; Relimal; Pol.: MST Continus; Sevredol; Vendal; Port.: Ethirfin; 1997; 33: 403–16. C 21 H 27 NO 4 ,HCl = 393.9.
MST; MXL†; Oramorph; Sevredol; Skenan; S.Afr.: MST Continus; SRM- C AS — 20594-83-6 (nalbuphine); 23277-43-2 (nalbu-
Rhotard; Singapore: MST Continus; SRM-Rhotard†; Statex; Spain: MST Effects on the lungs. Pulmonary fibrosis developed in a 68-
Continus; MST Unicontinus; Oglos†; Oramorph; Sevredol; Skenan; Swed.: phine hydrochloride).
year-old woman taking nabumetone 1.5 g; symptoms appeared
Depolan; Dolcontin; Switz.: Kapanol; M-retard; MST Continus; Sevre-Long; after 2 weeks of therapy and worsened during the next 6 weeks.1 ATC — N02AF02.
Sevredol; Turk.: M-Eslon; Vendal; UK: Filnarine; Morcap†; Morphgesic;
MST Continus; MXL; Oramorph; Rhotard; Sevredol; Zomorph; USA: As- There was rapid resolution on stopping nabumetone and treat- ATC Vet — QN02AF02.
tramorph; Avinza; DepoDur; Duramorph; Infumorph; Kadian; MS Contin; ment with oral corticosteroids.
MSIR; Oramorph; RMS; Roxanol; Venez.: MS Contin. 1. Morice A, et al. Pulmonary fibrosis associated with nabumetone.
Multi-ingredient: Austral.: Morphalgin†; Austria: Modiscop; Belg.: Postgrad Med J 1991; 67: 1021–2. HO
Spasma†; Irl.: Cyclimorph; Ital.: Cardiostenol; Pol.: Doltard; S.Afr.: Chlo-
ropect; Cyclimorph; Enterodyne; Pectrolyte; Swed.: Spasmofen; Switz.: Effects on the skin. Pseudoporphyria characterised by blister-
Spasmosol; UK: Collis Browne’s; Cyclimorph; Diocalm Dual Action; Opaz- ing on the neck and hands developed in a 36-year-old woman
imes.
taking nabumetone and auranofin for rheumatoid arthritis.1 Stop-
ping auranofin had no effect on the blistering which only re- O OH
solved once nabumetone was withdrawn. The authors of the re-
Morpholine Salicylate port stated that the UK CSM had received 3 additional reports of N
Morfoliinisalisylaatti; Morfolinsalicylat; Morpholini Salicylas; Sali- pseudoporphyria suspected to be caused by nabumetone.
cilato de morfolinio. 2-Hydroxybenzoic acid compounded with 1. Varma S, Lanigan SW. Pseudoporphyria caused by nabumetone. HO
morpholine (1 : 1). Br J Dermatol 1998; 138: 549–50. Correction. ibid. 139: 759.
[dose] (nalbuphine)
Морфолин Салицилат
C 11 H 15NO 4 = 225.2. Interactions
C AS — 147-90-0. For interactions associated with NSAIDs, see p.99. NOTE. The following terms have been used as ‘street names’ (see
ATC — N02BA08. p.vi) or slang names for various forms of nalbuphine hydrochlo-
ATC Vet — QN02BA08. Pharmacokinetics
Nabumetone is well absorbed from the gastrointestinal tract. ride:
Plasma concentrations after oral doses are too small to be meas- Nubian.
HO ured, as it undergoes rapid and extensive first-pass metabolism in Incompatibility. Incompatibility has been reported between in-
the liver to the principal active compound 6-methoxy-2-naphthyl- jections of nalbuphine hydrochloride and nafcillin sodium,1 di-
O NH O acetic acid (6-MNA) and other inactive metabolites. 6-MNA is azepam,2 pentobarbital sodium,2 or thiethylperazine maleate.2
more than 99% bound to plasma proteins. It diffuses into synovi- US licensed product information states that nalbuphine is also
al fluid, crosses the placenta, and is distributed into breast milk. physically incompatible with ketorolac.
HO There is considerable interindividual variation in the plasma 1. Jeglum EL, et al. Nafcillin sodium incompatibility with acidic
elimination half-life of 6-MNA, especially in the elderly; some solutions. Am J Hosp Pharm 1981; 38: 462–4.
Profile reported mean values at steady state include 22 to about 27 hours 2. Jump WG, et al. Compatibility of nalbuphine hydrochloride with
Morpholine salicylate is a salicylic acid derivative (see Aspirin, for young adults and about 25 and 34 hours in elderly patients. 6- other preoperative medications. Am J Hosp Pharm 1982; 39:
p.20) that has been used for musculoskeletal disorders. MNA eventually undergoes further metabolism by O-methyla- 841–3.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
92 Analgesics Anti-inflammatory Drugs and Antipyretics
Dependence and Withdrawal the placenta and small amounts are distributed into Naproxen (BAN, USAN, rINN)
As for Opioid Analgesics, p.101. breast milk.
Naprokseeni; Naproksen; Naproksenas; Naproxén; Naproxène;
◊ A WHO expert committee considered in 1989 that the likeli- ◊ References. Naproxeno; Naproxenum; RS-3540. (+)-2-(6-Methoxy-2-naph-
hood of nalbuphine abuse was low to moderate and was not great 1. Sear JW, et al. Disposition of nalbuphine in patients undergoing thyl)propionic acid.
enough to warrant international control.1 Abuse had been report- general anaesthesia. Br J Anaesth 1987; 59: 572–5. Напроксен
ed infrequently and the withdrawal syndrome produced when 2. Kay B, et al. Pharmacokinetics of oral nalbuphine in postopera- C 14 H 14O 3 = 230.3.
naloxone was given after continuous nalbuphine dosage was less tive patients. Br J Anaesth 1987; 59: 1327P.
severe than that in morphine dependence. Subsequently, there 3. Aitkenhead AR, et al. The pharmacokinetics of oral and intrave- C AS — 22204-53-1.
have been occasional reports of abuse2,3 including misuse among nous nalbuphine in healthy volunteers. Br J Clin Pharmacol ATC — G02CC02; M01AE02; M02AA12.
athletes.4,5 1988; 25: 264–8. ATC Vet — QG02CC02; QM01AE02; QM02AA12.
4. Jaillon P, et al. Pharmacokinetics of nalbuphine in infants, young
1. WHO. WHO expert committee on drug dependence: twenty- healthy volunteers, and elderly patients. Clin Pharmacol Ther
fifth report. WHO Tech Rep Ser 775 1989. Also available at: 1989; 46: 226–33.
http://libdoc.who.int/trs/WHO_TRS_775.pdf (accessed 26/06/08) CH3
2. Spadari M, et al. Pharmacodépendance à la nalbuphine (Nu- Pregnancy. References.
bain): à propos de 2 cas. Therapie 2002; 57: 504–5. 1. Wilson CM, et al. Transplacental gradient of pethidine and nal-
3. Klinzig F, et al. Hair analysis by LC-MS as evidence of nalbu- buphine in labour. Br J Clin Pharmacol 1986; 21: 571P–572P. COOH
phine abuse by a nurse. J Anal Toxicol 2007; 31: 62–5. 2. Dadabhoy ZP, et al. Transplacental transfer of nalbuphine in pa-
4. McBride AJ, et al. Three cases of nalbuphine hydrochloride de- tients undergoing cesarean section: a pilot study. Acta Anaesthe- H3CO
pendence associated with anabolic steroid use. Br J Sports Med siol Ital 1988; 39: 227–32.
1996; 30: 69–70. 3. Nicolle E, et al. Therapeutic monitoring of nalbuphine: transpla-
5. Wines JD, et al.. Nalbuphine hydrochloride dependence in ana- cental transfer and estimated pharmacokinetics in the neonate. Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US.
bolic steroid users. Am J Addict 1999; 8: 161–4. Eur J Clin Pharmacol 1996; 49: 485–9. Ph. Eur. 6.2 (Naproxen). A white or almost white, crystalline
powder. Practically insoluble in water; soluble in alcohol and in
Adverse Effects and Treatment Uses and Administration methyl alcohol. Protect from light.
USP 31 (Naproxen). A white to off-white, practically odour-
As for Opioid Analgesics in general, p.102. Nalbuphine hydrochloride, a phenanthrene derivative, less, crystalline powder. Practically insoluble in water; soluble in
Headache may occur. Nausea and vomiting occur less is an opioid analgesic (p.104). It has mixed opioid alcohol, in dehydrated alcohol, and in chloroform; sparingly sol-
than with other opioids. Hallucinations and other psy- agonist and antagonist activity. It is used for the relief uble in ether. Store in airtight containers.
chotomimetic effects are rare and have been reported of moderate to severe pain and as an adjunct to anaes-
less frequently than with pentazocine. As nalbuphine thesia. Nalbuphine hydrochloride is reported to act Naproxen Sodium (BANM, USAN, rINNM)
has both antagonist and agonist activity its effects may within 15 minutes of subcutaneous or intramuscular in- Naproksen Sodyum; Naproxène sodique; Naproxeno sódico;
be only partially reversed by naloxone, but use of the jection or within 2 to 3 minutes of intravenous injection Naproxenum natricum; Natrii Naproxenum; RS-3650.
latter is still recommended in nalbuphine overdose. and generally to produce analgesia for 3 to 6 hours. It Натрий Напроксен
is given subcutaneously, intramuscularly, or intrave- C 14 H 13NaO 3 = 252.2.
Effects on the respiratory system. Nalbuphine produces nously. Intravenous infusion as part of a patient-con- C AS — 26159-34-2.
similar respiratory depression to morphine at equianalgesic dos- Pharmacopoeias. In Chin., Eur. (see p.vii), and US.
es, but there is a ceiling effect with nalbuphine and, unlike mor-
trolled analgesia system has also been used.
Ph. Eur. 6.2 (Naproxen Sodium). A white or almost white, hy-
phine, respiratory depression does not increase appreciably with The usual adult dose of nalbuphine hydrochloride for groscopic, crystalline powder. Freely soluble in water; sparingly
higher doses.1 In a cumulative-dose study2 a plateau effect was pain relief is 10 to 20 mg every 3 to 6 hours as re- soluble in alcohol; freely soluble or soluble in methyl alcohol. A
seen with nalbuphine above a total dose of 30 mg per 70 kg in- quired. 2% solution in water has a pH of 7.0 to 9.8. Store in airtight con-
travenously. Similar ventilatory depression has been noted3 with tainers. Protect from light.
single intravenous doses of nalbuphine of 15, 30, or 60 mg per As an adjunct in balanced anaesthesia a usual dose is USP 31 (Naproxen Sodium). A white to creamy crystalline
70 kg; naloxone failed to reverse the depression at the highest 0.3 to 3 mg/kg given intravenously over 10 to 15 min- powder. Soluble in water and in methyl alcohol; sparingly solu-
dose. utes at induction. Maintenance doses of 250 to ble in alcohol; very slightly soluble in acetone; practically insol-
1. Klepper ID, et al. Respiratory function following nalbuphine and
500 micrograms/kg may be given as intravenous bo- uble in chloroform and in toluene. Store in airtight containers.
morphine in anaesthetized man. Br J Anaesth 1986; 58: 625–9.
2. Romagnoli A, Keats AS. Ceiling effect for respiratory depres- luses if required.
sion by nalbuphine. Clin Pharmacol Ther 1980; 27: 478–85.
Adverse Effects, Treatment, and Precau-
Action. Nalbuphine is generally described as a mixed agonist tions
3. Pugh GC, et al. Effect of nalbuphine hydrochloride on the venti-
latory and occlusion pressure responses to carbon dioxide in vol- and antagonist acting mainly as an agonist at κ opioid receptors As for NSAIDs in general, p.96.
unteers. Br J Anaesth 1989; 62: 601–9. and as an antagonist or partial agonist at μ receptors. It has shown
antagonist activity similar to that seen with naloxone in opioid- Suppositories containing naproxen may cause rectal ir-
dependent subjects.1 Nalbuphine is structurally related to ritation and occasional bleeding.
Precautions naloxone and oxymorphone. Pharmacologically nalbuphine is
As for Opioid Analgesics in general, p.103. qualitatively similar to pentazocine, but nalbuphine is a more po-
Naproxen should be used with caution in renal impair-
tent antagonist at μ opioid receptors, is less likely to produce psy- ment, and use is not recommended in patients whose
Nalbuphine may precipitate withdrawal symptoms if
chotomimetic effects such as hallucinations, and is reported to creatinine clearance is less than 20 mL/min.
given to patients physically dependent on opioids. produce no significant cardiovascular effects in patients with is-
◊ Reviews.
The dose of nalbuphine should be reduced in patients chaemic heart disease. It differs from pure μ agonists such as
1. Bansal V, et al. A look at the safety profile of over-the-counter
with hepatic or renal impairment. morphine in that its analgesic, sedative, and respiratory depres- naproxen sodium: a meta-analysis. J Clin Pharmacol 2001; 41:
sant actions are subject to a ‘ceiling’ effect and may not increase 127–38.
Abuse. See under Dependence and Withdrawal, above. proportionately with dose.
Breast feeding. The American Academy of Pediatrics1 states
1. Preston KL, et al. Antagonist effects of nalbuphine in opioid-
Pregnancy. When nalbuphine is used for analgesia during la- dependent human volunteers. J Pharmacol Exp Ther 1989; 248: that there have been no reports of any clinical effect on the infant
bour there is more placental transfer and sedation in mothers and 929–37. associated with the use of naproxen by breast-feeding mothers,
their infants than with pethidine.1 There have also been reports of and that therefore it may be considered to be usually compatible
bradycardia and respiratory depression in neonates whose moth- Administration. References to alternative routes or dosage with breast feeding. The BNF also considers that the amount of
ers received nalbuphine during labour.2,3 It was considered that schedules. naproxen distributed into breast milk is too small to be harmful
nalbuphine should be given with caution during labour, especial- 1. Krenn H, et al. Nalbuphine by PCA-pump for analgesia follow- to a breast-fed infant; however, some licensed product informa-
ly by the intravenous route. Some2 have recommended subcuta- ing hysterectomy: bolus application versus continuous infusion tion recommends that breast feeding should be avoided during
neous dosage and advised that nalbuphine should not be given with bolus application. Eur J Pain 2001; 5: 219–26. naproxen therapy.
around the expected time of delivery. 2. Woollard M, et al. Hitting them where it hurts? Low dose nalbu-
phine therapy. Emerg Med J 2002; 19: 565–70. In a study2 of a breast-fed infant only 0.26% of the mother’s dose
Further references on the transplacental transfer of nalbuphine 3. Sung KC, et al. Transdermal delivery of nalbuphine and its pro-
was recovered from the infant.
are given under Pharmacokinetics, below. drugs by electroporation. Eur J Pharm Sci 2003; 18: 63–70. 1. American Academy of Pediatrics. The transfer of drugs and oth-
4. Gear RW, et al. Dose ratio is important in maximizing naloxone er chemicals into human milk. Pediatrics 2001; 108: 776–89.
1. Wilson CM, et al. Transplacental gradient of pethidine and nal- Correction. ibid.; 1029. Also available at:
buphine in labour. Br J Clin Pharmacol 1986; 21: 571P–572P. enhancement of nalbuphine analgesia in humans. Neurosci Lett
2003; 351: 5–8. h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
2. Guillonneau M, et al. Perinatal adverse effects of nalbuphine pediatrics%3b108/3/776 (accessed 08/11/07)
given during parturition. Lancet 1990; 335: 1588. 5. Liu KS, et al. Antinociceptive effect of a novel long-acting nal- 2. Jamali F, Stevens DRS. Naproxen excretion in milk and its up-
buphine preparation. Br J Anaesth 2004; 92: 712–15. take by the infant. Drug Intell Clin Pharm 1983; 17: 910–11.
3. Sgro C, et al. Perinatal adverse effects of nalbuphine given dur-
ing labour. Lancet 1990; 336: 1070. 6. Woollard M, et al. Less IS less: a randomised controlled trial
comparing cautious and rapid nalbuphine dosing regimens. Effects on the blood. Haematological adverse effects reported
Emerg Med J 2004; 21: 362–4. in patients given naproxen include haemolytic anaemia,1,2 aplas-
Interactions 7. Gordon AT, et al. Open-label exploration of an intravenous nal- tic anaemia,3 agranulocytosis,4 and immune thrombocytopenia.5
For interactions associated with opioid analgesics, see buphine and naloxone mixture as an analgesic agent following 1. Hughes JA, Sudell W. Hemolytic anemia associated with
gynecologic surgery. Pain Med 2007; 8: 525–30. naproxen. Arthritis Rheum 1983; 26: 1054.
p.103. 2. Lo TCN, Martin MA. Autoimmune haemolytic anaemia associ-
Preparations ated with naproxen suppositories. BMJ 1986; 292: 1430.
Pharmacokinetics Proprietary Preparations (details are given in Part 3) 3. McNeil P, et al. Naproxen-associated aplastic anaemia. Med J
Aust 1986; 145: 53–4.
There appears to be considerable first-pass metabolism Arg.: Gobbinal; Naltrox; Nubaina; Nubak†; Onfor; Austria: Nubain; Braz.:
4. Nygard N, Starkebaum G. Naproxen and agranulocytosis. JAMA
Nubain; Canad.: Nubain†; Cz.: Nubain; Fr.: Nubain†; Ger.: Nubain†; Gr.:
of nalbuphine after oral doses. On intramuscular injec- Nubain; Hong Kong: Intapan; Nubain†; Hung.: Nubain; Israel: Nubain†; 1987; 257: 1732.
tion nalbuphine has been reported to produce peak Malaysia: Nubain†; Mex.: Bufigen; Bufilem; Nalcryn; Nubain†; NZ: Nu- 5. Bougie D, Aster R. Immune thrombocytopenia resulting from
bain†; Philipp.: Nubain; S.Afr.: Nubain†; Singapore: Nubain†; Switz.: sensitivity to metabolites of naproxen and acetaminophen. Blood
plasma concentrations after 30 minutes. It is metabo- Nubain; Thai.: Nubain; UK: Nubain†; USA: Nubain; Venez.: Bufidol; Nu- 2001; 97: 3846–50.
lised in the liver and is excreted in the urine and faeces bain†.
Effects on the cardiovascular system. For a discussion of
as unchanged drug and conjugates. Nalbuphine crosses the possible cardiovascular effects of naproxen, see p.96.
 Naproxen 93
Effects on the CNS. Aseptic meningitis has been associated 9. Parodi A, et al. Possible naproxen-induced relapse of subacute Uses and Administration
with naproxen therapy;1,2 attacks may be recurrent and cross- cutaneous lupus erythematosus. JAMA 1992; 268: 51–2.
10. Lang BA, Finlayson LA. Naproxen-induced pseudoporphyria in Naproxen, a propionic acid derivative, is an NSAID
sensitivity with other NSAIDs has occurred.2 patients with juvenile rheumatoid arthritis. J Pediatr 1994; 124: (p.99).
There has been a report3 of a patient with Parkinson’s disease 639–42.
whose symptoms had previously been well controlled but who 11. Cox NH, Wilkinson DS. Dermatitis artefacta as the presenting Naproxen is used in musculoskeletal and joint disor-
deteriorated when she was given naproxen. She improved on feature of auto-erythrocyte sensitization syndrome and naprox-
en-induced pseudoporphyria in a single patient. Br J Dermatol ders such as ankylosing spondylitis, osteoarthritis, and
withdrawal of naproxen and the effect was confirmed by rechal- 1992; 126: 86–9. rheumatoid arthritis including juvenile idiopathic
lenge. It was noted that the UK CSM had recorded a case of par-
kinsonism associated with a combined preparation of naproxen Hypersensitivity. In an early case-report in 11 aspirin-sensitive arthritis. It is also used in dysmenorrhoea, headache in-
and misoprostol and 12 other reports of tremor or ataxia precipi- asthmatic patients, all developed reactions (rhinorrhoea, tight- cluding migraine, postoperative pain, soft-tissue disor-
tated by naproxen. ness of chest, wheezing, dyspnoea) after taking naproxen in dos- ders, acute gout, and to reduce fever. Naproxen is usu-
es of 40 to 80 mg.1 More recently, angioedema occurred after a
1. Weksler BB, Lehany AM. Naproxen-induced recurrent aseptic
single dose of naproxen in a patient known to be aspirin-sensi-
ally given orally as the free acid or as the sodium salt.
meningitis. DICP Ann Pharmacother 1991; 25: 1183–4.
2. Seaton RA, France AJ. Recurrent aseptic meningitis following tive.2 Hypersensitivity to individual NSAIDs is believed to be The doses in the licensed product information are ex-
non-steroidal anti-inflammatory drugs – a reminder. Postgrad closely linked to the extent to which these drugs inhibit prosta- pressed in terms of the free acid or the sodium salt as
Med J 1999; 75: 771–2. glandin (see under Aspirin, p.21). There may therefore be a dose appropriate for an individual preparation; however, the
3. Shaunak S, et al. Exacerbation of idiopathic Parkinson’s disease threshold below which no detectable symptoms occur. Such an
by naproxen. BMJ 1995; 311: 422. doses given below are expressed in terms of the equiv-
effect has been reported3 in a patient previously stabilised on
Effects on the eyes. Keratopathy, characterised by whorl-like naproxen for about one year who had a hypersensitivity reaction alent amount of free acid only. Each 550 mg of naprox-
corneal opacities, occurred in a woman taking naproxen; com- after a dosage increase. en sodium is equivalent to about 500 mg of naproxen.
plete regression occurred after stopping the drug.1 There has also A hypersensitivity reaction characterised by pulmonary infil- In the treatment of rheumatic disorders, the usual
been a report of exacerbation of glaucoma in a 65-year-old wom- trates with eosinophilia4,5 has been reported in patients taking
an given naproxen.2 dose of naproxen or naproxen sodium is the equivalent
naproxen. There has also been a report of a generalised hypersen-
For reference to effects on the optic nerve associated with sitivity reaction with acute eosinophilic colitis in a 57-year-old of 500 mg to 1 g of naproxen daily either as a single
naproxen, see p.97. woman treated with naproxen for osteoarthritis.6 Bilateral swell- dose or in 2 divided doses. US licensed product infor-
1. Szmyd L, Perry HD. Keratopathy associated with the use of ing of the major salivary glands, a generalised rash, and eosi- mation states that patients who tolerate lower doses
naproxen. Am J Ophthalmol 1985; 99: 598. nophilia suggestive of a hypersensitivity response was reported may have their dosage increased to 1.5 g daily for a pe-
2. Fincham JE. Exacerbation of glaucoma in an elderly female tak- in another patient after use of naproxen.7 Leukocytoclastic vas-
ing naproxen sodium: a case report. J Geriatr Drug Ther 1989; culitis with peripheral neuropathy and nephritis has also been
riod of up to 6 months, if required. For dosage in chil-
3: 139–43.
noted in a 62-year-old woman after naproxen treatment.8 dren, see below.
Effects on the gastrointestinal tract. Gastrointestinal ad- 1. Szczeklik A, et al. Asthmatic attacks induced in aspirin-sensitive In other painful conditions such as dysmenorrhoea
verse effects are among the most frequently reported during patients by diclofenac and naproxen. BMJ 1977; 2: 231–2.
short- and long-term treatment with naproxen. Acute proctocoli- 2. Ghislain P-D, Ghislain E. Oedème de Quincke de la nuque induit and acute musculoskeletal disorders the usual regimen
tis associated with the use of naproxen has been reported.1 par l’acide acétylsalicylique, avec réaction croisée pour le is the equivalent of 500 mg of naproxen initially, fol-
Oesophageal ulceration reported in 7 patients2 may have arisen naproxène sodique. Ann Med Interne (Paris) 2000; 151: 227–9. lowed by 250 mg every 6 to 8 hours, up to a maximum
3. Briscoe-Dwyer L, Etzel JV. Dyspnea and periorbital edema fol-
due to incorrect consumption (such as taking the dosage without lowing an increase in naproxen dose. Ann Pharmacother 1994; daily dose of 1.25 g on the first day and 1 g thereafter.
fluids or lying down after a dose) but other causes could not be 28: 1110.
dismissed. 4. Nader DA, Schillaci RF. Pulmonary infiltrates with eosinophilia In acute gout an initial dose equivalent to 750 mg of
1. Ravi S, et al. Colitis caused by non-steroidal anti-inflammatory due to naproxen. Chest 1983; 83: 280–2. naproxen followed by 250 mg every 8 hours is used.
drugs. Postgrad Med J 1986; 62: 773–6. 5. Buscaglia AJ, et al. Pulmonary infiltrates associated with
2. Kahn LH, et al. Over-the-counter naproxen sodium and esopha- naproxen. JAMA 1984; 251: 65–6. For the treatment of migraine, the equivalent of
geal injury. Ann Intern Med 1997; 126: 1006. 6. Bridges AJ, et al. Acute eosinophilic colitis and hypersensitivity 750 mg of naproxen can be given at the first symptom
reaction associated with naproxen therapy. Am J Med 1990; 89:
Effects on the kidneys. Acute renal failure,1 renal papillary 526–7. of an impending attack and, if necessary, this may be
necrosis,2,3 interstitial nephritis,4 and hyperkalaemia1 have been 7. Knulst AC, et al. Salivary gland swelling following naproxen followed after at least half an hour by further doses of
reported in patients receiving naproxen. As with other NSAIDs, therapy. Br J Dermatol 1995; 133: 647–9. 250 to 500 mg throughout the day to a total maximum
renal adverse effects occur more frequently in patients with cer- 8. Schapira D, et al. Naproxen-induced leukocytoclastic vasculitis.
tain risk factors such as volume depletion, diuretic therapy, heart Clin Rheumatol 2000; 19: 242–4. daily dose of 1250 mg. See below for a suggested dose
failure, and pre-existing renal dysfunction.1 Parkinsonism. For a report of a patient whose symptoms of
for the prophylaxis of migraine.
1. Todd PA, Clissold SP. Naproxen: a reappraisal of its pharmacol- Parkinson’s disease were exacerbated by naproxen, see Effects Naproxen has been given rectally in similar doses to
ogy, and therapeutic use in rheumatic diseases and pain states. on the CNS, above.
Drugs 1990; 40: 91–137. those used orally.
2. Caruana RJ, Semble EL. Renal papillary necrosis due to naprox-
en. J Rheumatol 1984; 11: 90–1. Interactions Naproxen has also been used as the piperazine, ami-
3. Kovacevic L, et al. Renal papillary necrosis induced by naprox- For interactions associated with NSAIDs, see p.99. nobutanol, and lysine salts, and as naproxen cetrimo-
en. Pediatr Nephrol 2003; 18: 826–9. nium. Naproxen is available in a combination pack
4. Quigley MR, et al. Concurrent naproxen- and penicillamine-in- The excretion of naproxen is delayed by probenecid re-
duced renal disease in rheumatoid arthritis. Arthritis Rheum sulting in raised plasma concentrations of naproxen. with misoprostol (p.2013) for patients at risk of
1982; 25: 1016–19. NSAID-induced peptic ulceration. Alternatively,
Effects on the liver. There have been a few reports1,2 of mod- Antiepileptics. For the effect of naproxen on the protein bind- packs containing naproxen with lansoprazole capsules
erate to severe jaundice attributed to naproxen including one in ing of valproic acid, see p.510.
are available in some countries for such patients.
which the patient also had a similar reaction with fenoprofen.2
1. Victorino RMM, et al. Jaundice associated with naproxen. Post- Pharmacokinetics ◊ Reviews.
grad Med J 1980; 56: 368–70. Naproxen and naproxen sodium are readily absorbed 1. Todd PA, Clissold SP. Naproxen: a reappraisal of its pharmacol-
2. Andrejak M, et al. Cross hepatotoxicity between non-steroidal ogy, and therapeutic use in rheumatic diseases and pain states.
anti-inflammatory drugs. BMJ 1987; 295: 180–1. from the gastrointestinal tract. Peak plasma concentra- Drugs 1990; 40: 91–137.
Effects on the lungs. See Hypersensitivity, below.
tions are attained about 1 to 2 hours after ingestion of 2. Mason L, et al. Single dose oral naproxen and naproxen sodium
naproxen sodium and in about 2 to 4 hours after inges- for acute postoperative pain. Available in The Cochrane Data-
Effects on the salivary glands. For reference to salivary tion of naproxen. Food reduces the rate but not the ex- base of Systematic Reviews; Issue 4. Chichester: John Wiley;
gland swelling associated with naproxen therapy, see Hypersen- 2004 (accessed 08/11/07).
sitivity, below. tent of absorption. Naproxen and naproxen sodium are 3. Curran MP, Wellington K. Delayed-release lansoprazole plus
also well absorbed rectally. At therapeutic concentra- naproxen. Drugs 2004; 64: 1915–19.
Effects on the skin. Cutaneous reactions reported in patients
receiving naproxen include erythema nodosum,1 lichen planus,2 tions naproxen is more than 99% bound to plasma pro- Administration in children. In the treatment of juvenile idio-
toxic pustular skin eruption,3 bullous dermatosis,4 and fixed drug teins. Plasma concentrations of naproxen increase pro- pathic arthritis (p.10), US licensed product information recom-
eruption.5 Photodermatitis, characterised by vesicle formation or portionally with dose up to about 500 mg daily; at mends an oral dose of about 10 mg/kg daily of naproxen in 2
increased skin fragility on sun-exposed skin, has been reported in higher doses there is an increase in clearance caused by divided doses for children aged 2 years and over. In addition,
adults6-8 and children.9,10 saturation of plasma proteins. Naproxen diffuses into higher doses may also be used: the BNFC suggests a dose of 5 to
A relapse of subacute cutaneous lupus erythematosus was re- 10 mg/kg twice daily in children aged 1 month to 18 years which
ported to be possibly associated with naproxen.11
synovial fluid; it crosses the placenta and is distributed may be increased to 10 to 15 mg/kg twice daily (maximum of 1 g
For reference to facial scars of unknown origin developing in
into breast milk in small amounts. Naproxen has a plas- daily) for short-term use in severe disease.
children receiving NSAIDs, and in particular naproxen, see un- ma elimination half-life of about 12 to 17 hours. About
Headache. An NSAID such as naproxen is among the drugs
der NSAIDs, p.98. 95% of a dose is excreted in urine as naproxen and 6- tried first for the symptomatic treatment of various types of head-
1. Grattan CEH, Kennedy CTC. Naproxen induced erythema no- O-desmethylnaproxen and their conjugates. Less than ache including migraine (p.616) and tension-type headache
dosum. BMJ 1984; 288: 114.
2. Heymann WR, et al. Naproxen-induced lichen planus. J Am
5% of a dose appears in the faeces. (p.617). An NSAID given at the onset of symptoms can success-
fully treat an acute attack of migraine.1 Co-treatment with a
Acad Dermatol 1984; 10: 299–301. ◊ References. triptan may provide additional benefit and a preparation contain-
3. Page SR, Grattan CEH. Pustular reaction to naproxen with
cholestatic jaundice. BMJ 1986; 293: 510. 1. Bruno R, et al. Naproxen kinetics in synovial fluid of patients ing both sumatriptan succinate and naproxen sodium has recent-
4. Bouldin MB, et al. Naproxen-associated linear IgA bullous der- with osteoarthritis. Br J Clin Pharmacol 1988; 26: 41–4. ly been developed.2,3
matosis: case report and review. Mayo Clin Proc 2000; 75: 2. Bertin P, et al. Sodium naproxen: concentration and effect on
967–70. inflammatory response mediators in human rheumatoid synovial NSAIDs also appear to be effective for the prophylaxis of mi-
5. Leivo T, Heikkilä H. Naproxen-induced generalized bullous fluid. Eur J Clin Pharmacol 1994; 46: 3–7. graine, although propranolol is generally preferred. Studies have
fixed drug eruption. Br J Dermatol 2004; 151: 232. 3. Davies NM, Anderson KE. Clinical pharmacokinetics of naprox- indicated that naproxen sodium 550 mg [equivalent to 500 mg of
6. Howard AM, et al. Pseudoporphyria due to naproxen. Lancet en. Clin Pharmacokinet 1997; 32: 268–93. naproxen] given twice daily may be useful for reducing the
1985; i: 819–20. 4. Bowalgaha K, et al. S-Naproxen and desmethylnaproxen glu-
curonidation by human liver microsomes and recombinant hu-
number of attacks suffered.4-6
7. Rivers JK, Barnetson RS. Naproxen-induced bullous photoder-
matitis. Med J Aust 1989; 151: 167–8. man UDP-glucuronosyltransferases (UGT): role of UGT2B7 in 1. Treves TA, et al. Naproxen sodium versus ergotamine tartrate in
8. Levy ML, et al. Naproxen-induced pseudoporphyria: a distinc- the elimination of naproxen. Br J Clin Pharmacol 2005; 60: the treatment of acute migraine attacks. Headache 1992; 32:
tive photodermatitis. J Pediatr 1990; 117: 660–4. 423–33. 280–2.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
94 Analgesics Anti-inflammatory Drugs and Antipyretics
2. Winner P, et al. Twelve-month tolerability and safety of su-
Nefopam Hydrochloride in an equivalent concentration to that in plasma.2 It was calculat-
matriptan-naproxen sodium for the treatment of acute migraine. ed that on a body-weight basis a breast-fed infant would receive
Mayo Clin Proc 2007; 82: 61–8. (BANM, USAN, rINNM) less than 3% of the maternal dose.
3. Brandes JL, et al. Sumatriptan-naproxen for acute treatment of
migraine: a randomized trial. JAMA 2007; 297: 1443–54. Benzoxazocine; Fenazoxine; Hidrocloruro de nefopam; Né- 1. American Academy of Pediatrics. The transfer of drugs and oth-
4. Sargent J, et al. A comparison of naproxen sodium to pro- fopam, Chlorhydrate de; Nefopami Hydrochloridum; R-738. er chemicals into human milk. Pediatrics 2001; 108: 776–89.
pranolol hydrochloride and a placebo control for the prophylaxis 3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine Correction. ibid.: 1029. Also available at:
of migraine headache. Headache 1985; 25: 320–4. h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
hydrochloride. pediatrics%3b108/3/776 (accessed 10/10/06)
5. Welch KMA, et al. Successful migraine prophylaxis with
naproxen sodium. Neurology 1985; 35: 1304–10. Нефопама Гидрохлорид
2. Liu DTY, et al. Nefopam excretion in human milk. Br J Clin
6. Sances G, et al. Naproxen sodium in menstrual migraine proph- C 17 H 19NO,HCl = 289.8. Pharmacol 1987; 23: 99–101.
ylaxis: a double-blind placebo controlled study. Headache 1990;
30: 705–9. C AS — 13669-70-0 (nefopam); 23327-57-3 (nefopam
hydrochloride). Interactions
Malignant neoplasms. Some NSAIDs such as naproxen may ATC — N02BG06.
be of value both for the differential diagnosis and the manage- It has been recommended that nefopam should not be
ment of neoplastic fever1-4 as they appear to be more effective in ATC Vet — QN02BG06. given to patients receiving MAOIs and should be used
reducing this type of fever than against fever associated with in- cautiously in those receiving tricyclic antidepressants.
fections. However, the reliability of naproxen in the diagnosis of The adverse effects of nefopam may be additive to
neoplastic fever has been questioned.5 In a group of 72 patients,
naproxen decreased body temperature in 55% of patients with those of other drugs with antimuscarinic or sympatho-
neoplastic disorders and 38% of patients with other conditions. mimetic activity.
Thus, the sensitivity of the test was calculated as 55% and its
specificity as 62%, which the authors considered to be too low to
be reliable. O Pharmacokinetics
1. Chang JC, Gross HM. Neoplastic fever responds to the treatment Nefopam is absorbed from the gastrointestinal tract.
of an adequate dose of naproxen. J Clin Oncol 1985; 3: 552–8. Peak plasma concentrations occur 1 to 3 hours after a
2. Azeemuddin SK, et al. The effect of naproxen on fever in chil- N dose by mouth and up to 1 hour after intramuscular in-
dren with malignancies. Cancer 1987; 59: 1966–8.
jection. About 73% is bound to plasma proteins. Ne-
3. Economos K, et al. The effect of naproxen on fever in patients CH3
with advanced gynecologic malignancies. Gynecol Oncol 1995; fopam is distributed into breast milk. It has an elimina-
56: 250–4. tion half-life of about 4 hours. It is extensively
(nefopam)
4. Cunha BA, et al. Fever of unknown origin (FUO) caused by mul- metabolised and excreted mainly in urine, in which
tiple myeloma: the diagnostic value of the Naprosyn test. Heart
Lung 2006; 35: 358–62. less than 5% of a dose is excreted unchanged. About
Pharmacopoeias. In Chin. 8% of a dose is excreted via the faeces.
5. Vanderschueren S, et al. Lack of value of the naproxen test in the
differential diagnosis of prolonged febrile illnesses. Am J Med
2003; 115: 572–5. Adverse Effects and Treatment
Adverse effects occurring with nefopam include gas- Uses and Administration
Preparations
trointestinal disturbances, such as nausea and vomit- Nefopam hydrochloride is a non-opioid analgesic con-
BP 2008: Gastro-resistant Naproxen Tablets; Naproxen Oral Suspension; sidered to act centrally, although its mechanism of ac-
Naproxen Suppositories; Naproxen Tablets; ing, sweating, drowsiness, insomnia, urinary retention,
USP 31: Naproxen Delayed-Release Tablets; Naproxen Oral Suspension; dizziness, hypotension, tremor, paraesthesia, palpita- tion is unclear. It also has some antimuscarinic and
Naproxen Sodium Tablets; Naproxen Tablets. sympathomimetic actions. Nefopam hydrochloride is
tions, lightheadedness, nervousness, confusion,
Proprietary Preparations (details are given in Part 3) blurred vision, headache, dry mouth, syncope, angio- used for the relief of moderate acute and chronic pain.
Arg.: Aleve; Algioprux†; Alidase; Bumaflex N; Causalon Pro†; Congex; De- edema, allergic reactions, and tachycardia. Euphoria, The usual oral dose range is 30 to 90 mg three times
bril; Fabralgina; Fadalivio; Flaxvan; Flogocefal†; Melgar; Monarit; Naprofidex;
Naprogen; Naprontag; Naprux; Neuralprona; Sicadentol Plus†; Tundra; Ve- hallucinations, and convulsions have occasionally daily; the recommended initial dose is 60 mg (or 30 mg
radol†; Xicane†; Austral.: Aleve†; Anaprox; Chemists Own Period Pain been reported, as has temporary pink discoloration of in elderly patients) three times daily. Nefopam hydro-
Tablets; Crysanal; Femme Free; Inza; Naprogesic; Naprosyn; Nurolasts†;
Proxen; Austria: Aleve; Miranax; Naprobene; Nycopren; Proxen; Belg.: the urine. Symptoms of overdosage have included chloride may also be given in doses of 20 mg by intra-
Aleve; Apranax; Naproflam; Naprosyne; Braz.: Flanax; Napronax; CNS and cardiovascular toxicity. muscular injection, repeated every 6 hours if neces-
Naprosyn; Naprox; Canad.: Anaprox; Apo-Napro-Na; Naprosyn; Nax-
en†; Novo-Naprox; Nu-Naprox; Synflex†; Chile: Atac; Deucoval; Euroge- sary; it has been recommended that the patient should
sic; Inveoxel†; Naprogesic; Reprost†; Triox NF; Cz.: Aleve; Emoxen; Nalge- Effects on the urinary tract. In January 1989, the UK CSM1
reported that it had received 53 reports in which nefopam was always be lying down when receiving the injection and
sin; Naprobene†; Naprosyn†; Napsyn†; Denm.: Bonyl; Miranax†;
Naprosyn; Fin.: Alpoxen; Miranax; Naprometin; Napromex; Naprosyn†; associated with the development of urinary retention or symp- should remain so for 15 to 20 minutes afterwards. It has
Naxopren; Pronaxen; Fr.: Aleve; Apranax; Naprosyne; Ger.: Alacetan toms of hesitancy, poor stream, or dribbling. In one case there also been given by slow intravenous injection in doses
NNA; Aleve; Dolormin mit Naproxen; Dysmenalgit; prodolor†; Proxen; was a history of prostatism.
Gr.: Anaprox; Naprosyn; Nycopren-E; Hong Kong: Apo-Napro-Na; Inza; of 20 mg every 4 hours up to a maximum of 120 mg
Naprorex; Naprosyn; Napxen; Noflam-N; Proxen†; Soden; Soren†; Syn- 1. CSM. Nefopam hydrochloride (Acupan). Current Problems 24 daily.
flex†; Hung.: Aleve; Apranax; Napmel; Naprosyn; India: Artagen; Easy 1989. Also available at: http://www.mhra.gov.uk/home/
Dayz; Naprosyn; Xenobid; Indon.: Naxen; Synflex; Irl.: Gerinap; Napmel†; idcplg?IdcService=GET_FILE&dDocName=CON2024431&
Naprex†; Naprosyn; Synflex; Israel: Naproxi; Narocin; Naxyn; Point; Ital.: RevisionSelectionMethod=LatestReleased (accessed 14/07/08) Hiccup. In two case series1,2 involving 10 patients in total, hic-
Aleve; Algonapril; Aperdan; Axer†; Floginax; Flogogin†; Floxalin; Gibixen;
Gynestrel; Laser; Momendol; Napreben†; Naprius; Naprocet; Naprorex†; cups refractory to standard therapy stopped after treatment with
Overdosage. There have been reports of fatal overdoses with intravenous nefopam. For the management of intractable hiccups
Naprosyn; Neo Eblimon; Nitens; Prexan; Proxagol; Synalgo; Synflex;
Ticoflex†; Uninapro; Xenar†; Malaysia: Apo-Napro-Na; Inza†; Roxyn†; nefopam.1-3 One report1 also provided details of 9 other patients see under Chlorpromazine, p.976.
Seladin; Sunprox; Synflex; Mex.: Actiquim; Analgen; Anapsyl; Arsenal; Ar- who recovered with routine supportive treatment.
tron†; Arxen; Atiflan; Bioxan; Bixen; Dafloxen; Deflamox; Diferbest; Dolxen; 1. Bilotta F, Rosa G. Nefopam for severe hiccups. N Engl J Med
Donaprox; Edem; Faraxen; Flanax; Flavoxen; Flaxendol; Flexen†; Flogen; 1. Piercy DM, et al. Death due to overdose of nefopam. BMJ 1981;
Fuxen; Genalgen†; Inflanox; Iqfasol; Kenaprox†; Lixogan†; Lorexen†; Mes- 283: 1508–9. 2000; 343: 1973–4.
selxen; Naflapen; Napoxol; Naprodil; Nasocan†; Navixen; Naxen; Nax- 2. Urwin SC, Smith HS. Fatal nefopam overdose. Br J Anaesth
opaar; Neonaxil; Nixal†; Novaxen; Pactens; Praxedol; Pronat; Pronax-P†; 2. Bilotta F, et al. Nefopam for refractory postoperative hiccups.
1999; 83: 501–2.
Pronaxil; Pronoxen; Propional†; Proxalin; Proxem†; Salupran†; Sertrixen; Anesth Analg 2001; 93: 1358–60.
Sodixen; Tandax; Tanizona; Unirelaxed; Vantin; Velsay; Neth.: Aleve; Fe- 3. Tracqui A, et al. Fatal overdosage with nefopam (Acupan ). J
mex†; Momendol; Naprelan; Naprocoat; Naprovite; Nycopren†; Norw.: Anal Toxicol 2002; 26: 239–43.
Shivering. Nefopam is one of several drugs tried in the preven-
Alpoxen†; Ledox; Napren; Naprosyn; NZ: Naprogesic; Naprosyn; Naxen;
Noflam; Synflex; Philipp.: Alpron; Flanax; Naprelan; Naprosyn; Sanomed; tion of postoperative shivering (p.1779).
Pol.: Aleve; Anapran; Boloxen; Emochol†; Natrax; Port.: Momendol; Precautions
Naprocet; Naprosyn; Reuxen; Rus.: Nalgesin (Налгезин); S.Afr.: Acus- Nefopam is contra-indicated in patients with a history References.
prain; Aleve; Fibroxyn†; Nafasol; Napflam; Naprel†; Naproscript†;
Naprosyn†; Synflex; Traumox; Singapore: Aleve; Apo-Napro-Na; Bipro- of convulsive disorders. It should be used with caution 1. Bilotta F, et al. Nefopam and tramadol for the prevention of shiv-
nyl†; Gesiprox†; Inza; Noflam-N†; Nuprafen†; Seladin; Soden; Soproxen; in the elderly and in patients with glaucoma, urinary ering during neuraxial anesthesia. Reg Anesth Pain Med 2002;
Zynal†; Spain: Aleve; Aliviomas; Antalgin; Denaxpren; Lundiran; Momen; 27: 380–4.
Naprosyn; Naproval; Tacron; Swed.: Alpoxen; Naprosyn; Pronaxen; retention, or impaired hepatic or renal function.
Switz.: Aleve; Apranax; Naprosyn†; Nycopren; Proxen; Thai.: Annoxen; 2. Piper SN, et al. A comparison of nefopam and clonidine for the
Naproflex; Naprosian; Naprosyn; Napsen†; Napxen†; Narzen†; Polyxen; Abuse. Abuse of parenteral nefopam has been reported in 3 pa- prevention of postanaesthetic shivering: a comparative, double-
Proxen; Roxen†; Serviproxan; Sonap; Soproxen; Synflex; U-Proxyn; Vinsen; tients with a history of chronic pain.1 Psychostimulant-like blind and placebo-controlled dose-ranging study. Anaesthesia
Turk.: A-Nox; Aleve; Anaprotab; Apraljin; Apranax; Aprol; Apromed; symptoms such as agitation, impatience, and violence, were
Aprowell; Bonmin; Kapnax; Karoksen; Naponal; Napradol; Napren; 2004; 59: 559–64.
Naprodeva; Naprosyn; Naprotab; Opraks; Relokap; Romaksen; Romatim; noted in 2 of the patients; antimuscarinic effects were also seen.
Rumazolidin; Synax; Syndol; UK: Arthrosin†; Arthroxen; Feminax Ultra; All 3 patients were found to be psychologically dependent; in 2 3. Bilotta F, et al. Nefopam or clonidine in the pharmacologic pre-
Napratec; Naprosyn; Nycopren†; Synflex; Timpron†; USA: Aleve; Ana- who attempted to stop nefopam, withdrawal symptoms were vention of shivering in patients undergoing conscious sedation
prox; Naprelan; Naprosyn; Prevacid NapraPAC; Venez.: Apranax†; Syn- noted. for interventional neuroradiology. Anaesthesia 2005; 60: 124–8.
aprosyn†.
1. Villier C, Mallaret MP. Nefopam abuse. Ann Pharmacother
Multi-ingredient: Arg.: Naprontag Flex; Papasine; Ital.: Momendol; 2002; 36: 1564–6. Preparations
Mex.: Acxen†; Analgen Forte; Arsenal Compuesto; Arxen Compositum;
Bifardol; Blocacid; Brax; Contraxen; Dafloxen-F; Decosil; Deflamox Plus; Breast feeding. No adverse effects have been seen in breast- Proprietary Preparations (details are given in Part 3)
Dolotandax; Drunen; Farxen; Febrax; Fiverdol; Flucol; Grifed; Kensedal;
Movex; Naprodil Plus; Naxodol; Nedoxal; Neorpan Plus; Onexmol; Pen- fed infants whose mothers were receiving nefopam, and the
American Academy of Pediatrics considers1 that it is therefore Belg.: Acupan; Fr.: Acupan; Ger.: Ajan†; Silentan†; Irl.: Acupan; Ital.: Ne-
sodil; Polet; Profenlax; Proxalin Plus; Raxenol; Reucortil; Somalgesic; Tax- fam†; Oxadol†; NZ: Acupan; Rus.: Oxadol (Оксадол); Switz.: Acupan†;
enan; Ulpafie-N; Velsay-S Compuesto; Viplus; Rus.: Cefecon N (Цефекон usually compatible with breast feeding. UK: Acupan.
Н); Pentalgin-N (Пенталгин-Н).
Studies in 5 healthy nursing mothers given nefopam for post-epi-
siotomy pain indicated that nefopam was present in human milk
 Nefopam Hydrochloride/Nimesulide 95
Nepafenac (USAN, rINN) has also been used topically as a 3% cream or ointment or 2.5%
gel. The morpholinoethyl ester, morniflumate (p.86), has similar
AHR-9434; AL-6515; Népafénac; Nepafenaco; Nepafenacum. N uses.
2-(2-Amino-3-benzoylphenyl)acetamide. Niflumic acid glycinamide has been used topically in inflamma-
Непафенак O tory mouth disorders.
C 15 H 14N 2 O 2 = 254.3. Preparations
O Proprietary Preparations (details are given in Part 3)
C AS — 78281-72-8. Arg.: Flogovital; Belg.: Niflugel; Nifluril; Cz.: Niflugel; Nifluril; Fr.: Flunir†;
ATC — S01BC10. O H Niflugel; Nifluril; Gr.: Niflamol; Novopone†; Hung.: Donalgin; Ital.: Niflam;
Port.: Nifluril; Rus.: Donalgin (Доналгин); Spain: Niflactol.
ATC Vet — QS01BC10.
O NCH3 Multi-ingredient: Arg.: Flogodisten.

O N O
Nimesulide (BAN, rINN)
NH2 Nimesulid; Nimesulida; Nimesulidas; Nimésulide; Nimesulidi;
H2N Nimesulidinum; Nimesulidum; Nimeszulid; R-805. 4′-Nitro-2′-
(nicomorphine) phenoxymethanesulphonanilide.
Нимесулид
O Profile C 13 H 12 N 2 O 5 S = 308.3.
Nicomorphine hydrochloride is an opioid analgesic (p.101) used C AS — 51803-78-2.
Profile in the treatment of moderate to severe pain. It is given in oral ATC — M01AX17.
doses of 5 to 10 mg daily or by intramuscular, slow intravenous, ATC Vet — QM01AX17.
Nepafenac, an NSAID (p.96), is a prodrug of amfenac. It is used
or subcutaneous injection in doses of 10 to 20 mg; higher doses
in the treatment of pain and inflammation following cataract sur-
gery. An ophthalmic suspension containing nepafenac 0.1% is have also been used. It may also be given rectally in usual doses
of 10 to 20 mg daily.
instilled 3 times daily starting on the day before surgery and con-
tinuing for 2 weeks after surgery. ◊ References. O
1. Koopman-Kimenai PM, et al. Pharmacokinetics of intravenous-
◊ References. ly administered nicomorphine and its metabolites in man. Eur J
Anaesthesiol 1993; 10: 125–32. HN NO2
1. Colin J, Paquette B. Comparison of the analgesic efficacy and
safety of nepafenac ophthalmic suspension compared with di- 2. Koopman-Kimenai PM, et al. Rectal administration of nicomor- O
clofenac ophthalmic solution for ocular pain and photophobia af- phine in patients improves biological availability of morphine S
ter excimer laser surgery: a phase II, randomized, double- and its glucuronide conjugates. Pharm World Sci 1994; 16: O
248–53. H3C
masked trial. Clin Ther 2006; 28: 527–36.
3. Koopman-Kimenai PM, et al. The bioavailability of intramuscu-
2. Lane SS. Nepafenac: a unique nonsteroidal prodrug. Int Oph- larly administered nicomorphine (Vilan) with its metabolites and
thalmol Clin 2006; 46: 13–20. their glucuronide conjugates in surgical patients. Int J Clin Phar-
Pharmacopoeias. In Eur. (see p.vii).
macol Ther 1995; 33: 442–8. Ph. Eur. 6.2 (Nimesulide). A yellowish crystalline powder. It
3. Lane SS, et al. Nepafenac ophthalmic suspension 0.1% for the
prevention and treatment of ocular inflammation associated with
exhibits polymorphism. Practically insoluble in water; slightly
Preparations soluble in dehydrated alcohol; freely soluble in acetone.
cataract surgery. J Cataract Refract Surg 2007; 33: 53–8. Cor-
rection. ibid.; 564. Proprietary Preparations (details are given in Part 3)
Austria: Vilan; Denm.: Vilan; Neth.: MorZet; Vilan†; Switz.: Vilan. Profile
Preparations Nimesulide is an NSAID (p.96) reported to be a selective inhib-
itor of cyclo-oxygenase-2 (COX-2). It may be given in oral doses
Proprietary Preparations (details are given in Part 3) of up to 100 mg twice daily for inflammatory conditions, fever,
Arg.: Nevanac; Chile: Nevanac; Cz.: Nevanac; Port.: Nevanac; USA: Niflumic Acid (rINN) pain, and dysmenorrhoea; use in the EU is limited to a maximum
Nevanac. Acide niflumique; Ácido niflúmico; Acidum niflumicum; UP-83. 2- of 15 days due to reports of hepatotoxicity (see Adverse Effects,
(ααα-Trifluoro-m-toluidino)nicotinic acid. below). It has also been given rectally in a dose of 200 mg twice
daily or applied topically as a 3% gel. Nimesulide betadex
Нифлумовая Кислота (nimesulide betacyclodextrin complex) has been used similarly.
Nicoboxil (rINN) C 13 H 9 F 3 N 2 O 2 = 282.2.
C AS — 4394-00-7. ◊ References.
Butoxyethyl Nicotinate; Nicoboxilo; Nicoboxilum. 2-Butoxyethyl ATC — M01AX02; M02AA17. 1. Bennett A, et al. Nimesulide: a multifactorial therapeutic ap-
ATC Vet — QM01AX02; QM02AA17. proach to the inflammatory process? a 7-year clinical experi-
nicotinate. ence. Drugs 1993; 46: (suppl 1): 1–283.
2. Senna GE, et al. Nimesulide in the treatment of patients intoler-
Никобоксил ant of aspirin and other NSAIDs. Drug Safety 1996; 14: 94–103.
C 12 H 17NO 3 = 223.3. H 3. Vizzardi M, et al. Nimesulide beta cyclodextrin (nimesulide-
N N CF3 betadex) versus nimesulide in the treatment of pain after arthro-
C AS — 13912-80-6. scopic surgery. Curr Ther Res 1998; 59: 162–71.
4. Bernareggi A. Clinical pharmacokinetics of nimesulide. Clin
Pharmacokinet 1998; 35: 247–74.
COOH 5. Shah AA, et al. Selective inhibition of COX-2 in humans is as-
N sociated with less gastrointestinal injury: a comparison of
Pharmacopoeias. In Eur. (see p.vii). nimesulide and naproxen. Gut 2001; 48: 339–46.
Ph. Eur. 6.2 (Niflumic Acid). A pale yellow, crystalline powder. 6. Nüing RM, et al. Pathogenetic role of cyclooxygenase-2 in hy-
O perprostaglandin E syndrome/antenatal Bartter syndrome: thera-
O CH3 Practically insoluble in water; soluble in alcohol and in methyl peutic use of the cyclooxygenase-2 inhibitor nimesulide. Clin
alcohol; freely soluble in acetone. Pharmacol Ther 2001; 70: 384–90.
O
Adverse Effects, Treatment, and Precautions Adverse effects. Although thrombocytopenia is a common
As for NSAIDs in general, p.96. feature in patients infected with HIV, a group of workers consid-
Profile Fluoride-associated osteosis has been reported with prolonged ered that thrombocytopenia in one of their patients was related to
Nicoboxil is a nicotinate used in topical preparations as a rubefa- use. Niflumic acid should be stopped if hypersensitivity skin re- the use of nimesulide.1
cient. It is also included in some topical preparations used for the
treatment of acne vulgaris.
actions appear. There have been reports2-4 of hepatotoxicity after treatment with
Effects on the skin. From a case-control study1 of children ad- nimesulide. Data from spontaneous reports has also suggested
Preparations mitted to a hospital emergency department in Italy it was calcu- that nimesulide may be associated with a higher risk of hepato-
lated that the odds-ratio of users of niflumic acid, or its derivative toxicity than other NSAIDs.4 A cohort study5 involving about
Proprietary Preparations (details are given in Part 3) 400 000 users of NSAIDs in one region of Italy between 1997
morniflumate, developing serious cutaneous reactions was 4.9.
Multi-ingredient: Austral.: Finalgon; Austria: Finalgon; Canad.: Final- Given this figure and the fact that safer drugs were available the and 2001 found that those taking nimesulide were 1.3 times more
gon†; Ger.: Finalgon; Ital.: Anti-Acne; NZ: Finalgon†; Port.: Finalgon; Rus.: authors considered that there was no indication for which niflu- likely to develop hepatotoxicity than users of other NSAIDs and
Betalgon (Беталгон); Betanicomylon (Бетаникомилон); Finalgon
mic acid was required in children. However, a large cohort study2 1.9 times more likely to suffer severe liver injury. In May 2007
(Финалгон); Spain: Finalgon; UK: Actinac. the Irish regulatory authority withdrew nimesulide from the Irish
involving 193 727 children aged between 0 and 14 years found
that niflumic acid was not associated with a higher risk of muco- market after concerns about hepatotoxicity.6 Since being li-
cutaneous reactions when compared with other NSAIDs or para- censed in 1995, nimesulide had generated 53 adverse reaction
cetamol. The authors of the later study suggested that the conclu- reports involving liver toxicity, including 9 cases of liver failure,
Nicomorphine Hydrochloride (BANM, rINNM) sions of the original study may have been confounded because 3 of which resulted in death and 6 in liver transplantation; there
there was no adjustment for age or indication. had also been 1 other liver-related fatality. The EMEA7 subse-
Hidrocloruro de nicomorfina; Nicomorphine, Chlorhydrate de; quently recommended that treatment with nimesulide should be
Nicomorphini Hydrochloridum. 3,6-Di-O-nicotinoylmorphine 1. Menniti-Ippolito F, et al. Niflumic acid and cutaneous reactions
in children. Arch Dis Child 2001; 84: 430–1. limited to 15 days.
hydrochloride; (−)-(5R,6S)-4,5-Epoxy-9a-methylmorphin-7-en- 2. Sturkenboom M, et al. Incidence of mucocutaneous reactions in There have been reports8,9 of toxic pustuloderma (acute general-
3,6-diyl dinicotinate hydrochloride. children treated with niflumic acid, other nonsteroidal antiinflam- ised exanthematous pustulosis) after receiving oral nimesulide.
matory drugs, or nonopioid analgesics. Abstract: Pediatrics 2005; Fixed drug eruptions have also been seen.10
Никоморфина Гидрохлорид 116: 212. Full version: http://pediatrics.aappublications.org/
cgi/content/full/116/1/e26 (accessed 08/11/07) An infant developed hypotension and hypothermia after inad-
C 29 H 25N 3 O 5 ,HCl = 532.0. vertently taking an overdose of 8 times the recommended daily
C AS — 639-48-5 (nicomorphine); 12040-41-4 (nicomor- Uses and Administration dose of nimesulide.11 The patient recovered after gastric lavage
phine hydrochloride); 35055-78-8 (nicomorphine xHCl). Niflumic acid, a nicotinic acid derivative, is an NSAID (p.99). It with activated charcoal and supportive therapy.
has been used in inflammatory and musculoskeletal and joint 1. Pasticci MB, et al. Nimesulide, thrombocytopenic purpura, and
ATC — N02AA04. disorders in usual oral doses of about 250 mg three or four times human immunodeficiency virus (HIV) infection. Ann Intern
ATC Vet — QN02AA04. daily; up to 1500 mg daily has been used in severe disorders. It Med 1990; 112: 233–4.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
96 Analgesics Anti-inflammatory Drugs and Antipyretics
2. McCormick PA, et al. COX 2 inhibitor and fulminant hepatic Sulidin; Venez.: Ainex; Aulin; Drexel; Nimecox; Nimelid; Nimepirex†; Ni- Fluid retention may occur, rarely precipitating heart
failure. Lancet 1999; 353: 40–1. prolide†; Nise†; Normosilen†; Reduben; Scaflan.
3. Sbeit W, et al. Nimesulide-induced acute hepatitis. Ann Phar- Multi-ingredient: Arg.: Doloctaprin Plus†; Metaflex Plus†; Mio Aldoron;
failure in susceptible patients. Other cardiovascular ad-
macother 2001; 35: 1049–52. Mio-Virobron; India: Cipzen N; Niciflex-T; Nicip Cold; Nicip D; Nicip MR; verse effects of NSAIDs, including those selective for
4. Maciá MA, et al. Hepatotoxicity associated with nimesulide: Nicip Plus; Nicip Super; Nicip T; Nicispas; Nimica Plus; Nimulid MR; Nimulid COX-2 inhibition, are discussed in detail below.
data from the Spanish pharmacovigilance system. Clin Pharma- Nugel; Nimulid SP; Nimvista Plus; Nizer; Mex.: Amoxiclide; Zithroflam.
col Ther 2002; 72: 596–7. Other adverse effects include photosensitivity. Alveo-
5. Traversa G, et al. Cohort study of hepatotoxicity associated with litis, pulmonary eosinophilia, pancreatitis, Stevens-
nimesulide and other non-steroidal anti-inflammatory drugs.
BMJ 2003; 327: 18–22. Nonivamide (rINN) Johnson syndrome, and toxic epidermal necrolysis are
6. Irish Medicines Board. Immediate suspension of the marketing Nonivamida; Nonivamidum; Noniwamid; Nonylvanillamide; PA- other rare adverse effects. Induction or exacerbation of
of medicines containing nimesulide (issued 15th May, 2007).
Available at: http ://www.i mb.i e/EN/Safet y--Quality/ VA; Pelargonyl Vanillylamide; Pseudocapsaicin. N-Vanillylnona- colitis has also been reported.
Advisory-Warning--Recall-Notices/Human-Medicines/ mide; N-[(4-Hydroxy-3-methoxyphenyl)methyl]nonanamide. Further details concerning the adverse effects of the in-
Nimesulide-Suspension.aspx?page=1&noticetypeid=-1&year= Нонивамид
2007 (accessed 08/11/07) dividual NSAIDs may be found under their respective
7. EMEA. Questions and answers on the CHMP recommendation C 17 H 27NO 3 = 293.4. monographs.
on nimesulide-containing medicines (issued 21st September, C AS — 2444-46-4.
2007). Available at: http://www.emea.europa.eu/pdfs/human/ Incidence of adverse effects. The relative toxicity of
opinion/43098807en.pdf (accessed 08/11/07) NSAIDs is a subject of debate.1 Attempts have been made to
8. Lateo S, Boffa MJ. Localized toxic pustuloderma associated O rank these drugs according to their toxicity on various body sys-
with nimesulide therapy confirmed by patch testing. Br J Der- tems.2 The toxicity of selective cyclo-oxygenase-2 (COX-2) in-
matol 2002; 147: 624–5. CH3 hibitors has also been reviewed.3 For further details see below
9. Teixeira M, et al. Acute generalized exanthematous pustulosis N
induced by nimesulide. Dermatol Online J 2006; 12: 20. Avail- H under individual headings.
able at: http://dermatology.cdlib.org/126/case_presentations/ 1. Skeith KJ, et al. Differences in NSAID tolerability profiles: fact
agep/teixeira.html (accessed 08/11/07) HO or fiction? Drug Safety 1994; 10: 183–95.
10. Malheiro D, et al. Nimesulide-induced fixed drug eruption. Al- 2. CSM/MCA. Relative safety of oral non-aspirin NSAIDs. Cur-
O rent Problems 1994; 20: 9–11. Also available at: http://
lergol Immunopathol (Madr) 2005; 33: 285–7. CH3 w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _
11. Yapakci E, et al. Hypoglycaemia and hypothermia due to
nimesulide overdose. Arch Dis Child 2001; 85: 510. FILE&dDocName=CON2015615&RevisionSelectionMethod=
LatestReleased (accessed 08/11/07)
NOTE. Use of the term ‘synthetic capsaicin’ to describe noniva- 3. Chaiamnuay S, et al. Risks versus benefits of cyclooxygenase-2-
Pregnancy. Irreversible end-stage renal failure has been report- mide has arisen from the use of nonivamide as an adulterant for
ed in a neonate born to a mother who received nimesulide as a selective nonsteroidal antiinflammatory drugs. Am J Health-Syst
capsaicin and capsicum oleoresin. Pharm 2006; 63: 1837–51.
tocolytic from the 26th to the 32nd week of pregnancy.1 Others
have reported neonatal renal failure associated with nimesulide.2 Profile Effects on the blood. The UK CSM has provided data on the
Premature closure of the ductus arteriosus leading, in some cas- Nonivamide is a synthetic analogue of capsaicin (p.32) that is reports it had received between July 1963 and January 1993 on
es, to persistent pulmonary hypertension has also been seen in 10 used in topical preparations for the relief of muscular and rheu- agranulocytosis and neutropenia.1 Several groups of drugs were
neonates whose mothers self-medicated with nimesulide during matic pain. commonly implicated, among them NSAIDs for which there
the third trimester of pregnancy.3 Nonivamide has also been used as a food flavour and in ‘pepper were 133 reports of agranulocytosis (45 fatal) and 187 of neutro-
1. Peruzzi L, et al. Neonatal end-stage renal failure associated with sprays’ for law enforcement and self defence. penia (15 fatal). The most frequently implicated NSAID was
maternal ingestion of cyclo-oxygenase-type-2 selective inhibitor Preparations phenylbutazone with 74 reports of agranulocytosis (39 fatal) and
nimesulide as tocolytic. Lancet 1999; 354: 1615. Correction. 40 of neutropenia (4 fatal).
ibid. 2000; 355: 238. Proprietary Preparations (details are given in Part 3) 1. CSM/MCA. Drug-induced neutropenia and agranulocytosis.
Austria: ABC Hydrogel-Warmepflaster; Ger.: ABC Warme-Pflaster Sen-
2. Balasubramaniam J. Nimesulide and neonatal renal failure. Lan- sitive†; Gothaplast Capsicum-Warmepflaster; Hansaplast ABC Warme- Current Problems 1993; 19: 10–11. Also available at: http://
cet 1999; 355: 575. Pflaster Sensitive†. w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _
3. Paladini D, et al. Severe ductal constriction in the third-trimester FILE&dDocName=CON2024456&RevisionSelectionMethod=
Multi-ingredient: Austral.: Finalgon; Austria: Finalgon; Rubriment; Ca- LatestReleased (accessed 08/11/07)
fetus following maternal self-medication with nimesulide. Ul- nad.: Finalgon†; Cz.: Pain Expeller†; Ger.: Finalgon; Infrotto Ultra†; Loma-
trasound Obstet Gynecol 2005; 25: 357–61. zell forte N†; Ostochont†; Rheumasalbe†; Rubriment; Vertebralon N†; Effects on bone. Prostaglandins have been shown to play an
NZ: Finalgon†; Port.: Finalgon; Rus.: Betalgon (Беталгон); Betanicomylon important role in the bone-healing process and, consequently, the
Premature labour. Nimesulide has been tried as an alternative (Бетаникомилон); Capsicam (Капсикам); Finalgon (Финалгон); Spain: Fi-
to indometacin to delay labour in patients with a history of pre- decrease in prostaglandin levels produced by NSAID use may
nalgon; Switz.: Forapin†; Histalgane; Radalgin; Thermocutan†; Thai.: Am-
term delivery (p.2003). Nimesulide was given from 16 to 34 meltz. impair the healing process.1 Under experimental conditions,
weeks of gestation and a successful delivery started 6 days after many NSAIDs including the cyclo-oxygenase-2 (COX-2) inhib-
withdrawal.1 There appeared to be no adverse effect on fetal re- itors have been shown to reduce healing.1 However, clinical evi-
nal function or the ductus arteriosus. The authors suggested that dence of such an effect is rare.2 There is also concern that some
fetal prostaglandin synthesis might be mainly mediated through Nonsteroidal Anti-inflammatory NSAIDs such as indometacin may accelerate the rate of cartilage
destruction in patients with osteoarthritis.3,4
cyclo-oxygenase-1 (COX-1) and that a relatively selective COX-
2 inhibitor such as nimesulide might produce fewer adverse ef-
Drugs 1. Harder AT, An YH. The mechanisms of the inhibitory effects of
nonsteroidal anti-inflammatory drugs on bone healing: a concise
fects on the fetus than other non-selective NSAIDs. However, in AINE; AINS; Fármacos antiinflamatorios no esteroideos; review. J Clin Pharmacol 2003; 43: 807–15.
a small study short-term effects on the fetus were similar for NSAIDs; NSAİİ’ler. 2. Glassman SD. et al. The effect of postoperative nonsteroidal
nimesulide, indometacin, and sulindac.2 НПВП; НПВС; НСПВП; Нестероидные anti-inflammatory drug administration on spinal fusion. Spine
Adverse effects have been reported in some neonates whose 1998; 23: 834–8.
Противовоспалительные Препараты 3. Rashad S, et al. Effect of non-steroidal anti-inflammatory drugs
mothers received nimesulide during their pregnancies, see on the course of osteoarthritis. Lancet 1989; ii: 519–22.
above. Adverse Effects and Treatment 4. Huskisson EC, et al. Effects of antiinflammatory drugs on the
1. Sawdy R, et al. Use of a cyclo-oxygenase type-2-selective non- progression of osteoarthritis of the knee. J Rheumatol 1995; 22:
steroidal anti-inflammatory agent to prevent preterm delivery.
The commonest adverse effects of NSAIDs are gener- 1941–6.
Lancet 1997; 350: 265–6. ally gastrointestinal disturbances, such as gastrointesti- Effects on the cardiovascular system. BLOOD PRESSURE. A
2. Sawdy RJ, et al. A double-blind randomized study of fetal side nal discomfort, nausea, and diarrhoea; these are usually meta-analysis1 of 50 randomised studies of the effects of
effects during and after the short-term maternal administration of
indomethacin, sulindac, and nimesulide for the treatment of pre- mild and reversible but in some patients peptic ulcera- NSAIDs on blood pressure in a total of 771 patients found
term labor. Am J Obstet Gynecol 2003; 188: 1046–51. tion and severe gastrointestinal bleeding may occur. It that NSAIDs had elevated mean supine blood pressure by
5 mmHg. Piroxicam, indometacin, and ibuprofen had pro-
Preparations is generally agreed that inhibition of cyclo-oxygenase- duced the greatest increase but the effect was only found to be
Proprietary Preparations (details are given in Part 3) 1 (COX-1) plays an important role in the gastrointesti- statistically significant for piroxicam. Aspirin, sulindac, and
Arg.: Aldoron; Aulin†; Doloctaprin†; Flogovital NF; Metaflex†; Virobron; nal effects of NSAIDs; the selective inhibition of flurbiprofen produced the smallest elevation in blood pres-
Austria: Aulin; Mesulid; Belg.: Mesulid; Braz.: Antiflogil†; Cimelide; Deflo- COX-2 improves gastrointestinal tolerance. sure while the effect of tiaprofenic acid, diclofenac, and
gen; Deltaflan; Fasulide; Flogilid†; Inflalid; Maxsulid; Neosulida; Nimalgex†; naproxen was intermediate. The increase was more marked in
Nimedalin†; Nimeflan†; Nimesilam; Nimesubal; Nimesulin; Nimesulix; CNS-related adverse effects include headache, vertigo, studies in which patients had received antihypertensive ther-
Nimesulon; Nisalgen†; Nisoflan; Nisuflex; Nisulid; Optaflan†; Scaflam; Scalid; dizziness, nervousness, tinnitus, depression, drowsi-
Sintalgin; Chile: Ainex; Aulin†; Doloc; Nimepast; Nimesyl; Nimex†; Nisulid; apy than in those where such treatment had not been used.
Nisural; Cz.: Aulin; Coxtral; Mesulid; Nimed; Nimesil; Fin.: Nimed†; Fr.: ness, and insomnia. Hypersensitivity reactions may oc- NSAIDs had antagonised all antihypertensive therapy but the
Nexen; Gr.: Aflogen; Alencast; Algosulid; Algover; Amocetin; Aulin; Au- cur occasionally and include fever, angioedema, bron- effect had been greater against beta blockers and vasodilators
romelid; Chemisulide†; Cliovyl; Discorid; Dolostop; Edrigyl; Elinap; Erlecit; than against diuretics. An earlier meta-analysis of interven-
Fladalgin; Flogostop; G-Revm; Kartal; Lalide; Lasazin; Lemesil; Lizepat; Lon- chospasm, and rashes. Hepatotoxicity and aseptic
dopon†; Lovirem; Melicate; Melimont; Mesulid; Mesupon; Min-A-Pon; Mo- tion studies had produced similar results.2 Of the 1324 pa-
suolit; Multiformil; Myxina; Naofid; Niberan; Nimegel; Nimelide; Nimesul;
meningitis, which occur rarely, may also be hypersen- tients who had received NSAIDs, increases in mean arterial
Omnibus; Rhemid; Ristolzit; Ritamine; Rolaket; Scaflam†; Specilid; Sudinet; sitivity reactions. Some patients may experience visual pressure were greatest in hypertensive patients who had taken
Tranzicalm; Ventor; Volonten; Hong Kong: Mesulid; Nidol; Nimm; Hung.: disturbances. either indometacin, naproxen, or piroxicam, although results
Mesulid; Nidol; Nimelid; Xilox; India: Beta Nicip; Mesulid; Nicip; Nilide;
Nimcet; Nimfast; Nimica; Nimodol; Nimulid; Nimusyp; Nimutab; Nimvista; Haematological adverse effects of NSAIDs include were only significant for indometacin and naproxen. Sulindac
Nise; Willgo†; Indon.: Arnid; Aulin; Nicox; Nimed; Nimost; Sohoflam; Xi- and aspirin had minimal effects on mean arterial pressure.
mede; Irl.: Aulin†; Mesine†; Mesulid†; Israel: Mesulid; Ital.: Algimesil; Al- anaemias, thrombocytopenia, neutropenia, eosi- It has been suggested that the use of NSAIDs in the elderly may
golider; Antalgo; Areuma; Aulin; Biosal†; Delfos; Dimesul; Doleside†; nophilia, and agranulocytosis. Unlike aspirin, inhibi- increase the risk of the need for antihypertensive therapy.3 A
Doloxtren†; Domes; Edemax†; Efridol; Erreflog; Eudolene; Fansidol†; Fan-
sulide; Flolid; Idealid; Isodol; Laidor†; Ledolid†; Ledoren; Lidenix†; Mesulid; tion of platelet aggregation is reversible with other study3 of 9411 patients aged 65 years or older who had just start-
Migraless; Nerelid; Nide†; Nimedex; Nimenol; Nimesil; Nimesulene; NSAIDs. ed treatment with antihypertensives found that 41% had used
Nimexan†; Nims; Noalgos; Noxalide; Pantames; Remov; Resulin; Solving; NSAIDs in the previous year compared with 26% of 9629 con-
Sulidamor; Sulide; Malaysia: Nidol†; Mex.: Apolide; Cargespril; Defam; Some NSAIDs have been associated with nephrotoxic- trol patients not being treated with antihypertensives.
Degorflan; Dexlin; Eskaflam; Fenoxil; Flamide; Flamozin; Inim; Lesiden; Luse- ity such as interstitial nephritis and nephrotic syn-
min; Meliden; Mesulid; Minus†; Nimepis; Nizurin; Quidofril; Redaflam; Sev- 1. Johnson AG, et al. Do nonsteroidal anti-inflammatory drugs af-
erin; Sidel; Sindel; Sulidek; Sundir; Ul-Flam; Philipp.: Aulin; Flamesul; drome; renal failure may be provoked by NSAIDs es- fect blood pressure? Ann Intern Med 1994; 121: 289–300.
Mesulid; Nidolid; Sorini; Pol.: Aulin; Minesulin; Nimesil; Port.: Aulin; 2. Pope JE, et al. A meta-analysis of the effects of nonsteroidal
Donulide; Gerilide; Jabasulide; Nimalge; Nimartin; Nimed; Nimesulene; Re-
pecially in patients with pre-existing renal impairment. anti-inflammatory drugs on blood pressure. Arch Intern Med
umolide; Sulidor; Sulimed; Vitolide; Rus.: Actasulid (Актасулид); Aponil Haematuria has also occurred. Long-term use or abuse 1993; 153: 477–84.
(Апонил); Coxtral (Кокстрал); Nimesil (Нимесил); Nimica (Нимика); Nise of analgesics, including NSAIDs, has been associated 3. Gurwitz JH, et al. Initiation of antihypertensive treatment during
(Найз); Singapore: Nidol†; Nise†; Switz.: Aulin; Nisulid; Thai.: Neptide; nonsteroidal anti-inflammatory drug therapy. JAMA 1994; 272:
Nidol; Nilide; Nimes†; Nimind; Nimulid; Turk.: Mesulid; Motival; Nimes; with nephropathy. 781–6.
 Nonivamide/Nonsteroidal Anti-inflammatory Drugs 97
HEART FAILURE. The recent use of NSAIDs has been associated Effects on the CNS. A literature review1 revealed that head- administration, and is less drug specific; it is this effect that is
with an increased risk of developing heart failure in elderly ache, hearing loss, and tinnitus are the most frequent CNS ad- thought to involve COX-1 inhibition.
patients.1 A case-control study2 found that the use of an verse effects in patients taking NSAIDs. Aseptic meningitis had Risk factors continue to be studied and so far the most important
NSAID in the previous week doubled the odds of being ad- occurred rarely in patients using NSAIDs such as naproxen, patient-related factors for upper gastrointestinal toxicity are old
mitted to hospital with heart failure; this risk was increased sulindac, or tolmetin, but the most common reports were in pa- age, a history of peptic ulcers or bleeding of the gastrointestinal
tenfold in those with a history of heart disease. The study also tients with SLE who were receiving ibuprofen (see also p.64). tract, and concomitant use of corticosteroids.9 It has also been
suggested an association between both high-dose and long Reports of psychosis appear to be rare1,2 and have involved in- suggested that risk is increased in children.10 Helicobacter pylori
drug plasma half-life and an increased risk of heart failure. dometacin or sulindac, but in some reviewers’ experience it was infection exacerbates the risk of ulceration, but patients remain at
1. Bleumink GS, et al. Nonsteroidal anti-inflammatory drugs and probably under-reported and was typically seen in elderly pa- increased risk even if infection is eradicated.11 Duration of ther-
heart failure. Drugs 2003; 63: 525–34. tients given indometacin.1 apy is not thought to influence the risk for serious events; a co-
2. Page J, Henry D. Consumption of NSAIDs and the development hort study12 found that the risk of gastrointestinal bleeding or
of congestive heart failure in elderly patients: an underrecog-
Adverse CNS effects have also been reported with the selective
nised public health problem. Arch Intern Med 2000; 160: cyclo-oxygenase-2 (COX-2) inhibitors.2 perforation with NSAIDs was constant throughout treatment,
777–84. The role of NSAIDs in the development of cognitive decline in and risk quickly declines after NSAID withdrawal.13
THROMBOTIC EVENTS. After the introduction of the selective
the elderly is unclear. They have been associated with memory Several studies14-17 have been conducted on the relative toxicity
cyclo-oxygenase-2 (COX-2) inhibitors, concerns arose that impairment and attention deficits in elderly patients,1,3 especially of oral NSAIDs on the upper gastrointestinal tract and various
when given in high doses;4 however, some authors have also re- rankings of these drugs have been discussed.18-22 The UK CSM20
the risk of thrombotic events such as myocardial infarction
and stroke might be increased in patients treated with these ported that long-term NSAID use may reduce the rate of cogni- examined 10 epidemiological studies for 7 oral non-aspirin
selective NSAIDs, and their safety was continuously re- tive decline4,5 or the risk of developing Alzheimer’s disease6-8 NSAIDs and also examined the spontaneous reports they had re-
viewed by some regulatory bodies. Subsequently, clinical (see also Dementia, under Uses and Administration, below). ceived of gastrointestinal effects associated with NSAIDs. The
study data confirmed that there was a small increased risk of 1. Hoppmann RA, et al. Central nervous system side effects of non- CSM concluded that:
steroidal anti-inflammatory drugs: aseptic meningitis, psychosis, • azapropazone was associated with the highest risk of gastroin-
these events with the COX-2 inhibitors which prompted the and cognitive dysfunction. Arch Intern Med 1991; 151:
general world-wide withdrawal of rofecoxib (see p.121) and testinal reactions
1309–13.
valdecoxib (see p.132). For those selective NSAIDs that re- 2. Onder G, et al. NSAID-related psychiatric adverse events: who • ibuprofen carried the lowest risk (but this may be related to
mained, prescribing restrictions were imposed (for further de- is at risk? Drugs 2004; 64: 2619–27. dose, see below)
tails, see under Celecoxib, p.34). 3. Saag KG, et al. Nonsteroidal antiinflammatory drugs and cogni- • piroxicam, ketoprofen, indometacin, naproxen, and di-
tive decline in the elderly. J Rheumatol 1995; 22: 2142–7. clofenac had an intermediate risk; it was considered that the
Concerns have also been raised that the increased risk of throm- 4. Karplus TM, Saag KG. Nonsteroidal anti-inflammatory drugs
botic events seen with the selective COX-2 inhibitors may also and cognitive function - do they have a beneficial or deleterious risk for piroxicam might be higher than for the other NSAIDs
apply to the non-selective NSAIDs. After a review of data avail- effect? Drug Safety 1998; 19: 427–33. with intermediate toxicity
able at the time, the FDA1 reported in April 2005 that the use of 5. Rozzini R, et al. Protective effect of chronic NSAID use on cog- A later update23 by the CSM confirmed these findings.
non-selective NSAIDs may potentially increase cardiovascular nitive decline in older persons. J Am Geriatr Soc 1996; 44:
1025–9. The relative gastrointestinal toxicity of NSAIDs has also been
risk. In August 2005, the UK CSM advised that any cardiovas- reviewed by the EMEA21 using data from epidemiological stud-
cular risk with the non-selective NSAIDs was likely to be small 6. Stewart WF, et al. Risk of Alzheimer’s disease and duration of
NSAID use. Neurology 1997; 48: 626–32. ies and spontaneous adverse drug reaction reports. Available ev-
and associated with continuous long-term treatment and higher 7. in ’t Veld BA, et al. Nonsteroidal antiinflammatory drugs and the idence suggested that piroxicam and ketoprofen, particularly in
doses;2 no changes to current prescribing practices were recom- risk of Alzheimer’s disease. N Engl J Med 2001; 345: 1515–21. high doses, were associated with the greatest risk of gastrointes-
mended. This advice was endorsed a few months later by the 8. Vlad SC, et al. Protective effects of NSAIDs on the development tinal toxicity when compared to diclofenac, etodolac, ibuprofen,
EMEA in Europe.3 However, new information has since become of Alzheimer disease. Neurology 2008; 70: 1672–7. indometacin, meloxicam, nabumetone, naproxen, and
available and, in October 2006, the EMEA updated its advice.4 Effects on electrolytes. See Effects on the Kidneys, below. nimesulide. No firm conclusions were made for the other
Based on data which included the MEDAL programme5 and re- NSAIDs although there was weak evidence to suggest that the
views of several important epidemiological studies6-8 the follow- Effects on the eyes. Ocular effects such as blurred vision oc-
risk of toxicity was slightly higher for indometacin and naproxen
ing points were made: cur rarely in patients taking NSAIDs. Other more serious effects
than for diclofenac and ibuprofen. As a result of this review the
• the results from the MEDAL programme suggest that di- on the eyes associated with NSAIDs also appear to be rare. In the
EMEA carried out a full benefit-risk assessment for piroxicam
clofenac (150 mg daily) has a risk of thrombotic events simi- USA the National Registry of Drug-Induced Ocular Side Effects
and subsequently placed restrictions on its systemic usage (see
lar to that of etoricoxib (60 mg or 90 mg daily); however, fur- analysed 144 reports they received of possible adverse optic
p.118).
ther issues need to be considered before this can be considered nerve reactions associated with the use of NSAIDs.1 Of the 24
cases of papilloedema with or without pseudotumor cerebri more In a systematic review24 of controlled epidemiological studies
conclusive that found a relation between NSAID use and hospital admission
than half were associated with propionic acid derivatives, but it
• based on study and epidemiological evidence, diclofenac, par- was considered that the data indicated that, on rare occasions, for gastric haemorrhage or perforation, the low risk of serious
ticularly at a high dose (150 mg daily), may be associated with most NSAIDs could cause this effect; the number of reports for gastric toxicity with ibuprofen appeared to be attributable mainly
an increased risk of thrombotic events individual drugs was: 7 for ibuprofen, 5 each for indometacin to the low doses used clinically; higher doses of ibuprofen were
• clinical study data suggest that high-dose ibuprofen (2.4 g dai- and naproxen, 3 for meclofenamate, and 1 each for diflunisal, associated with a similar risk to indometacin and naproxen. For
ly) is associated with an increased risk of thrombotic events; ketoprofen, sulindac, and tolmetin. Almost two-thirds of the 120 reference to an association between aspirin and the most severe
however, overall, epidemiological studies do not support an cases of optic or retrobulbar neuritis were also associated with gastric lesions compared with other NSAIDs, see p.21.
increased risk with low-dose ibuprofen (1.2 g daily or less) propionic acid derivatives; the number of reports for individual Results from controlled studies have confirmed that the selective
• naproxen (1 g daily) may be associated with a lower risk for drugs was: ibuprofen 43, naproxen 17, indometacin 9, benoxa- COX-2 inhibitors are associated with a lower incidence of seri-
thrombotic events than the COX-2 inhibitors, but a small risk profen 8, phenylbutazone 8, piroxicam 8, zomepirac 7, sulindac ous gastrointestinal effects, such as bleeding, perforation, and
cannot be excluded; overall, there is no evidence of a cardio- 6, fenoprofen 5, oxyphenbutazone 3, meclofenamate 2, tolmetin obstruction, than the traditional NSAIDs25 (see also Celecoxib,
protective effect 2, diflunisal 1, and ketoprofen 1. p.35 for further details). However, since the risk of such effects
• for all other non-selective NSAIDs there are insufficient data Ocular adverse effects have also been reported with the selective is inherently low in those with no history of peptic ulcer disease,
to assess the thrombotic risk and consequently an increased Cyclo-oxygenase-2 (COX-2) inhibitors.2 the general prescribing of selective COX-2 inhibitors to all pa-
risk cannot be excluded; a small increase in absolute risk There have been reports of severe corneal toxicity associated tients requiring an NSAID is questioned, particularly in the light
seems most likely when used in high doses and for long-term with the use of some topical NSAIDs, such as diclofenac and of concerns about their cardiovascular effects (see Thrombotic
treatment ketorolac, in the eye (see p.45). Events, above). In the UK, the use of selective COX-2 inhibitors
is limited to patients with good cardiovascular health and at high
It has been suggested that NSAIDs may reduce the cardioprotec- 1. Fraunfelder FT, et al. Possible optic nerve side effects associated
risk of developing serious gastrointestinal problems if given a
tive effect of aspirin, but see under Interactions of Aspirin, p.23. with nonsteroidal anti-inflammatory drugs. J Toxicol Cutan Ocul
Toxicol 1994; 13: 311–16. non-selective NSAID. High-risk patients include the elderly,
1. FDA. FDA announces series of changes to the class of marketed those already receiving gastrotoxic drugs, and those with exist-
2. Coulter DM, et al. Celecoxib, rofecoxib, and acute temporary
non-steroidal anti-inflammatory drugs (NSAIDs) (issued 7th
April, 2005). Available at: http://www.fda.gov/bbs/topics/news/
visual impairment. BMJ 2003; 327: 1214–15. ing gastrointestinal disorders.
2005/NEW01171.html (accessed 08/11/07) Effects on fertility. Reversible infertility has been reported in There has been concern that topical use of NSAIDs may also be
2. CSM. Cardiovascular safety of NSAIDs: review of evidence. women on long-term NSAIDs.1-3 Prostaglandins are considered associated with gastrointestinal toxicity but a case-controlled
Message from Professor G Duff, Chairman of CSM (issued Au- to be involved in the processes of ovulation and it is thought that study26 concluded that this route was not associated with signif-
gust 2005). Available at: http://www.mhra.gov.uk/home/ icant upper gastrointestinal bleeding or perforation.
idcplg?IdcService=GET_FILE&dDocName=con1004303& NSAIDs may compromise ovulation via inhibition of cyclo-oxy-
RevisionSelectionMethod=Latest (accessed 08/11/07) genase-2 (COX-2). Women trying to become pregnant may need Apart from the selection of an NSAID with a lower risk for gas-
3. EMEA. European Medicines Agency update on non-selective to avoid treatment with NSAIDs. trointestinal toxicity, other methods used for the prevention or
NSAIDs (issued 17th October, 2005). Available at: http:// 1. Mendonça LLF, et al. Non-steroidal anti-inflammatory drugs as treatment of NSAID-associated ulceration are discussed under
www.emea.europa.eu/pdfs/human/press/pr/29896405en.pdf (ac- a possible cause for reversible infertility. Rheumatology (Oxford) the treatment of peptic ulcer disease on p.1702.
cessed 29/08/08) 2000; 39: 880–2.
1. Kwo PY, Tremaine WJ. Nonsteroidal anti-inflammatory drug-
4. EMEA. Opinion of the Committee for Medicinal Products for 2. Norman RJ. Reproductive consequences of COX-2 inhibition. induced enteropathy: case discussion and review of the litera-
Human Use pursuant to article 5(3) of regulation (EC) no Lancet 2001; 358: 1287–8. ture. Mayo Clin Proc 1995; 70: 55–61.
726/2004, for non-selective non steroidal anti-inflammatory 3. Stone S, et al. Nonsteroidal anti-inflammatory drugs and revers- 2. Gleeson MH, et al. Non-steroidal anti-inflammatory drugs, sal-
drugs (NSAIDs) (issued 18th October, 2006). Available at: ible female infertility: is there a link? Drug Safety 2002; 25: icylates, and colitis. Lancet 1996; 347: 904–5.
http://www.emea.europa.eu/pdfs/human/opiniongen/nsaids.pdf 545–51. 3. Evans JMM, et al. Non-steroidal anti-inflammatory drugs are
(accessed 08/11/07)
Effects on the gastrointestinal tract. NSAIDs can cause associated with emergency admission to hospital for colitis due
5. Cannon CP, et al. Cardiovascular outcomes with etoricoxib and to inflammatory bowel disease. Gut 1997; 40: 619–22.
diclofenac in patients with osteoarthritis and rheumatoid arthritis clinically important damage of the gastrointestinal tract, increas- 4. Hayllar J, Bjarnason I. NSAIDs, Cox-2 inhibitors, and the gut.
in the Multinational Etoricoxib and Diclofenac Arthritis Long- ing the incidence of bleeding in the upper gastrointestinal tract Lancet 1995; 346: 521–2.
term (MEDAL) programme: a randomised comparison. Lancet and of perforation, although serious complications and death are 5. Bjorkman DJ. Nonsteroidal anti-inflammatory drug-induced
2006; 368: 1771–81. relatively infrequent. They have also been associated with dam- gastrointestinal injury. Am J Med 1996; 101 (suppl 1A):
6. Kearney PM, et al. Do selective cyclo-oxygenase-2 inhibitors 25S–32S.
and traditional non-steroidal anti-inflammatory drugs increase
age to the distal small intestine and colon.1-3
6. Soll A. Pathogenesis of nonsteroidal anti-inflammatory drug-re-
the risk of atherothrombosis? Meta-analysis of randomised tri- The complex mechanisms involved are not fully understood, al- lated upper gastrointestinal toxicity. Am J Med 1998; 105 (suppl
als. BMJ 2006; 332: 1302–8. though it is generally accepted that the inhibition of cyclo-oxy- 5A): 10S–16S.
7. Hernández-Díaz S, et al. Non-steroidal antiinflammatory drugs genase-1 (COX-1) plays a role in gastrointestinal toxicity and 7. Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. Cor-
and the risk of acute myocardial infarction. Basic Clin Pharma- that the selective COX-2 inhibitors are less gastrotoxic than the rection. ibid. 1440. [dose]
col Toxicol 2006; 98: 266–74. 8. Wolfe MM, et al. Gastrointestinal toxicity of nonsteroidal anti-
traditional NSAIDs (see below).4-8 The gastric mucosa is dam-
8. McGettigan P, Henry D. Cardiovascular risk and inhibition of inflammatory drugs. N Engl J Med 1999; 340: 1888–99.
cyclooxygenase: a systematic review of the observational studies aged both by local and systemic effects of NSAIDs.5 The local 9. Seager JM, Hawkey CJ. ABC of the upper gastrointestinal tract:
of selective and nonselective inhibitors of cyclooxygenase 2. effect is pH-dependent and varies between individual drugs. The indigestion and non-steroidal anti-inflammatory drugs. BMJ
JAMA 2006; 296: 1633–44. systemic effect is pH-independent, can occur with any route of 2001; 323: 1236–9.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
98 Analgesics Anti-inflammatory Drugs and Antipyretics
10. Mulberg AE, et al. Identification of nonsteroidal antiinflamma- the long-term use of NSAIDs and paracetamol without phenace- For further references see under individual monographs.
tory drug-induced gastroduodenal injury in children with juve- tin.19 1. Underwood TW, Frye CB. Drug-induced pancreatitis. Clin
nile rheumatoid arthritis. J Pediatr 1993; 122: 647–9. Pharm 1993; 12: 440–8.
11. Pounder RE. Helicobacter pylori and NSAIDs—the end of the 1. O’Callaghan CA, et al. Renal disease and use of topical non-
steroidal anti-inflammatory drugs. BMJ 1994; 308: 110–11. 2. Sørensen HT, et al. Newer cyclo-oxygenase-2 selective inhibi-
debate? Lancet 2002; 358: 3–4. tors, other non-steroidal anti-inflammatory drugs and the risk of
2. Kendall MJ, Horton RC. Clinical pharmacology and therapeu-
12. MacDonald TM, et al. Association of upper gastrointestinal tox- tics. Postgrad Med J 1990; 66: 166–85. acute pancreatitis. Aliment Pharmacol Ther 2006; 24: 111–16.
icity of non-steroidal anti-inflammatory drugs with continued 3. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory
exposure: cohort study. BMJ 1997; 315: 1333–7. drugs: effects on kidney function. J Clin Pharmacol 1991; 31:
Effects on the skin. The diverse cutaneous reactions to
13. Mellemkjaer L, et al. Upper gastrointestinal bleeding among us- 588–98. NSAIDs including those selective for cyclo-oxygenase-2 (COX-
ers of NSAIDs: a population-based cohort study in Denmark. Br 4. Harris K. The role of prostaglandins in the control of renal func- 2) inhibition have been reviewed.1-3
J Clin Pharmacol 2002; 53: 173–81. tion. Br J Anaesth 1992; 69; 233–5. Of 250 children attending a rheumatology clinic 34 (13.6%)
14. Kaufman DW, et al. Nonsteroidal anti-inflammatory drug use in 5. Kenny GNC. Potential renal, haematological and allergic ad-
relation to major upper gastrointestinal bleeding. Clin Pharma- were found to have 4 or more facial scars of unknown origin.4
verse effects associated with nonsteroidal anti-inflammatory
col Ther 1993; 53: 485–94. drugs. Drugs 1992; 44 (suppl 5): 31–7. This number of scars was found in 22.2% of the 116 children
15. García Rodríguez LA, Jick H. Risk of upper gastrointestinal 6. MacDonald TM. Selected side-effects: 14. non-steroidal anti- who had received naproxen and in 9.2% of the 87 who had re-
bleeding and perforation associated with individual non-steroi- inflammatory drugs and renal damage. Prescribers’ J 1994; 34: ceived other NSAIDs. Children affected were more likely to
dal anti-inflammatory drugs. Lancet 1994; 343: 769–72. 77–80. have light skin and blue or green eyes. It was not known whether
16. Langman MJS, et al. Risks of bleeding peptic ulcer associated 7. Henry D, et al. Consumption of non-steroidal anti-inflammatory this was a form of phototoxic reaction but pseudoporphyria-like
with individual non-steroidal anti-inflammatory drugs. Lancet drugs and the development of functional renal impairment in
1994; 343: 1075–8. elderly subjects: results of a case-control study. Br J Clin Phar- eruptions associated with NSAIDs, and naproxen in particular
17. Lewis SC, et al. Dose–response relationships between individ- macol 1997; 44: 85–90. (see p.93), have been reported.5,6
ual nonaspirin nonsteroidal anti-inflammatory drugs (NAN- 8. Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a Concern by the EMEA over the serious nature of skin reactions
SAIDs) and serious upper gastrointestinal bleeding: a meta- pattern of nephrotoxicity similar to traditional nonsteroidal anti- associated with piroxicam has led to restrictions on the systemic
analysis based on individual patient data. Br J Clin Pharmacol inflammatory drugs. Am J Med 2001; 111: 64–7.
2002; 54: 320–6. 9. Noroian G, Clive D. Cyclo-oxygenase-2 inhibitors and the kid- use of piroxicam in the EU (see p.118).
18. Bateman DN. NSAIDs: time to re-evaluate gut toxicity. Lancet ney: a case for caution. Drug Safety 2002; 25: 165–72. See also Hypersensitivity, below.
1994; 343: 1051–2. 10. Adverse Drug Reactions Advisory Committee (ADRAC). ACE 1. Bigby M, Stern R. Cutaneous reactions to nonsteroidal anti-in-
19. Smith CC, et al. NSAIDs and gut toxicity. Lancet 1994; 344: inhibitor, diuretic and NSAID: a dangerous combination. Aust flammatory drugs. J Am Acad Dermatol 1985; 12: 866–76.
56–7. Adverse Drug React Bull 2003; 22: 14–15. Also available at: 2. La Grenade L, et al. Comparison of reporting of Stevens-John-
http://www.tga.health.gov.au/adr/aadrb/aadr0308.htm (ac- son syndrome and toxic epidermal necrolysis in association with
20. CSM/MCA. Relative safety of oral non-aspirin NSAIDs. Cur- cessed 08/11/07)
rent Problems 1994; 20: 9–11. Also available at: http:// selective COX-2 inhibitors. Drug Safety 2005; 28: 917–24.
w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ 11. Loboz KK, Shenfield GM. Drug combinations and impaired re- 3. Layton D, et al. Serious skin reactions and selective COX-2 in-
FILE&dDocName=CON2015615&RevisionSelectionMethod= nal function – the ‘triple whammy’. Br J Clin Pharmacol 2005;
59: 239–43. hibitors: a case series from prescription-event monitoring in
LatestReleased (accessed 08/11/07) England. Drug Safety 2006; 29: 687–96.
12. Petersson I, et al. Water intoxication associated with non-steroi-
21. EMEA. Public CHMP assessment report of medicinal products dal anti-inflammatory drug therapy. Acta Med Scand 1987; 221: 4. Wallace CA, et al. Increased risk of facial scars in children tak-
containing non-selective non steroidal anti-inflammatory drugs 221–3. ing nonsteroidal antiinflammatory drugs. J Pediatr 1994; 125:
(NSAIDs) (issued 7th November, 2006). Available at: http:// 13. Cheung NT, et al. Syndrome of inappropriate secretion of anti- 819–22.
www.emea.europa.eu/pdfs/human/opiniongen/44213006en.pdf diuretic hormone induced by diclofenac. BMJ 1993; 306: 186. 5. Checketts SR, et al. Nonsteroidal anti-inflammatory-induced
(accessed 08/11/07) pseudoporphyria: is there an alternative drug? Cutis 1999; 63:
14. Ravnskov U. Glomerular, tubular and interstitial nephritis asso-
22. Laporte J-R, et al. Upper gastrointestinal bleeding associated ciated with non-steroidal antiinflammatory drugs. Evidence of a 223–5.
with the use of NSAIDs: newer versus older agents. Drug Safety common mechanism. Br J Clin Pharmacol 1999; 47: 203–10. 6. Al-Khenaizan S, et al. Pseudoporphyria induced by propionic
2004; 27: 411–20. 15. Sandler DP, et al. Nonsteroidal anti-inflammatory drugs and the acid derivatives J Cutan Med Surg 1999; 3: 162–6.
23. CSM/MCA. Non-Steroidal Anti-Inflammatory Drugs risk for chronic renal disease. Ann Intern Med 1991; 115:
(NSAIDs) and gastrointestinal (GI) safety. Current Problems Hypersensitivity. NSAIDs have produced a wide range of hy-
165–72.
2002; 28: 5. Also available at: http://www.mhra.gov.uk/home/ 16. De Broe ME, Elseviers MM. Analgesic nephropathy. N Engl J persensitivity reactions in susceptible individuals; the most com-
idcplg?IdcService=GET_FILE&dDocName=CON007454& Med 1998; 338: 446–52. mon include skin rashes, urticaria, rhinitis, angioedema, bron-
RevisionSelectionMethod=LatestReleased (accessed 08/11/07) 17. Sandler DP, et al. Analgesic use and chronic renal disease. N choconstriction, and anaphylactic shock. Hypersensitivity to
24. Henry D, et al. Variability in risk of gastrointestinal complica- Engl J Med 1989; 320: 1238–43. NSAIDs appears to occur more frequently in patients with asth-
tions with individual non-steroidal anti-inflammatory drugs: re- 18. Dubach UC, et al. An epidemiologic study of abuse of analgesic
sults of a collaborative meta-analysis. BMJ 1996; 312: 1563–6. ma or allergic disorders but other risk factors have been identi-
drugs: effects of phenacetin and salicylate on mortality and car-
25. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of diovascular morbidity (1968 to 1987). N Engl J Med 1991; 324: fied (for further details see under Aspirin, p.21). The occurrence
cyclooxygenase-2. N Engl J Med 2001; 345: 433–42. 155–60. of aspirin sensitivity in patients with asthma and nasal polyps has
26. Evans JMM, et al. Topical non-steroidal anti-inflammatory 19. Perneger TV, et al. Risk of kidney failure associated with the use been referred to as the ‘aspirin triad’. There is considerable cross-
drugs and admission to hospital for upper gastrointestinal bleed- of acetaminophen, aspirin, and nonsteroidal antiinflammatory reactivity between aspirin and other NSAIDs and it is generally
ing and perforation: a record linkage case-control study. BMJ drugs. N Engl J Med 1994; 331: 1675–9. recommended that patients who have had a hypersensitivity re-
1995; 311: 22–6.
Effects on the liver. A retrospective study involving over action to aspirin or any other NSAID should avoid all NSAIDs.
Effects on the kidneys. NSAIDs can produce renal disorders 220 000 adults who were either using, or had used, NSAIDs For references to hypersensitivity reactions associated with
on systemic or topical use,1 some of which are due to their inhi- identified a small excess risk of serious, acute non-infectious liv- NSAIDs, see under individual monographs. See also Effects on
bition of prostaglandin synthesis.2,3 In the presence of renal va- er injury; in current users there was a twofold increase in risk and the Skin (p.73) for a report suggesting that ketoprofen is more
soconstriction the vasodilator action of prostaglandins increases there was a predominance of the cholestatic type of liver injury allergenic than other topical NSAIDs.
renal blood flow and thereby helps to maintain renal function.4,5 among such patients. Nonetheless, admissions to hospital for liv- Overdosage. In general, symptoms of NSAID poisoning are
Patients whose renal function is being maintained by prostaglan- er injury had been rare.1 In a review2 of cohort and case-control mild, and usually include nausea and vomiting, headache, drow-
dins are therefore at risk from NSAIDs. Such patients include studies describing an association between NSAIDs and liver dis- siness, blurred vision, and dizziness. There have been isolated
those with impaired circulation, the elderly, those on diuretics, ease, the strongest evidence emerged for sulindac. There were case reports of more serious toxicity, including seizures, hypo-
and those with heart failure or renal vascular disease.2,4 Other also a significant number of reports of hepatotoxicity on rechal- tension, apnoea, coma, and renal failure, although usually after
risk factors for renal impairment with NSAIDs include dehydra- lenge with diclofenac. Evidence of hepatotoxicity for other ingestion of substantial quantities. Seizures are a particular prob-
tion, cirrhosis, surgery, sepsis,6 and a history of gout or hyperuri- NSAIDs was weak, although the risk appeared to be high when lem with mefenamic acid overdosage.
caemia.6,7 The half-life of an NSAID may be a more important they were used with other hepatotoxic drugs. However, the over-
determinant of the risk of developing functional renal impair- Treatment of NSAID overdosage is entirely supportive. Gastric
all incidence of liver disease with NSAIDs was very low.
ment than the ingested dose.7 Evidence of renal toxicity due to lavage and activated charcoal may be of benefit within 1 hour of
A later review has also concluded that NSAID-induced hepato- ingestion of a potentially toxic amount. Multiple doses of activat-
cyclo-oxygenase-2 (COX-2) selective inhibitors is less exten- toxicity is an uncommon event.3 Nevertheless, an increased risk
sive; however, such NSAIDS appear to have effects on renal ed charcoal may be useful in enhancing elimination of NSAIDs
of hepatotoxicity has been associated with the selective cyclo- with long half-lives such as piroxicam and sulindac. Forced diu-
function similar to those of the non-selective NSAIDs.8,9 oxygenase-2 (COX-2) inhibitor lumiracoxib which led to its sub- resis, haemodialysis, or haemoperfusion are unlikely to be of
ACE inhibitors and angiotensin receptor antagonists can also sequent withdrawal in many countries (see p.78). For similar rea- benefit for NSAID overdosage, although haemodialysis may be
produce renal impairment and combined use with NSAIDs sons, nimesulide has been withdrawn in some countries and its required if oliguric renal failure develops.
should be undertaken with great care.10,11 The Australian Ad- use is limited in others (see p.95).
verse Drug Reactions Advisory Committee10 stated in August 1. García Rodríguez LA, et al. The role of non-steroidal anti-in-
2003 that over 50% of cases of renal failure reported to the com- flammatory drugs in acute liver injury. BMJ 1992; 305: 865–8. Precautions
mittee were associated with use of NSAIDs, ACE inhibitors, or Correction. ibid.: 920. All NSAIDs are contra-indicated in patients with ac-
diuretics (alone or together); where all these were taken together 2. Manoukian AV, Carson JL. Nonsteroidal anti-inflammatory tive peptic ulceration; in addition, the non-selective
drug-induced hepatic disorders. Drug Safety 1996; 15: 64–71.
the fatality rate for reported cases of renal failure was 10%. 3. O’Connor N, et al. Hepatocellular damage from non-steroidal NSAIDs should be used with caution, if at all, in pa-
Prostaglandin inhibition may also lead to salt and water retention anti-inflammatory drugs. Q J Med 2003; 96: 787–91. tients with a history of such disorders. To reduce the
particularly when there is pre-existing hypertension or sodium Effects on the lungs. Adverse pulmonary effects such as pneu- risk of gastrointestinal effects, NSAIDs may be taken
depletion.4 NSAIDs, therefore, tend to counteract the action of monitis, alveolitis, pulmonary infiltrates, and pulmonary fibro-
diuretics and antihypertensives.2,4 There have been isolated re- with or after food or milk. Histamine H2-antagonists,
sis, often suggestive of an allergic or immune reaction, have been proton pump inhibitors such as omeprazole, or misopr-
ports of severe hyponatraemia and other symptoms resembling reported with a number of NSAIDs. For references, see under
the syndrome of inappropriate antidiuretic hormone secretion in individual monographs. ostol may be used for a similar purpose in high-risk pa-
patients taking NSAIDs.12,13 tients taking non-selective NSAIDs (see Peptic Ulcer
Potassium homoeostasis is less dependent on prostaglandins and Effects on the pancreas. A review1 of drug-induced pancrea-
titis considered that sulindac was amongst the drugs for which a Disease, p.1702). However, food, milk, and such
hyperkalaemia occurs infrequently with NSAIDs.3 It is more measures may reduce the rate and extent of drug ab-
likely to occur in patients with specific risk factors such as those definite association with pancreatitis had been established. There
receiving potassium supplements or potassium-sparing diuret- had been isolated reports of pancreatitis with ketoprofen, sorption. The UK CSM recommends that NSAIDs as-
ics.3 Indometacin appears to be the main NSAID implicated. mefenamic acid, and piroxicam but any association was consid- sociated with the lowest risk of gastrointestinal toxicity
ered to be questionable. A more recent population-based, case- (see Effects on the Gastrointestinal Tract, under Ad-
NSAIDs may cause acute interstitial nephritis, perhaps involving controlled study found a substantial variation in the risk of pan-
an allergic response,2,3,14 and it may progress to interstitial fibro- creatitis between individual NSAIDs.2 The increase in risk was verse Effects, above) should be tried first in the lowest
sis or papillary necrosis.3,15 highest for diclofenac and ketoprofen (adjusted odds ratios of 5.0 recommended dose, and not more than one oral
Analgesic abuse or prolonged excessive use can produce neph- and 4.8, respectively), with indometacin and ibuprofen showing NSAID should be used at a time; selective inhibitors of
ropathy, a condition characterised by renal papillary necrosis and smaller but nonetheless significant increases (odds ratios of 3.6 cyclo-oxygenase-2 (COX-2) should be reserved for
chronic interstitial nephritis, and, eventually, renal failure.16 and 1.5, respectively). Of the other NSAIDs studied (celecoxib,
Phenacetin, a para-aminophenol derivative, has long been recog- etodolac, naproxen, and rofecoxib), all showed a small but non-
patients at highest risk of ulcer, perforation, or bleed-
nised as being one of the main drugs responsible for analgesic significant increase in risk of pancreatitis in current NSAID ing, and after assessment of cardiovascular risk. There
nephropathy,17,18 but nephropathy has also been associated with users. is no evidence to justify the use of gastroprotective
 Nonsteroidal Anti-inflammatory Drugs 99
drugs with selective inhibitors of COX-2 to further re- carefully monitored; they should be avoided if possible in pa- Aspirin. It has been suggested that NSAIDS such as ibuprofen
duce the risk of gastrointestinal effects. tients with moderate to severe renal impairment. may reduce the cardioprotective effect of aspirin but see under
See also under individual monographs. Interactions of Aspirin, p.23.
All NSAIDs are contra-indicated in severe heart fail-
ure; furthermore selective COX-2 inhibitors should not Thyroid function tests. References1,2 to the interference with
thyroid function tests by some NSAIDs. Pharmacokinetics
be used in patients with moderate heart failure, ischae- 1. Bishnoi A, et al. Effect of commonly prescribed nonsteroidal Details of the pharmacokinetics of individual NSAIDs
mic heart disease, peripheral arterial disease, or cere- anti-inflammatory drugs on thyroid hormone measurements. Am may be found under their respective monographs.
brovascular disease. NSAIDs should be used with cau- J Med 1994; 96: 235–8.
2. Samuels MH, et al. Variable effects of nonsteroidal antiinflam- ◊ General reviews.
tion in patients with hypertension; the selective COX- matory agents on thyroid test results. J Clin Endocrinol Metab 1. Woodhouse KW, Wynne H. The pharmacokinetics of non-steroi-
2 inhibitors should also be used with caution in patients 2003; 88: 5710–16. dal anti-inflammatory drugs in the elderly. Clin Pharmacokinet
with left ventricular failure, oedema, or a history of car- Varicella. The French regulatory authorities noted in July 2004 1987; 12: 111–22.
2. Walson PD, Mortensen ME. Pharmacokinetics of common anal-
diac failure, and in patients with risk factors for devel- that after the report of 3 cases of septic shock, 1 fatal, in children gesics, anti-inflammatories and antipyretics in children. Clin
oping heart disease. treated with NSAIDs for fever and pain, pharmacovigilance Pharmacokinet 1989; 17 (suppl 1): 116–37.
studies had discovered a number of other cases of severe compli- 3. Simkin PA, et al. Articular pharmacokinetics of protein-bound
NSAIDs should be used with caution in patients with cations relating to infection of the skin lesions of chickenpox in antirheumatic agents. Clin Pharmacokinet 1993; 25: 342–50.
infections, since symptoms such as fever and inflam- NSAID-treated children.1 Although these, and a few reports in 4. Lapicque F, et al. Protein binding and stereoselectivity of nons-
the literature2,3 could not establish a causal relation, it was con- teroidal anti-inflammatory drugs. Clin Pharmacokinet 1993; 25:
mation may be masked (for the suggestion that they 115–25.
sidered prudent to avoid the use of NSAIDs in children with
should not be used in children with varicella see be- chickenpox, and licensed product information for the relevant
5. Day RO, et al. Pharmacokinetics of nonsteroidal anti-inflamma-
low). They should also be used with caution in patients tory drugs in synovial fluid. Clin Pharmacokinet 1999; 36:
drugs was to be modified appropriately.1 More recently, a nested 191–210.
with asthma or allergic disorders. NSAIDs (including case-control study4 of nearly 250 000 patients with chickenpox
topical NSAIDs) are contra-indicated in patients with a or shingles in the UK General Practice Research Database found Uses and Administration
history of hypersensitivity reactions to such drugs, in- an increased risk of severe skin and soft tissue complications as-
sociated with the use of NSAIDs, mostly in children with chick- Given as single doses or in short-term intermittent ther-
cluding those in whom attacks of asthma, angioedema, enpox. apy NSAIDs can relieve mild to moderate pain. How-
urticaria, or rhinitis have been precipitated by aspirin or 1. Agence Française de Sécurité Sanitaire des Produits de Santé. ever, it may take up to 3 weeks of use before their anti-
any other NSAID. L’utilisation d’anti-inflammatoires nonstéroïdiens (AINS), dans inflammatory effects become evident. The combined
le traitement de la fièvre et/ou de la douleur, n’est pas recom-
Other general precautions to be observed include use in mandée chez l’enfant atteint de varicelle (issued 15th July, analgesic and anti-inflammatory effects make them
patients with haemorrhagic disorders or impaired renal 2004). Available at: http://www.agmed.sante.gouv.fr/htm/10/ particularly useful for the symptomatic relief of painful
filltrpsc/lp040701.htm (accessed 08/11/07)
or hepatic function. Patients undergoing therapy with 2. Zerr DM, et al. A case-control study of necrotizing fasciitis dur- and/or inflammatory conditions including rheumatic
some NSAIDs may need to be monitored for the devel- ing primary varicella. Pediatrics 1999; 103: 783–90. disorders such as rheumatoid arthritis, osteoarthritis,
opment of blood, kidney, liver, or eye disorders. 3. Lesko SM, et al. Invasive group A streptococcal infection and and the spondyloarthropathies, and also in peri-articu-
nonsteroidal antiinflammatory drug use among children with pri-
NSAIDs should be used with caution in the elderly and mary varicella. Pediatrics 2001; 107: 1108–15. lar disorders, and soft-tissue rheumatism. Some
may need to be given in reduced doses. 4. Mikaeloff Y, et al. Nonsteroidal anti-inflammatory drug use and NSAIDs are used in the management of dental or post-
the risk of severe skin and soft tissue complications in patients
Some NSAIDs can interfere with thyroid function tests with varicella or zoster disease. Br J Clin Pharmacol 2008; 65: operative pain. Some NSAIDs, but not aspirin or other
by lowering serum-thyroid hormone concentrations. 203–9. salicylates, are also used to treat acute gouty arthritis.
Further details concerning the precautions of the indi- Generally, it is felt that there are only small differences
Interactions in anti-inflammatory activity between the various
vidual NSAIDs may be found under their respective Interactions involving NSAIDs include enhancement
monographs. NSAIDs and choice is largely empirical. Responses of
of the effects of oral anticoagulants (especially by aza-
individual patients vary widely. Thus, if a patient fails
Pregnancy. Most licensed product information recommends propazone and phenylbutazone) and increased plasma
to respond to one NSAID, another drug may be suc-
avoidance of NSAIDs during pregnancy, unless the proposed concentrations of lithium, methotrexate, and cardiac
benefit outweighs the risks, but in many cases published data on cessful. However, it has been recommended that
glycosides. The risk of nephrotoxicity may be in-
use of the drugs in pregnancy is scanty or absent, making an in- NSAIDs associated with a low risk of gastrointestinal
formed decision difficult. Use of NSAIDs during pregnancy may creased if given with ACE inhibitors, ciclosporin, tac-
toxicity should generally be preferred and the lowest
delay the onset of labour and increase its duration. rolimus, or diuretics. Effects on renal function may
effective dose used. Treatment with NSAIDs that are
Use of NSAIDs during the third trimester of pregnancy may re- lead to reduced excretion of some drugs. There may
selective inhibitors of cyclo-oxygenase-2 (COX-2),
sult in the premature closure of fetal ductus arteriosus. A recent also be an increased risk of hyperkalaemia with ACE
meta-analysis1 suggested that the short-term use of NSAIDs was
such as celecoxib, is limited in the UK to those patients
inhibitors and some diuretics, including potassium-
associated with a fifteen fold increase in the risk of premature with a history of serious gastrointestinal problems or
sparing diuretics. The antihypertensive effects of some
closure when compared to either placebo or other non-NSAIDs. considered to be at high risk of developing such prob-
There was insufficient data to predict the outcome of long-term antihypertensives including ACE inhibitors, beta
lems if given a non-selective NSAID (see Effects on
NSAID treatment in late pregnancy; however, it seemed likely blockers, and diuretics may be reduced. Convulsions
the Gastrointestinal Tract, above).
that the risk of premature closure would be even greater with may occur due to an interaction with quinolones.
such treatment. NSAIDs may increase the effects of phenytoin and sul- NSAIDs are usually given orally, with or after food,
Results from a case-control interview study2 suggested that pre- fonylurea antidiabetics. although some such as diclofenac, ketoprofen, ketoro-
natal ingestion of aspirin or other NSAIDs might be implicated lac, parecoxib, piroxicam, and tenoxicam can be given
in persistent pulmonary hypertension of the newborn. The au- Use of more than one NSAID together (including aspi-
intramuscularly; diclofenac, ketorolac, parecoxib, and
thors suggested that these drugs may be responsible for gesta- rin) should be avoided because of the increased risk of
tenoxicam can also be given intravenously. Some
tional structural or functional alterations of the pulmonary vascu- adverse effects. The risk of gastrointestinal bleeding
lature. However, the primary cause might also have been the NSAIDs are applied topically or given rectally as sup-
and ulceration associated with NSAIDs is increased
underlying disorder for which the NSAIDs or aspirin were in- positories.
gested. They were unable to pinpoint in which trimester the
when used with corticosteroids, the SSRIs, the SNRI
venlafaxine, the antiplatelets clopidogrel and ticlopi- Several NSAIDs are used in ophthalmic preparations
drugs might have their proposed action. A more recent study3 has
found that persistent pulmonary hypertension of the newborn is dine, iloprost, erlotinib, sibutramine, or, possibly, alco- for the inhibition of intra-operative miosis, control of
significantly associated with in-utero NSAID exposure, particu- hol, bisphosphonates, or pentoxifylline. There may be postoperative ocular inflammation, and prevention of
larly to aspirin, ibuprofen, and naproxen. Fetal exposure to an an increased risk of haematotoxicity if zidovudine is cystoid macular oedema.
NSAID was confirmed by meconium analysis.
used with NSAIDs. Ritonavir may increase the plasma Action. Cyclo-oxygenases play an important role in the biosyn-
The risk of miscarriage may be increased with NSAID use;4,5 thesis of prostaglandins (p.2374). Non-selective NSAIDs inhibit
however, this observation remains to be confirmed. One study4 concentrations of NSAIDs. Licensed product informa-
both cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2
also found no association between NSAID use and congenital tion for mifepristone advises of a theoretical risk that (COX-2); the idea that inhibition of COX-1 is associated with
abnormalities, low birth weight, or preterm birth. prostaglandin synthetase inhibition by NSAIDs or as- adverse gastrointestinal effects while inhibition of COX-2 is as-
1. Koren G, et al. Nonsteroidal antiinflammatory drugs during third pirin may alter the efficacy of mifepristone. There have sociated with anti-inflammatory activity, 1-6 led to the
trimester and the risk of premature closure of the ductus arterio- been occasional reports of increased adverse effects development7 of preferential or selective inhibitors of COX-2.
sus: a meta-analysis. Ann Pharmacother 2006; 40: 824–9.
when NSAIDs were given with misoprostol although Meloxicam and nimesulide are preferential inhibitors of COX-2,
2. Van Marter LJ, et al. Persistent pulmonary hypertension of the
(i.e. they have a higher selectivity for COX-2 than COX-1 but are
newborn and smoking and aspirin and nonsteroidal antiinflam- such combinations have sometimes been used to de- not exclusive COX-2 inhibitors); etodolac and nabumetone are
matory drug consumption during pregnancy. Pediatrics 1996;
97: 658–63. crease the gastrointestinal toxicity of NSAIDs. also claimed to have preference for COX-2 although there is less
3. Alano MA, et al. Analysis of nonsteroidal antiinflammatory Further details concerning the interactions of the indi- evidence for this. Drugs with a very high selectivity for COX-2
drugs in meconium and its relation to persistent pulmonary hy- are also available; celecoxib and parecoxib are two examples.
pertension of the newborn. Pediatrics 2001; 107: 519–23. vidual NSAIDs may be found under their respective
Although the selective inhibition of COX-2 may be associated
4. Nielsen GL, et al. Risk of adverse birth outcome and miscarriage monographs. with reduced gastrointestinal toxicity, adverse effects associated
in pregnant users of non-steroidal anti-inflammatory drugs: pop-
ulation based observational study and case-control study. BMJ ◊ References. with such inhibition have been noted in other body systems, see
2001; 322: 266–70. 1. Brouwers JRBJ, de Smet PAGM. Pharmacokinetic-pharmacody- Thrombotic Events under Effects on the Cardiovascular System,
5. Li D-K, et al. Exposure to non-steroidal anti-inflammatory drugs namic drug interactions with nonsteroidal anti-inflammatory and Effects on the Kidneys, above.
during pregnancy and risk of miscarriage: population based co- drugs. Clin Pharmacokinet 1994; 27: 462–85. There is evidence that NSAIDs may also have a central mecha-
hort study. BMJ 2003; 327: 368–71. nism of action that augments the peripheral mechanism.6
Antihypertensives. For reference to the relative effects of
Renal impairment. The BNF recommends that NSAIDs in NSAIDs in antagonising different types of antihypertensive Many NSAIDs possess centres of chirality within their molecu-
general should be given at the lowest effective dose in patients drugs, see Effects on the Cardiovascular System and Effects on lar structure, with different chiral forms (enantiomers) having
with mild renal impairment and that renal function should be the Kidneys under Adverse Effects, above. different degrees of pharmacological activity.8,9 For example, in-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
100 Analgesics Anti-inflammatory Drugs and Antipyretics
dometacin, its analogues, and some arylpropionic acids are chiral eration. Prophylaxis is also required if mature ectopic bone is to 4. Flach AJ, et al. Effectiveness of ketorolac tromethamine 0.5%
drugs with the S(+)-enantiomer in most cases showing the dom- be surgically excised in order to minimise the rate of recurrence. ophthalmic solution for chronic aphakic and pseudophakic cyst-
inant pharmacological activity. However, the ratio of S/R activity Low-dose radiotherapy is as effective as high-dose, and pre-op- oid macular edema. Am J Ophthalmol 1987; 103: 479–86.
5. Jampol LM, et al. Nonsteroidal anti-inflammatory drugs and cat-
varies between drugs and between animal species. NSAIDs are erative irradiation is as effective as postoperative.4 Studies sug- aract surgery. Arch Ophthalmol 1994; 112: 891–4.
generally used clinically as the racemate with only a few current- gest that NSAID prophylaxis is of similar efficacy to radiothera- 6. Sivaprasad S, et al. Non-steroidal anti-inflammatory agents for
ly being given as the (S)-enantiomer (for example, dexibuprofen py.4 NSAIDs appear to significantly reduce the incidence of cystoid macular oedema following cataract surgery: a systematic
and dexketoprofen). The chirality of a drug may have subtle ef- ectopic bone formation,2-5 possibly by inhibiting inflammation review. Br J Ophthalmol 2005; 89: 1420–2.
fects on its toxicity and interactions, and it may be more desirable and suppressing mesenchymal cell proliferation.3 While contro- 7. Sivaprasad S, et al. Non-steroidal anti-inflammatory agents for
to use a drug as its active enantiomer.9 versy exists as to duration and doses, indometacin is considered treating cystoid macular oedema following cataract surgery.
the NSAID of choice by some; naproxen, tenoxicam, and di- Available in The Cochrane Database of Systematic Reviews; Is-
1. Hayllar J, Bjarnason I. NSAIDs, Cox-2 inhibitors, and the gut.
sue 3. Chichester: John Wiley; 2004 (accessed 31/10/07).
Lancet 1995; 346: 521–2. clofenac may also be of benefit.4 Ibuprofen has been tried; how-
2. Bennett A, Tavares IA. NSAIDs, Cox-2 inhibitors, and the gut. ever, a recent study6 has found that, although it significantly re- Fever. Paracetamol, salicylates, and some other NSAIDs are the
Lancet 1995; 346: 1105. main antipyretics used to control fever (p.10). Paracetamol is
3. Vane JR. NSAIDs, Cox-2 inhibitors, and the gut. Lancet 1995;
duced the rate of ectopic bone formation, there were no clinical
346: 1105–6. benefits 6 to 12 months after surgery. Bisphosphonates that in- usually the antipyretic of choice in infants and children but ibu-
4. Jouzeau J-Y, et al. Cyclo-oxygenase isoenzymes: how recent hibit the mineralisation of the deposited bone, such as etidronate, profen is an effective alternative; alternation of the two may be
findings affect thinking about nonsteroidal anti-inflammatory have also been used but they do not prevent the formation of the better than either alone, although this is controversial. Salicylates
drugs. Drugs 1997; 53: 563–82. osteoid matrix. Also when etidronate is stopped, some minerali- are generally contra-indicated in these patients because of the
5. Richardson C, Emery P. The clinical implications of inhibition of sation can occur, resulting in delayed ectopic or rebound ossifi- possible link between their use and the development of Reye’s
the inducible form of cyclo-oxygenase. Drug Safety 1996; 15: syndrome (see under Adverse Effects of Aspirin, p.22).
249–60. cation, though it is usually less severe. Prolonged treatment may
6. Cashman JN. The mechanisms of action of NSAIDs in analgesia. be needed.2,3 A systematic review,7 however, found insufficient Gout. NSAIDs are the drugs usually used first for the treatment
Drugs 1996; 52 (suppl 5): 13–23. evidence to recommend the use of etidronate for the treatment of of acute attacks of gout (p.552). Since the drug treatment of
7. Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. Cor- acute ectopic ossification.
rection. ibid. 1440. [dose] chronic gout can lead to the mobilisation of urate crystals from
1. Shehab D, et al. Heterotopic ossification. J Nucl Med 2002; 43: established tophi to produce acute attacks, NSAIDs may also be
8. Kean WF, et al. Chirality in antirheumatic drugs. Lancet 1991; 346–53.
338: 1565–8. 2. Vanden Bossche L, Vanderstraeten G. Heterotopic ossification: a used for the prophylaxis of acute gout during the first few months
9. Hayball PJ. Chirality and nonsteroidal anti-inflammatory drugs. review. J Rehabil Med 2005; 37: 129–36. of urate-lowering therapy.
Drugs 1996; 52 (suppl 5): 47–58. 3. van Kuijk AA, et al. Neurogenic heterotopic ossification in spi-
nal cord injury. Spinal Cord 2002; 40: 313–26. Headache. An NSAID is often tried first for the symptomatic
Colic pain. Prostaglandins have been implicated in the aetiolo- treatment of various types of headache including migraine
gy of biliary colic (p.5), and some NSAIDs such as diclofenac, 4. Fijn R, et al. Prevention of heterotopic ossification after total hip
replacement with NSAIDs. Pharm World Sci 2003; 25: 138–45. (p.616) and tension-type headache (p.617). NSAIDs may also be
indometacin, and ketoprofen have been used to relieve such pain. 5. Fransen M, Neal B. Non-steroidal anti-inflammatory drugs for effective prophylactic drugs for migraine, although propranolol
Dementia. A systematic review1 of observational studies sug- preventing heterotopic bone formation after hip arthroplasty. is generally preferred. Paroxysmal hemicrania, a rare variant of
gested that the risk of developing dementia (p.362) is lower in Available in The Cochrane Database of Systematic Reviews; Is- cluster headache (p.616), responds to indometacin.
sue 3. Chichester: John Wiley; 2004 (accessed 08/11/07).
patients who are taking NSAIDs. However, a randomised trial2 6. Fransen M, et al. Safety and efficacy of routine postoperative Kidney disorders. Although NSAIDs can produce adverse ef-
found no benefit from treatment with naproxen or rofecoxib in ibuprofen for pain and disability related to ectopic bone forma- fects on the kidney (see above) they may have a role in the man-
patients with existing mild to moderate Alzheimer’s disease. An- tion after hip replacement surgery (HIPAID): randomised con-
agement of some types of glomerular kidney disease (p.1504).
other systematic review3 has suggested that the beneficial effects trolled trial. BMJ 2006; 333: 519–21.
7. Haran M, et al. Pharmacological interventions for treating acute They may be of use for the control of proteinuria due to nephrotic
of NSAIDs seen in some studies are likely to be due to biases
heterotopic ossification. Available in The Cochrane Database of syndrome except when there is overt renal failure.
such as recall introduced by the study’s design; the benefit of Systematic Reviews; Issue 4. Chichester: John Wiley; 2004 (ac-
NSAIDs in preventing dementia or cognitive impairment was cessed 08/11/07). Malignant neoplasms. An early study by the American Can-
50% in studies with prevalent (pre-existing) dementia cases, cer Society1 suggested that regular use of aspirin might reduce
which decreased to 20% in studies of incident dementia cases Eye disorders. Miosis resistant to conventional mydriatics of- the risk of developing fatal cancer of the oesophagus, stomach,
(those developing during the study period), and was absent in ten develops during ocular surgery, possibly due to release of colon, or rectum. Death rates due to other gastrointestinal can-
those which used cognitive decline as an end-point. Further stud- prostaglandins and other substances associated with trauma. cers did not appear to be affected. Some studies2-11 appear to sup-
ies are needed to determine the role of NSAIDs in dementia.4,5 NSAIDs, which are prostaglandin synthetase inhibitors, are port this reduced risk of colorectal cancer (see Prophylaxis, un-
1. Etminan M, et al. Effect of non-steroidal anti-inflammatory
therefore used prophylactically as eye drops before ocular sur- der Malignant Neoplasms of the Gastrointestinal Tract, p.666) in
drugs on risk of Alzheimer’s disease: systematic review and gery to ameliorate intra-operative miosis but there has been some regular users of aspirin or other NSAIDs, particularly in high-
meta-analysis of observational studies. BMJ 2003; 327: 128–31. doubt that the effect they produce is of clinical significance. risk patients, conclusions that were cautiously endorsed by a sys-
2. Aisen PS, et al. Effects of rofecoxib or naproxen vs placebo on Those commonly used include diclofenac, indometacin, and tematic review.12 However, other studies13,14 have found no evi-
Alzheimer disease progression: a randomized controlled trial. flurbiprofen. These drugs do not possess intrinsic mydriatic
JAMA 2003; 289: 2819–26. dence of an association between the use of aspirin or NSAIDs
properties. and the incidence of colorectal cancer, although the authors sug-
3. de Craen AJM, et al. Meta-analysis of nonsteroidal antiinflam-
matory drug use and risk of dementia. Am J Epidemiol 2005; Some NSAIDs are used topically or systemically in inflammato- gest that these results may be explained by the short treatment
161: 114–20. ry ocular disorders, including inflammation and cystoid macular period and the low dose of aspirin used. Although a subsequent
4. Launer LJ. Nonsteroidal anti-inflammatory drug use and the risk oedema following ocular surgery (see below). Topical NSAIDs review15 prepared for the US Preventive Services Task Force
for Alzheimer’s disease: dissecting the epidemiological evi- are also effective analgesics when used in the management of
dence. Drugs 2003; 63: 731–9. (USPSTF) indicated that cyclo-oxygenase-2 (COX-2) inhibitors
corneal abrasions. However, their role in the treatment of macu- and NSAIDs reduce the incidence of colonic adenomas and that
5. Townsend KP, Praticò D. Novel therapeutic opportunities for
Alzheimer’s disease: focus on nonsteroidal anti-inflammatory lar oedema associated with uveitis (p.1515) is less clear. NSAIDs NSAIDs also reduce the incidence of colorectal cancer, the USP-
drugs. FASEB J 2005; 19: 1592–1601. are also used in the treatment of scleritis (see p.1512). Diclofenac STF issued a statement16 that, because of the adverse cardiovas-
and ketorolac have also both been used in the management of cular and gastrointestinal effects associated with these agents,
Diabetes insipidus. NSAIDs such as indometacin have been
seasonal allergic conjunctivitis (see p.564). their use to prevent colorectal cancer could not be recommended
used in the treatment of diabetes insipidus; for some references,
see p.68. References. in those at average risk of colorectal cancer.
1. Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv The potential role that inhibition of COX-2 may play in the man-
Ectopic ossification. Ectopic ossification (heterotopic ossifi- Ophthalmol 1992; 36: 259–84.
cation) is a condition in which mature bone develops in non-skel- 2. Koay P. The emerging roles of topical non-steroidal anti-inflam- agement of cancer has been discussed17,18 and a recent study19
etal tissues, commonly the connective tissue of muscles. It oc- matory agents in ophthalmology. Br J Ophthalmol 1996; 80: has found that regular use of aspirin appears to reduce the risk of
curs after local trauma, for example after joint dislocation or 480–5. colorectal cancers that overexpress COX-2 but not those with
3. Schalnus R. Topical nonsteroidal anti-inflammatory therapy in weak or absent expression of COX-2.
surgery such as total hip replacement, and also after neurological ophthalmology. Ophthalmologica 2003; 217: 89–98.
damage such as severe head or spinal cord injuries.1,2 Ectopic 4. Calder LA, et al. Topical nonsteroidal anti-inflammatory drugs A large case-control study,20 using data held on the UK general
bone formation usually starts about 2 weeks after the injury, for corneal abrasions: meta-analysis of randomized trials. Acad practice research database, has examined information on NSAID
though symptoms, which include localised pain, fever, swelling, Emerg Med 2005; 12: 467–73. use and the development of common cancers. This study also
erythema, and restriction of movement, may not appear for 8 to POSTOPERATIVE INFLAMMATORY OCULAR DISORDERS. Corticos-
found that the use of NSAIDs (including aspirin) may protect
12 weeks.1,3 Neurogenic ectopic ossification may develop even teroids are used topically for the control of postoperative oc- against cancer of the oesophagus, stomach, colon, and rectum.
several years after spinal cord injury.3 A congenital form of ec- ular inflammation but caution is required as they can delay However, the study failed to show any decrease in risk of non-
topic ossification, myositis ossificans progressiva (fibrodyspla- wound healing and mask postoperative infection. They gastrointestinal cancers. More recently, 2 meta-analyses21,22
sia ossificans progressiva), also occurs but is rare. The principal should only be used for short periods as they can cause glau- have also suggested that aspirin and NSAID use reduce the risk
complications of ectopic ossification are loss of joint mobility coma in susceptible individuals. Topical NSAIDs have also of other gastrointestinal cancers such as oesophageal or stomach
and function.1,2 been tried and appear to be as effective as corticosteroids in cancer. In addition, one analysis21 considered the effect of
Ectopic ossification should be distinguished from the calcifica- controlling signs of inflammation after ocular surgery,1 but NSAID and aspirin use on non-gastrointestinal cancers: aspirin
tion of soft tissue which may occur in connective tissue disorders there has been some concern about reports of corneal toxicity use showed a chemoprotective effect in pancreatic cancer al-
or in parathyroid disorders as a result of high circulating concen- (see p.45). though this was not significant statistically; there was also a
trations of calcium and or phosphate; in these conditions calcifi- slight, but nonetheless significant, reduction in the risk of breast
Cystoid macular oedema may follow cataract or retinal detach- cancer associated with both aspirin and NSAID use. The results
cation occurs without bone formation. ment surgery due to a disturbance of the blood-retinal barrier. A for other sites, namely ovary, lung, bladder, and prostate, sug-
Surgical resection can improve joint motion1,3 in patients with number of NSAIDs,1-7 including diclofenac, flurbiprofen, in- gested no effect or possibly a slight reduced risk. The authors
ectopic ossification, but may be associated with severe compli- dometacin, and ketorolac are used topically with or without cor- considered that it was unclear if any potential benefit in non-gas-
cations and poor outcome, and ossification may recur postopera- ticosteroids to prevent or relieve cystoid macular oedema. trointestinal cancers may be offset by the known adverse effects
tively.3 Delaying surgery as long as possible until bone formation NSAIDs such as indometacin are also used systemically in its associated with the long-term use of these drugs particularly in
has decreased may lessen the likelihood of these complications,1 management. However, a recent systematic review6,7 has found those cancers with a low incidence.
although earlier surgery may prevent fibrous ankylosis and mus- insufficient evidence for the efficacy of NSAIDs (topical and
cle contracture.3 Although there is no consensus on treatment, oral) in acute or chronic cystoid macular oedema after cataract Treatment with sulindac (see Gastrointestinal Disorders, p.127)
early, regular and cautious physiotherapy is recommended to surgery although topical ketorolac may have a positive effect in has been found to reduce the number of polyps in patients with
mobilise joints;1-3 aggressive manipulation may cause further os- chronic disease. familial adenomatous polyposis, a condition which predisposes
sification. 1. Colin J. The role of NSAIDs in the management of postoperative to development of colorectal cancer. Celecoxib has similar ef-
Prophylactic measures include radiotherapy or drug therapy. ophthalmic inflammation. Drugs 2007; 67: 1291–1308. fects (see p.36) and it is now licensed for use in such patients.
While prophylaxis does not always prevent the development of 2. Italian Diclofenac Study Group. Efficacy of diclofenac eyedrops 1. Thun MJ, et al. Aspirin use and the risk of fatal cancer. Cancer
in preventing postoperative inflammation and long-term cystoid Res 1993; 53: 1322–7.
ectopic ossification, it can decrease its occurrence and severity. macular edema. J Cataract Refract Surg 1997; 23: 1183–9. 2. Rosenberg L, et al. A hypothesis: nonsteroidal anti-inflammato-
Prophylactic measures should be begun as early as possible and 3. Jampol LM. Pharmacologic therapy of aphakic and pseudopha- ry drugs reduce the incidence of large-bowel cancer. J Natl Can-
with regard to orthopaedic surgery may be started before the op- kic cystoid macular edema. Ophthalmology 1985; 92: 807–10. cer Inst 1991; 83: 355–8.
 Nonsteroidal Anti-inflammatory Drugs/Opioid Analgesics 101
3. Logan RFA, et al. Effect of aspirin and non-steroidal anti-in- above which, increasing the dose has no further therapeutic ef- Diagnosis. Naloxone (p.1455) and other opioid antagonists
flammatory drugs on colorectal adenomas: case-control study of fect. have been used to diagnose opioid dependence.
subjects participating in the Nottingham faecal occult blood
screening programme. BMJ 1993; 307: 285–9. Rheumatic disorders. NSAIDs provide symptomatic relief Treatment of opioid dependence. The treatment of opioid
4. Giovannucci E, et al. Aspirin use and the risk for colorectal can- for rheumatic disorders such as rheumatoid arthritis (p.11) and dependence has been the subject of a number of reviews and dis-
cer and adenoma in male health professionals. Ann Intern Med
1994; 121: 241–6. spondyloarthropathies (p.13), but they do not alter the course of cussions.1-10
5. Giovannucci E, et al. Aspirin and the risk of colorectal cancer the disease and additional antirheumatic drugs may need to be Planned withdrawal (detoxification) may be effected slowly or
in women. N Engl J Med 1995; 333: 609–14. given to prevent irreversible joint damage. NSAIDs may also be rapidly. The usual method in many countries is to replace the
6. Sandler RS, et al. Aspirin and nonsteroidal anti-inflammatory used as an alternative to paracetamol for osteoarthritis (p.11). drug of dependence with methadone (an opioid agonist) given as
agents and risk for colorectal adenomas. Gastroenterology Short-term use of oral NSAIDs may help to relieve pain and re-
1998; 114: 441–7. a liquid oral preparation, and then gradually withdraw the meth-
7. Smalley W, et al. Use of nonsteroidal anti-inflammatory drugs duce inflammation of soft-tissue rheumatism (p.13); topical for- adone if possible. Methadone is suitable for withdrawal therapy
and incidence of colorectal cancer: a population-based study. mulations of some NSAIDs are also used. because it can be given orally and its long half-life allows once
Arch Intern Med 1999; 159: 161–6. daily use. Oral diamorphine has been used similarly to metha-
8. Jolly K, et al. NSAIDs and gastrointestinal cancer prevention. Scleroderma. NSAIDs should be used with caution in sclero-
derma (p.1817) because of the risk of exacerbating renal and oth- done; reefers containing diamorphine have also been used in
Drugs 2002; 62: 945–56.
9. Sandler RS, et al. A randomized trial of aspirin to prevent color- er problems. some centres. Dihydrocodeine tablets have been used successful-
ectal adenomas in patients with previous colorectal cancer. N ly. The partial opioid agonist buprenorphine, given sublingually,
Engl J Med 2003; 348: 883–90. is another alternative to methadone in the treatment of opioid de-
10. Baron JA, et al. A randomized trial of aspirin to prevent color- pendence, and withdrawal symptoms may possibly resolve more
ectal adenomas. N Engl J Med 2003; 348: 891–9. quickly than with methadone.11 However, it should only be given
11. Chan AT, et al. Long-term use of aspirin and nonsteroidal anti-
inflammatory drugs and risk of colorectal cancer. JAMA 2005;
Opioid Analgesics to patients with moderate dependence; those dependent on high
294: 914–23. doses of opioids may experience withdrawal symptoms when
Analgésicos opioides u opiáceos; Analgésiques Opioïdes; Opio-
12. Asano TK, McLeod RS. Non steroidal anti-inflammatory drugs given buprenorphine. The methadone derivative levacetylmeth-
(NSAID) and aspirin for preventing colorectal adenomas and id-analgetika. adol was a more recent introduction but its proarrhythmic effects
carcinomas. Available in The Cochrane Database of Systematic Опиоидные Аналгетики have led to its use being suspended.
Reviews; Issue 1. Chichester: John Wiley; 2004 (accessed
08/11/07). Iatrogenic opioid dependence may occur in patients receiving μ-
13. Stürmer T, et al. Aspirin use and colorectal cancer: post-trial Dependence and Withdrawal agonists such as morphine, fentanyl, or pethidine for the manage-
follow-up data from the Physicians’ Health Study. Ann Intern ment of acute pain or in an intensive care setting for more than 5
Med 1998; 128: 713–20. Repeated use of opioids is associated with the develop-
to 10 days. Methadone has been used successfully to manage
14. Stürmer T, et al. Colorectal cancer after start of nonsteroidal ment of psychological and physical dependence. Al- opioid withdrawal in adult intensive care patients.12 However,
anti-inflammatory drug use. Am J Med 2006; 119: 494–502.
15. Rostom A, et al. Preventive Services Task Force. Nonsteroidal
though this is less of a problem with legitimate thera- some13 avoid using methadone to manage withdrawal in children
anti-inflammatory drugs and cyclooxygenase-2 inhibitors for peutic use, dependence may develop rapidly when because of the stigma of its associations with managing with-
primary prevention of colorectal cancer: a systematic review opioids are regularly abused for their euphoriant ef- drawal in drug addicts. In physically dependent but non-addicted
prepared for the U.S. Preventive Services Task Force. Ann In- patients, gradual weaning using the same opioid that was used
tern Med 2007; 146: 376–89. fects. Drug dependence of the opioid type is character-
16. U.S. Preventive Services Task Force. Routine aspirin or nons- therapeutically is preferred where possible, although in some
teroidal anti-inflammatory drugs for the primary prevention of
ised by an overwhelming need to keep taking the drug cases, it may be necessary to change to a different opioid because
colorectal cancer: U.S. Preventive Services Task Force recom- (or one with similar properties), by a physical require- of ease of use, duration of action, and ability to taper the dose;
mendation statement. Ann Intern Med 2007; 146: 361–4. ment for the drug in order to avoid withdrawal symp- virtually any opioid can be used.13
17. Liao Z, et al. Cyclo-oxygenase-2 and its inhibition in cancer: is
there a role? Drugs 2007; 67: 821–45. toms, and by a tendency to increase the dose owing to Other drugs used in the management of opioid withdrawal in-
18. Markowitz SD. Aspirin and colon cancer—targeting preven- the development of tolerance. clude alpha2-adrenoceptor agonists such as clonidine and opioid
tion? N Engl J Med 2007; 356: 2195–8. antagonists such as naltrexone and naloxone. Clonidine may
19. Chan AT, et al. Aspirin and the risk of colorectal cancer in rela- Abrupt withdrawal of opioids from persons physically help to suppress symptoms of opioid withdrawal, such as anxie-
tion to the expression of COX-2. N Engl J Med 2007; 356: dependent on them precipitates a withdrawal syn- ty, insomnia, and muscle aches. It appears to be more effective
2131–42.
20. Langman MJS, et al. Effect of anti-inflammatory drugs on over- drome, the severity of which depends on the individu- when used in the control of symptoms after abrupt withdrawal
all risk of common cancer: case-control study in general prac- al, the drug used, the size and frequency of the dose, than when used during gradual withdrawal of methadone. Hypo-
tice research database. BMJ 2000; 320: 1642–6. tension may limit its usefulness in some patients. The clonidine
21. González-Pérez A, et al. Effects of non-steroidal anti-inflamma- and the duration of drug use. Withdrawal symptoms analogue lofexidine may produce similar results to those ob-
tory drugs on cancer sites other than the colon and rectum: a may also follow the use of an opioid antagonist such as tained with clonidine and appears to be less sedating and hypo-
meta-analysis. BMC Cancer 2003; 3: 28. Available at: http://
www.biomedcentral.com/1471-2407/3/28 (accessed 08/11/07) naloxone or a mixed agonist and antagonist such as tensive.14
22. Wang WH, et al. Non-steroidal anti-inflammatory drug use and pentazocine in opioid-dependent persons. Neonatal ab- Naltrexone and naloxone block the euphoriant effects of opioids
the risk of gastric cancer: a systematic review and meta-analy- although their use as monotherapy in detoxification is limited by
sis. J Natl Cancer Inst 2003; 95: 1784–91. stinence syndrome may occur in the offspring of opio-
unacceptable opioid withdrawal effects. Naltrexone may be used
Menstrual disorders. Menorrhagia (p.2126) is thought to be id-dependent mothers and these infants can suffer with alpha2-adrenoceptor agonists such as clonidine or lofexi-
associated with abnormalities of prostaglandin production. withdrawal symptoms at birth. dine to ameliorate symptoms but there are insufficient data to de-
Treatment with NSAIDs such as ibuprofen, mefenamic acid, or Opioid analgesics can be classified according to the re- termine whether such combinations reduce the duration of with-
naproxen during menstruation, can reduce uterine blood loss by drawal treatment or increase the rate of transfer to maintenance
an average of 30% in women with menorrhagia. There does not ceptors at which they act (see Uses and Administra- therapy with an opioid antagonist.15 Naloxone and naltrexone are
appear to be any evidence that one NSAID is more effective than tion, below) and withdrawal syndromes are character- also being used in the relatively new technique of rapid or ultra
another. istic for a receptor type. Cross-tolerance and cross- rapid opioid detoxification,16-18 which is achieved while the pa-
NSAIDs are usually the first choice for the pain of dysmenor- dependence can be expected between opioids acting at tient is heavily sedated or under general anaesthesia and hence
rhoea (p.6). Mefenamic acid may have a theoretical advantage the same receptors. Dependence associated with mor- unaware of any unpleasant withdrawal symptoms. However, al-
over other NSAIDs in being able to inhibit both the synthesis and though detoxification may be achieved within 24 hours and has
phine and closely related μ-agonists appears to result in a high initial success rate, the technique itself is not without risks
the peripheral action of prostaglandins, but clinical studies have
not shown fenamates to be more effective, and systematic review more severe withdrawal symptoms than those associat- and it does not obviate the need for maintenance treatment (see
has suggested that ibuprofen may have the best risk/benefit ratio. ed with κ-receptor agonists. Onset and duration of below).
Migraine. See Headache, above. withdrawal symptoms also vary according to the dura- Concomitant counselling and other psychosocial services have
tion of action of the specific drug. With morphine and been shown to be important in the outcome of withdrawal thera-
Orthostatic hypotension. Fludrocortisone is usually the first
diamorphine withdrawal symptoms usually begin py.19,20 Detoxification alone does not ensure long-term absti-
drug tried in the treatment of orthostatic hypotension (p.1530) nence.
when nonpharmacological treatment has failed. NSAIDs such as within a few hours, reach a peak within 36 to 72 hours, A number of other drugs may be of use as adjuncts in the man-
flurbiprofen, ibuprofen, or indometacin may be used alone or and then gradually subside; they develop more slowly agement of withdrawal symptoms. Diphenoxylate with atropine
added to treatment if the response is inadequate. with methadone. Withdrawal symptoms include yawn- or loperamide may be used for the control of diarrhoea. Promet-
Pain. NSAIDs have a similar analgesic effect to aspirin and pa- ing, mydriasis, lachrymation, rhinorrhoea, sneezing, hazine has been used for its antiemetic and sedative actions. Beta
racetamol in single doses but, in regular full dosage, they have muscle tremor, weakness, sweating, anxiety, irritabili- blockers such as propranolol may be of use for patients with pro-
both a lasting analgesic and an anti-inflammatory effect. They nounced somatic anxiety symptoms. Benzodiazepines or clome-
ty, disturbed sleep or insomnia, restlessness, anorexia, thiazole can be given to relieve anxiety and associated insomnia
are used in the management of mild to moderate pain (see Choice
of Analgesic, p.2) and are of particular value in pain due to in- nausea, vomiting, loss of weight, diarrhoea, dehydra- but only short courses should be used in order to minimise the
flammation. NSAIDs may be of benefit for inflammatory pain in tion, leucocytosis, bone pain, abdominal and muscle risk of dependence and abuse.
infants and children (p.3), although paracetamol is generally the cramps, gooseflesh, vasomotor disturbances, and in- Long-term maintenance treatment (stabilisation treatment) with
preferred non-opioid analgesic in this age group. NSAIDs may creases in heart rate, respiratory rate, blood pressure, an opioid is sometimes used, in conjunction with psychosocial
be used in the treatment of acute low back pain (p.7) if paraceta- support, to enable the patient to acquire some form of social sta-
mol fails to provide adequate pain relief. NSAIDs may also be
and temperature. Some physiological values may not bility. Methadone is most commonly used; the use of diamor-
used as an adjunct to opioids in the management of severe pain return to normal for several months after the acute phine although feasible21,22 is controversial23 and is advocated by
such as cancer pain (p.5) and are particularly effective in bone withdrawal syndrome. only a few individual centres. Buprenorphine is another possibil-
pain of malignant origin. NSAIDs may be used for postoperative Withdrawal symptoms may be terminated by a suitable ity.24 The use of methadone for maintenance has been re-
analgesia (p.4), and are of particular value after day-case surgery viewed.25-27 Naltrexone can be effective in maintaining absti-
because of their lack of sedative effects. They are not usually dose of the original or a related opioid. Tolerance di- nence in opioid addicts after detoxification, especially after rapid
considered to be strong enough as the sole analgesic after major minishes rapidly after withdrawal so that a previously or ultra rapid detoxification. It is considered that naltrexone
surgery, but may be used with stronger analgesics and may allow tolerated dose may prove fatal. would probably be of most use in highly motivated addicts with
dosage reduction of opioids. The pain of mild sickle-cell crises good sociological and psychological support to discourage im-
(p.9) may be controlled by analgesics such as NSAIDs or less For a discussion of the treatment of opioid dependence pulsive use of opioids.1,28,29
potent opioids, for example codeine or dihydrocodeine; NSAIDs and neonatal abstinence syndrome, see below. The problems associated with the management of the pregnant
may be used with more potent opioids such as morphine for se- ◊ Review. patient with opioid dependence have been discussed.30 The aim
vere crises. should be to stabilise the patient first using methadone since
1. Van Ree JM, et al. Opioids, reward and addiction: an encounter
Dependence and tolerance are not a problem with non-opioid of biology, psychology, and medicine. Pharmacol Rev 1999; 51: acute withdrawal can result in fetal death. Drug withdrawal is
analgesics such as NSAIDs, but there is a ceiling of efficacy, 341–96. best done slowly during the second trimester. It has been suggest-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
102 Analgesics Anti-inflammatory Drugs and Antipyretics
ed that if patients present during the final trimester and cannot be AAP1 made no definite recommendations but considered that, of the use of opioids in chronic pain it was noted that, despite
detoxified, maintenance with diamorphine might be preferable when appropriate, specific drug therapy should be used for treat- worries to the contrary, respiratory depression and dependence
to the use of methadone as it might produce less severe with- ment of withdrawal symptoms. Thus for opioid withdrawal, tinc- liability are not generally a problem when appropriate doses are
drawal symptoms in the neonate.31 The management of neonatal ture of opium was the preferred drug. Others favour treatment used to treat opioid-sensitive pain. In fact the presence of opioid-
abstinence syndrome is discussed below. with oral morphine solution.2 The BNFC notes that although sensitive pain appears to protect against the respiratory depres-
1. Herridge P, Gold MS. Pharmacological adjuncts in the treatment morphine is widely used and the dose can be easily adjusted, sant effect, although it may occur if the source of opioid-sensitive
of opioid and cocaine addicts. J Psychoactive Drugs 1988; 20: methadone may provide smoother control of symptoms. pain is removed (e.g. by surgery) without adequate reduction in
233–42. opioid dosage. The adverse effects of opioid analgesics when
2. Guthrie SK. Pharmacologic interventions for the treatment of Practice varies widely and evidence for the efficacy of particular
opioid dependence and withdrawal. DICP Ann Pharmacother drugs in the management of neonatal abstinence syndrome is used in advanced cancer have also been discussed.4 Constipation
1990; 24: 721–34. scanty and difficult to compare.3,4 It has been suggested that di- was considered to be the most troublesome adverse effect; signif-
3. Wodak A. Managing illicit drug use: a practical guide. Drugs azepam may be less useful than phenobarbital or paregoric but icant respiratory depression was rarely seen with recommended
1994; 47: 446–57. regimens, since pain antagonises the central depressant effects of
4. Mattick RP, Hall W. Are detoxification programmes effective? the use of paregoric (which contains both camphor and alcohol)
Lancet 1996; 347: 97–100. has been questioned. In the UK, chlorpromazine has also been morphine.
5. Seivewright NA, Greenwood J. What is important in drug mis- widely used5 although a systematic review6 found insufficient In the context of acute postoperative pain opioid-induced respi-
use treatment? Lancet 1996; 347: 373–6. evidence to support such use. The authors6 also found that phe- ratory depression is of concern but short-term postoperative use
6. National Concensus Development Panel on Effective Medical nobarbital may reduce the severity of withdrawal symptoms in is unlikely to cause dependence (although see Treatment of Opi-
Treatment of Opiate Addiction. Effective medical treatment of
opiate addition. JAMA 1998; 280: 1936–43. those receiving an opioid; there was insufficient evidence to sup- oid Dependence, above for references to iatrogenic physical de-
7. DOH. Drug misuse and dependence: guidelines on clinical port the use of clonidine. pendence).5 It was hoped that giving opioids by the spinal route
management. London: The Stationery Office, 1999. Also avail- 1. American Academy of Pediatrics, Committee on Drugs. Neona- would result in fewer adverse effects, especially respiratory de-
able at: http://www.dh.gov.uk/prod_consum_dh/groups/ tal drug withdrawal. Pediatrics 1998; 101: 1079–88. Correction. pression. In postoperative pain relief with spinal opioids, the in-
dh_digitalassets/04.00dh/04.00en/documents/digitalasset/ ibid.; 102: 660 [dosage error].
dh_4078198.pdf (accessed 28/08/08) cidence of adverse effects is said to be low when patients are
2. Gregg JEM, et al. Maternal narcotic abuse and the newborn. properly monitored.6 However, some7 have reported pruritus,
8. O’Connor PG, Fiellin DA. Pharmacological treatment of heroin- Arch Dis Child 1988; 63: 684.
dependent patients. Ann Intern Med 2000; 133: 40–54.
3. Theis JGW, et al. Current management of the neonatal absti-
nausea and vomiting, and urinary retention to be common and
9. Gonzalez G, et al. Treatment of heroin (diamorphine) addiction: respiratory depression to occur; more seriously the appearance of
current approaches and future prospects. Drugs 2002; 62: nence syndrome: a critical analysis of the evidence. Biol Neonate
1331–43. 1997; 71: 345–56. respiratory depression could be considerably delayed. These ef-
10. Raisch DW, et al. Opioid dependence treatment, including bu- 4. Johnson K, et al. Treatment of neonatal abstinence syndrome. fects were more common with morphine, but all opioid analge-
prenorphine/naloxone. Ann Pharmacother 2002; 36: 312–21. Arch Dis Child Fetal Neonatal Ed 2003; 88: F2–F5. sics had the propensity to produce respiratory depression when
11. Gowing L, et al. Buprenorphine for the management of opioid 5. Morrison CL, Siney C. A survey of the management of neonatal given spinally.7 Delayed respiratory depression has been attribut-
withdrawal. Available in The Cochrane Database of Systematic opiate withdrawal in England and Wales. Eur J Pediatr 1996; ed to the poor lipid solubility of morphine, but does occur after
Reviews; Issue 2. Chichester: John Wiley; 2006 (accessed 155: 323–6.
26/06/08). 6. Osborn DA, et al. Sedatives for opiate withdrawal in newborn other opioids. Some have considered that despite earlier worries,
12. Böhrer H, et al. Methadone treatment of opioid withdrawal in infants. Available in The Cochrane Database of Systematic Re- potentially fatal late respiratory depression was as rare with the
intensive care patients. Lancet 1993; 341: 636–7. views; Issue 3. Chichester: John Wiley; 2005 (accessed spinal route as postoperative respiratory depression with the con-
13. Yaster M, et al. The management of opioid and benzodiazepine 26/06/08). ventional route.8,9 Disputes regarding the frequency of respirato-
dependence in infants, children, and adolescents. Pediatrics ry depression associated with even conventional use of opioid
1996; 98: 135–40.
14. Gowing L, et al. Alpha2 adrenergic agonists for the manage- Adverse Effects analgesics might be due to the methods used for measuring res-
ment of opioid withdrawal. Available in The Cochrane Database In usual doses the commonest adverse effects of opioid piratory effects.10 The incidence of ventilatory depression has
of Systematic Reviews; Issue 4. Chichester: John Wiley; 2004 been reported to be higher after intrathecal than epidural use of
(accessed 26/06/08). analgesics are nausea, vomiting, constipation, drowsi- morphine.11
15. Gowing L, et al. Opioid antagonists with minimal sedation for ness, and confusion; tolerance to these (except consti-
opioid withdrawal. Available in The Cochrane Database of Sys- 1. Duthie DJR, Nimmo WS. Adverse effects of opioid analgesic
tematic Reviews; Issue 1. Chichester: John Wiley; 2006 (ac- pation) generally develops with long-term use. Mictu- drugs. Br J Anaesth 1987; 59: 61–77.
cessed 26/06/08). 2. Schug SA, et al. Adverse effects of systemic opioid analgesics.
rition may be difficult and there may be ureteric or Drug Safety 1992; 7: 200–13.
16. Justins D. Rapid opioid detoxification under anaesthesia. Hosp
Med 1998; 59: 180. biliary spasm; the latter may be associated with altera- 3. McQuay HJ. Opioids in chronic pain. Br J Anaesth 1989; 63:
17. Cook TM, Collins PD. Rapid opioid detoxification under anaes- tions in liver enzyme values. There is also an antidiu- 213–26.
thesia. Hosp Med 1998; 59: 245–7. 4. Twycross RG, Lack SA. Oral morphine in advanced cancer. 2nd
18. Gowing L, et al. Opioid antagonists under heavy sedation or retic effect. Dry mouth, dizziness, sweating, facial ed. Beaconsfield: Beaconsfield Publishers, 1989.
anaesthesia for opioid withdrawal. Available in The Cochrane flushing, headache, vertigo, bradycardia, tachycardia, 5. Mitchell RWD, Smith G. The control of acute postoperative
Database of Systematic Reviews; Issue 2. Chichester: John Wi- pain. Br J Anaesth 1989; 63: 147–58.
ley; 2006 (accessed 26/06/08). palpitations, orthostatic hypotension, hypothermia, 6. Lutz LJ, Lamer TJ. Management of postoperative pain: review
19. McLellan AT, et al. The effects of psychosocial services in sub- restlessness, changes of mood, decreased libido or of current techniques and methods. Mayo Clin Proc 1990; 65:
stance abuse treatment. JAMA 1993; 269: 1953–9. 584–96.
20. Amato L, et al. Psychosocial and pharmacological treatments potency, hallucinations, and miosis also occur. These 7. Morgan M. The rational use of intrathecal and extradural opio-
versus pharmacological treatments for opioid detoxification. effects tend to occur more commonly in ambulant pa- ids. Br J Anaesth 1989; 63: 165–88.
Available in The Cochrane Database of Systematic Reviews; Is- 8. Anonymous. Spinal opiates revisited. Lancet 1986; i: 655–6.
sue 3. Chichester: John Wiley; 2008 (accessed 26/06/08). tients than in those at rest in bed and in those without 9. McQuay HJ. Spinal opiates. Br J Hosp Med 1987; 37: 354–5.
21. Perneger TV, et al. Randomised trial of heroin maintenance pro- severe pain. Raised intracranial pressure occurs in 10. Wheatley RG, et al. Postoperative hypoxaemia: comparison of
gramme for addicts who fail in conventional drug treatments. extradural, i.m. and patient-controlled opioid analgesia. Br J
BMJ 1998; 317: 13–18. some patients. Muscle rigidity has been reported after Anaesth 1990; 64: 267–75.
22. Rehm J, et al. Feasibility, safety, and efficacy of injectable her- high doses. The euphoric activity of opioids has led to 11. Gustafsson LL, et al. Adverse effects of extradural and intrath-
oin prescription for refractory opioid addicts: a follow-up study. ecal opiates: report of a nationwide survey in Sweden. Br J
Lancet 2001; 358: 1417–20. their abuse. For a discussion of opioid dependence, see Anaesth 1982; 54: 479–85.
23. Farrell M, Hall W. The Swiss heroin trials: testing alternative above.
approaches. BMJ 1998; 316: 639. Effects on the cardiovascular system. For reference to hist-
24. Kakko J, et al. 1-year retention and social function after bu- Larger doses of opioids produce respiratory depression amine release and cardiovascular effects following the intrave-
prenorphine-assisted relapse prevention treatment for heroin de- and hypotension, with circulatory failure and deepen- nous administration of some opioids see under Pethidine, p.114.
pendence in Sweden: a randomised, placebo-controlled trial.
Lancet 2003; 361: 662–8. ing coma. Convulsions may occur, especially in infants Effects on the endocrine system. Endogenous opioid pep-
25. Farrell M, et al. Methadone maintenance treatment in opiate de- and children. Rhabdomyolysis progressing to renal tides may have a role in the regulation of endocrine function.
pendence: a review. BMJ 1994; 309: 997–1001.
26. Ward J, et al. Role of maintenance treatment in opioid depend- failure has been reported in overdosage. Death may oc- Like endorphin and enkephalins, morphine has been found to
ence. Lancet 1999; 353: 221–6. cur from respiratory failure. Toxic doses of specific stimulate prolactin release1 and synthetic analogues of morphine
27. Bell J, Zador D. A risk-benefit analysis of methadone mainte- are reported to have similar properties; long-term intrathecal opi-
nance treatment. Drug Safety 2000; 22: 179–90. opioids vary considerably with the individual and reg- oids (morphine or hydromorphone) have been reported to pro-
28. Ginzburg HM, MacDonald MG. The role of naltrexone in the ular users may tolerate large doses. The triad of coma,
management of drug abuse. Med Toxicol 1987; 2: 83–92. duce hypogonadotrophic hypogonadism, adrenal insufficiency,
29. Gonzalez JP, Brogden RN. Naltrexone: a review of its pharma- pinpoint pupils, and respiratory depression is consid- and growth hormone deficiency, although tolerance to the effects
codynamic and pharmacokinetic properties and therapeutic effi- ered indicative of opioid overdosage; dilatation of the on prolactin develops with long-term use.2 Opioids such as mor-
cacy in the management of opioid dependence. Drugs 1988; 35: phine are also part of a large group of drugs implicated in causing
192–213. pupils occurs as hypoxia develops. Pulmonary oedema
30. Gerada C, et al. Management of the pregnant opiate user. Br J
hyperglycaemia.3
after overdosage is a common cause of fatalities among 1. Hell K, Wernze H. Drug-induced changes in prolactin secretion:
Hosp Med 1990; 43: 138–41.
31. Thomas CS, Osborn M. Inhaling heroin during pregnancy. BMJ opioid addicts. clinical implications. Med Toxicol 1988; 3: 463–98.
1988; 296: 1672. 2. Abs R, et al. Endocrine consequences of long-term intrathecal
Morphine and some other opioids have a dose-related administration of opioids. J Clin Endocrinol Metab 2000; 85:
NEONATAL ABSTINENCE SYNDROME. Infants born to opioid-de- histamine-releasing effect which may be responsible in 2215–22.
pendent mothers may suffer withdrawal, with signs including 3. O’Byrne S, Feely J. Effects of drugs on glucose tolerance in non-
CNS hyperirritability, gastrointestinal dysfunction, respirato-
part for reactions such as urticaria and pruritus as well
insulin-dependent diabetics (part II). Drugs 1990; 40: 203–19.
ry distress, yawning, sneezing, mottling, and fever. Onset of as hypotension and flushing. Contact dermatitis has
symptoms is partly dependent on the drug and varies from been reported and pain and irritation may occur on in- Treatment of Adverse Effects
shortly after birth to 2 weeks of age, although most symptoms jection. Anaphylactic reactions after intravenous injec-
appear within 72 hours. Some symptoms may persist for 3
Activated charcoal may be given orally in conscious
tion have been reported rarely. patients if a substantial overdose has been ingested
months or more.
The American Academy of Pediatrics (AAP)1 recommended ◊ The adverse effects associated with individual opioid analge- within 1 hour provided that the airway can be protected
that treatment of the neonate with abstinence syndrome should sics may reflect to some extent their activity at specific opioid (see below); it should be considered in all patients if a
be primarily supportive and considered that many infants with receptors (see Uses and Administration, below) or may result substantial amount of a modified-release preparation
signs of drug withdrawal could be managed in this way. They from a direct toxic effect.1,2 Some adverse effects of pure opioid
agonists, such as the respiratory depressant effect of morphine, has been ingested.
advised adoption of abstinence scoring methods to judge the
need for drug therapy, although such systems do not appear to are dose related, whereas agonist-antagonists such as buprenor- Intensive supportive therapy may be required to cor-
have been validated. Drugs that have been used for opioid with- phine, butorphanol, and nalbuphine exhibit a ‘ceiling effect’ as rect respiratory failure and shock. In addition, the spe-
drawal include paregoric (a USP 31 preparation containing opi- the dose increases.
cific antagonist naloxone is used for rapid reversal of
um), diluted tincture of opium, morphine, methadone, diazepam, The type and extent of adverse effects experienced in practice
chlorpromazine, phenobarbital, and clonidine. Naloxone should may depend on whether or not opioid-sensitive pain is present,
the severe respiratory depression and coma produced
not routinely be given to infants of opioid-dependent mothers be- whether the opioid analgesic is being given for the control of by excessive doses of opioid analgesics (see p.1454).
cause of the risk of seizures with abrupt opioid withdrawal. The chronic severe pain or acute pain, and the route used. In a review3 Since naloxone has a shorter duration of action than
 Opioid Analgesics 103
many opioids patients who have already responded biliary colic (p.5) or other biliary-tract disorders. Biliary-type be safe. Similar recommendations have been made for patients
should be kept under close observation for signs of re- pain after cholecystectomy has also been associated with with end-stage renal disease who are not undergoing dialysis.2
codeine2 and morphine.3 See also under the individual monographs.
lapse and repeated injections given according to the 1. Dean M. Opioids in renal failure and dialysis patients. J Pain
Morphine caused a more marked delay in gallbladder emptying
respiratory rate and depth of coma. Alternatively, in sit- than pethidine, pentazocine, or butorphanol in a study4 in healthy Symptom Manage 2004; 28: 497–504.
uations where repeated administration is required, such subjects; this was considered confirmation that morphine should 2. Murtagh FE, et al. The use of opioid analgesia in end-stage renal
disease patients managed without dialysis: recommendations for
as where a longer acting opioid is known or suspected be avoided in biliary disorders. In another study5 fentanyl and practice. J Pain Palliat Care Pharmacother 2007; 21: 5–16.
to be the cause of symptoms, a continuous intravenous sufentanil did not constrict the common bile duct like morphine;
they may be suitable for perioperative pain control in patients in Interactions
infusion of naloxone, adjusted according to response, whom spasm of the common bile duct is undesirable. The sug-
may be used. All patients should be observed for at gestion that pethidine should be preferred to morphine in patients As serious and sometimes fatal reactions have fol-
least 6 hours after the last dose of naloxone. with acute pancreatitis (p.9), because of its lesser effect on the lowed use of pethidine in patients receiving MAOIs
The use of opioid antagonists such as naloxone in per- bile duct, has been questioned.6 (including moclobemide), pethidine and related drugs
1. Helm JF, et al. Effects of morphine on the human sphincter of are contra-indicated in patients taking MAOIs or with-
sons physically dependent on opioids may induce Oddi. Gut 1988; 29: 1402–7.
withdrawal symptoms. 2. Druart-Blazy A, et al. The underestimated role of opiates in pa- in 14 days of stopping such treatment; other opioid
tients with suspected sphincter of Oddi dysfunction after chole- analgesics should be avoided or given with extreme
Activated charcoal. The National Poisons Information Serv- cystectomy. Gastroenterol Clin Biol 2005; 29: 1220–3.
ice in the UK considers the benefit of gastric decontamination in 3. Roberts-Thomson IC, et al. Sympathetic activation: a mecha- caution (for further details, see p.418). Life-threatening
the management of overdosage with opioid analgesics to be un- nism for morphine induced pain and rises in liver enzymes after reactions have also been reported when selegiline, a se-
certain. However, it is suggested that oral activated charcoal may cholecystectomy? Gut 1990; 31: 217–21. lective inhibitor of monoamine oxidase type B, has
4. Hahn M, et al. The effect of four narcotics on cholecystokinin
be considered if given within 1 hour of ingestion and the quantity octapeptide stimulated gall bladder contraction. Aliment Phar- been given with pethidine. The depressant effects of
of opioid analgesic is substantial or, for these specific drugs, ex- macol Ther 1988; 2: 129–34.
ceeds the following amount:
opioid analgesics are enhanced by other CNS depres-
5. Vieira ZEG, et al. Evaluation of fentanyl and sufentanil on the
• buprenorphine: 100 micrograms/kg (adult); diameter of the common bile duct by ultrasonography in man: a sants such as alcohol, anaesthetics, anxiolytics, hypno-
100 micrograms/kg (child) double blind, placebo controlled study. Int J Clin Pharmacol tics, tricyclic antidepressants, and antipsychotics. Cy-
Ther 1994; 32: 274–7.
• codeine: 350 mg (adult); 5 mg/kg (child) 6. Thompson DR. Narcotic analgesic effects on the sphincter of clizine may counteract the haemodynamic benefits of
• dihydrocodeine: 420 mg (adult); 3 mg/kg (child) Oddi: a review of the data and therapeutic implications in treat- opioids. Cimetidine inhibits the metabolism of some
ing pancreatitis. Am J Gastroenterol 2001; 96: 1266–72. opioids, especially pethidine.
• methadone: any amount in an opioid-naive patient or more
than the prescribed daily dose if on methadone therapeutically Children. Children under 6 months of age may be more sensi- The actions of opioids may in turn affect the activities
• tramadol: 500 mg (adult); 10 mg/kg (child) tive to opioids; neonates in particular may be more sensitive to
respiratory depression with morphine than adults. Pharmacoki- of other drugs. For instance, their gastrointestinal ef-
See also under individual monographs. fects may delay absorption as with mexiletine or may
netic differences may contribute to this increased sensitivity.
Constipation. For reference to the use of opioid antagonists, Nonetheless, neonates can be treated with opioids such as mor- be counteractive as with cisapride, metoclopramide, or
particularly naloxone, to relieve opioid-induced constipation phine (see p.90) if receiving respiratory support. domperidone. Opioid premedicants such as papavere-
without compromising analgesic control in patients receiving Older infants and children can be treated effectively with mor-
long-term therapy with opioids, see Reversal of Opioid Effects tum have been reported to reduce serum concentrations
phine or other opioid analgesics and from the age of 5 or 6
under Uses and Administration of Naloxone, p.1454. months morphine metabolism follows the course seen in adults. of ciprofloxacin.
References. For a discussion of the choice of analgesic in children see p.3. Alcohol. Rapid release or dose-dumping of hydromorphone
1. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: patho- The use of opioids for sedation and analgesia in neonates in in- from a modified-release preparation (Palladone; Purdue Freder-
physiology and potential new therapies. Drugs 2003; 63: tensive care is mentioned on p.957. ick, USA) has been associated with the ingestion of alcohol (for
649–71.
References. further details, see under Interactions of Hydromorphone, p.63).
1. Choonara IA. Pain relief. Arch Dis Child 1989; 64: 1101–2. Health Canada1 has warned that this interaction may occur with
Precautions 2. Lloyd-Thomas AR. Pain management in paediatric patients. Br all modified-release formulations of opioid analgesics. Licensed
Opioid analgesics are generally contra-indicated in J Anaesth 1990; 64: 85–104. product information for some modified-release preparations of
acute respiratory depression and obstructive airways 3. Bhatt-Mehta V. Current guidelines for the treatment of acute pain morphine sulfate also warns against such use (see Interactions of
in children. Drugs 1996; 51: 760–76. Morphine, p.88).
disease, although opioids such as morphine are used in 4. Marsh DF, et al. Opioid systems and the newborn. Br J Anaesth
1. Health Canada. Potentially fatal interaction between slow-re-
some forms of dyspnoea (see below). They are also 1997; 79: 787–95.
lease opioid painkillers and alcohol (issued 3rd August, 2005).
contra-indicated or should be used with great caution The elderly. Ageing can affect the pharmacokinetics and phar- Av ai l ab l e a t : h t t p : / / w w w. h c -s c. g c . c a / ah c- a s c / m e d i a /
macodynamics of opioids although the net effects of these advisories-avis/_2005/2005_84-eng.php (accessed 26/06/08)
in acute alcoholism, convulsive disorders, head inju-
changes on opioid analgesia in the elderly remain unclear.1 Prac- Antivirals. Interactions between opioid analgesics and HIV-
ries, and conditions in which intracranial pressure is tical recommendations include careful review of indication for protease inhibitors or reverse transcriptase inhibitors are com-
raised. They should not be given to comatose patients. opioid use both initially and at regular intervals thereafter, start- plex, and the results of the limited number of studies and reports
Opioid analgesics should be given with caution or in ing opioids cautiously at lower doses and with longer dosing in- in vivo have not always borne out predictions about the nature of
reduced doses to patients with hypothyroidism, adren- tervals, and regular consideration given to dose reduction and potential interactions.
drug substitution or discontinuation. If possible, further drugs • Substantial decreases in the area under the plasma concentra-
ocortical insufficiency, asthma or decreased respiratory should not be prescribed to manage the adverse effects of opio-
reserve, renal or hepatic impairment, prostatic hyper- tion-time curve (AUC) and in the plasma concentration have
ids. been reported for pethidine when given with ritonavir; how-
plasia, hypotension, shock, inflammatory or obstruc- 1. Wilder-Smith OHG. Opioid use in the elderly. Eur J Pain 2005; ever, plasma concentrations of the toxic metabolite norpethi-
tive bowel disorders, or myasthenia gravis. Dosage 9: 137–40.
dine are greatly increased, and licensed product information
should be reduced in elderly or debilitated patients. Hepatic impairment. The pharmacokinetics of opioids may for ritonavir counsels against such combined use. Ritonavir is
be altered in patients with hepatic dysfunction. A review1 of opi- predicted to reduce plasma concentrations of morphine. Plas-
Opioid analgesics should be given with great care to oid use in this patient group considered that opioids such as mor- ma concentrations of methadone may be reduced if given with
infants, especially neonates. Their use during labour phine and hydromorphone that are metabolised by glucuronida- HIV-protease inhibitors although the effect may not be clini-
may cause respiratory depression in the neonate. Ba- tion were relatively safe when compared with those metabolised cally significant. The NNRTIs nevirapine and efavirenz have
bies born to opioid-dependent mothers may suffer by cytochrome P450 isoenzymes; the half-lives of glucuronidat- also been reported to reduce plasma-methadone levels and
withdrawal symptoms (see Neonatal Abstinence Syn- ed opioids were found to be maintained until late disease where- withdrawal symptoms have occurred when given to patients
as the prolonged half-lives seen with opioids metabolised by receiving methadone. (For further details on the interactions
drome, above). P450 isoenzymes were not accurately predicted by disease sever- of methadone with antivirals, see p.84.) In addition, efavirenz
Therapy with opioid analgesics should be stopped ity. It was also recommended that oral immediate-release or has been reported to decrease the AUC of buprenorphine (see
gradually in patients who may have developed physi- parenteral, short-acting opioids were preferable to long-acting p.30).
preparations such as transdermal or modified-release formula- • In contrast, an increase in AUC and in elimination half-life of
cal dependence, to avoid precipitating withdrawal tions. fentanyl has been reported in subjects also receiving ritonavir
symptoms (see Dependence, above). Opioid analge- 1. Davis M. Cholestasis and endogenous opioids: liver disease and (see p.57). Licensed product information for ritonavir also
sics with some antagonist activity, such as buprenor- exogenous opioid pharmacokinetics. Clin Pharmacokinet 2007; considers that increased plasma concentrations of buprenor-
phine, butorphanol, nalbuphine, or pentazocine, may 46: 825–50.
phine (p.30), dextropropoxyphene, and tramadol, with an in-
precipitate withdrawal symptoms in physically de- Phaeochromocytoma. Morphine and some other opioids can creased likelihood of opioid toxicity, may occur if these drugs
pendent patients who have recently used pure agonists induce the release of endogenous histamine and thereby stimu- are given during ritonavir treatment. Licensed information for
late catecholamine release. Both diamorphine1 and pethidine2 meptazinol also states that increased plasma concentrations of
such as morphine. have been reported to cause hypertension when given to patients meptazinol have been noted when given with ritonavir. The
Drowsiness may affect the ability to perform skilled with phaeochromocytoma and histamine-releasing opioids NNRTI delavirdine has been reported to increase the plasma
tasks; those so affected should not drive or operate ma- should be avoided in such patients. Alfentanil, like fentanyl, does concentrations of buprenorphine (see p.30) and methadone
not release histamine and may be the opioid of choice in the (p.84).
chinery. anaesthetic management of patients with phaeochromocytoma.3
Histamine H2-antagonists. Histamine H2-antagonists may
Asthma. Opioids appear to be safe and may be used with cau- 1. Chaturvedi NC, et al. Diamorphine-induced attack of paroxys-
enhance the effects of some opioid analgesics. Cimetidine was
tion in controlled asthma; however, they should be avoided dur- mal hypertension in phaeochromocytoma. BMJ 1974; 2: 538.
2. Lawrence CA. Pethidine-induced hypertension in phaeochromo- reported to alter the clearance and volume of distribution of
ing acute exacerbations.1 pethidine1 whereas ranitidine did not.2 Morphine has been con-
cytoma. BMJ 1978; 1: 149–50.
1. Barnes PJ, Chung KF. Difficult asthma. BMJ 1989; 299: 1031–2. 3. Hull CJ. Phaeochromocytoma: diagnosis, preoperative prepara- sidered less likely to interact with cimetidine than pethidine be-
Biliary-tract disorders. It is usually recommended that opio- tion and anaesthetic management. Br J Anaesth 1986; 58: cause of differences in metabolism. In a study3 cimetidine did not
ids such as morphine should either be avoided in patients with 1453–68. affect the disposition of morphine in healthy subjects. A later
biliary disorders or that they should be given with an antispas- Renal impairment. A literature review1 concluded that co- study4 in patients undergoing major surgery suggested that pre-
modic. Morphine can cause an increase in intrabiliary pressure as deine and morphine are best avoided in patients with renal failure or postoperative intravenous cimetidine did not significantly af-
a result of effects on the sphincter of Oddi1 and may therefore be and/or on dialysis; hydromorphone may be used with caution fect outcomes such as morphine consumption and incidence of
expected to exacerbate rather than relieve pain in patients with and monitoring, and use of fentanyl and methadone appeared to adverse effects when compared with placebo. Nevertheless,
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
104 Analgesics Anti-inflammatory Drugs and Antipyretics
there have been isolated reports of possible interactions between The full agonist morphine produces maximum activa- naloxone. For a discussion of the various drugs used to achieve
morphine and H2-antagonists; apnoea, confusion, and muscle tion at the μ receptor and its effects increase with dose, and maintain conditions suitable for surgery, including the use of
twitching have been associated with cimetidine plus morphine,5 opioids in the induction and maintenance of anaesthesia, see
and confusion associated with ranitidine plus morphine.6 There whereas partial agonists and agonist-antagonists may p.1780. Opioid analgesics, most commonly fentanyl, have been
has also been a report7 of a patient receiving regular analgesia demonstrate a ‘ceiling effect’ in that above a certain used with an antipsychotic to induce a state known as neurolep-
with oral methadone and subcutaneous morphine who became level their effects do not increase proportionately with tanalgesia in which the patient is calm and indifferent to the sur-
unresponsive 6 days after starting cimetidine for prophylaxis of dose. roundings yet is responsive to commands. For a brief discussion
peptic ulcer; treatment with naloxone was required. of neuroleptanalgesia and similar anaesthetic techniques, see
1. Guay DRP, et al. Cimetidine alters pethidine disposition in man.
Other differences between opioid analgesics may re- p.1780.
Br J Clin Pharmacol 1984; 18: 907–14. late to their lipid solubility and pharmacokinetics;
POSTOPERATIVE SHIVERING. Pethidine appears to be effective in
2. Guay DRP, et al. Ranitidine does not alter pethidine disposition speed of onset and duration of action may influence the the treatment of postoperative shivering (see p.1779) but not
in man. Br J Clin Pharmacol 1985; 20: 55–9.
choice of analgesic. all opioids are necessarily effective.
3. Mojaverian P, et al. Cimetidine does not alter morphine disposi-
tion in man. Br J Clin Pharmacol 1982; 14: 809–13. Opioid analgesics were traditionally classified as weak Cough. Opioids are used to suppress cough (p.1547). Pholcod-
4. Chia Y-Y, et al. Randomized, double-blind study comparing or strong opioids; however this classification has large-
postoperative effects of treatment timing with histamine H -re- ine (p.1570) and dextromethorphan (p.1555), which lack classi-
ceptor antagonist cimetidine. Acta Anaesthesiol Scand 2005; 49: ly been replaced by the one used in the WHO three- cal analgesic activity and have fewer adverse effects, are the
865–9. step analgesic ladder (see Cancer Pain, p.5). In this sys- most commonly used opioids. Of the analgesic opioids, codeine
5. Fine A, Churchill DN. Potentially lethal interaction of cimeti- tem opioids are divided into those that are used for is the most widely used as a cough suppressant. However, these
dine and morphine. Can Med Assoc J 1981; 124: 1434, 1436. opioids are seldom sufficiently potent to be effective in severe
6. Martinez-Abad M, et al. Ranitidine-induced confusion with con- mild to moderate pain and those that are used for cough. Morphine and diamorphine are used for the relief of in-
comitant morphine. Drug Intell Clin Pharm 1988; 22: 914–15. moderate to severe pain. Examples of opioids in the tractable cough in terminal illness, although morphine is now
7. Sorkin EM, Ogawa GS. Cimetidine potentiation of narcotic ac- first group include codeine, dextropropoxyphene, and preferred. Methadone has also been used but should be avoided
tion. Drug Intell Clin Pharm 1983; 17: 60–1. as it has a long duration of action and tends to accumulate.
dihydrocodeine; such opioids are distinguished by the
existence of a ceiling effect and are often used with Cough suppressants containing codeine or similar opioids are
Uses and Administration generally not recommended for use in children, and should be
Opioid analgesics possess some of the properties of non-opioid analgesics. The principal opioid for the
avoided in those under 2 years of age.
naturally occurring or endogenous opioid peptides. treatment of moderate to severe pain is morphine. Oth-
ers include diamorphine, fentanyl, methadone, and Diarrhoea. Oral rehydration therapy, which is the treatment of
Endogenous opioid peptides are widely distributed in choice for acute diarrhoea (p.1694), prevents dehydration, but it
the CNS and are also found in other parts of the body. pethidine.
does not necessarily shorten the duration of the diarrhoea. Prep-
They appear to function as neurotransmitters, modula- In addition to the relief of pain, opioids are used in arations containing codeine, morphine, or other opioids have
tors of neurotransmission, or neurohormones. Their anaesthesia for premedication, induction, or mainte- therefore been used for their antimotility action as adjuncts in the
presence in the hypothalamus suggests a role in the nance; however, pre-operative use is generally limited management of acute diarrhoea. However, the WHO considers
that such antidiarrhoeal drug therapy is of limited value, and
regulation of endocrine function. Opioids have been to patients who require control of existing pain. In bal- should never be given to children. Furthermore opioids should
shown to stimulate the release of some pituitary hor- anced anaesthesia they are used with an anaesthetic not be used in conditions where inhibition of peristalsis should be
mones, including prolactin and growth hormone, and and a neuromuscular blocker. When used with an avoided, where abdominal distension develops, or in diarrhoeal
to inhibit the release of others, including corticotropin. antipsychotic they can produce a state of mild sedation conditions such as severe ulcerative colitis or antibiotic-associat-
with analgesia called neuroleptanalgesia. ed colitis.
Endogenous peptides include the enkephalins, endor-
phins, and dynorphins; their polypeptide precursors Some opioids are used for analgesia, sedation, and sup- Dyspnoea. Dyspnoea (a subjective feeling of abnormally
pression of respiration in the management of mechani- uncomfortable, difficult, or laboured breathing) is associated
may also be precursors for non-opioid peptides. Pro- with diseases that interfere with oxygenation of the blood. It is
enkephalin is the precursor of met- and leu-enkephalin; cally ventilated patients under intensive care (p.957). best relieved by treatment of the underlying disorder (the treat-
pro-opiomelanocortin is the precursor of beta-endor- Opioids such as codeine, hydrocodone, and hydromor- ment of dyspnoea associated with asthma and chronic obstruc-
phin, beta-lipotrophin, melanocyte-stimulating hor- phone are used for the suppression of cough; for intrac- tive pulmonary disease is discussed on p.1108 and p.1112, re-
spectively). Where this is impossible or ineffective, symptomatic
mone, and corticotropin; and prodynorphin is the pre- table cough in terminal illness morphine may be used. management is required.
cursor of dynorphins and neoendorphins. Opioids may relieve some forms of dyspnoea; mor- Oxygen may reduce dyspnoea in some patients even if dyspnoea
Pharmacologically the opioid analgesics are broadly phine and diamorphine are probably the most com- is not related to hypoxia. A flow of air directed across the face by
similar; qualitative and quantitative differences may be monly used in the UK, but dihydrocodeine, hydroco- a fan can also be effective. Despite the hazards of using benzodi-
dependent on their interaction with opioid receptors. done, and oxymorphone have also been tried. azepines in patients with any form of respiratory depression or
pulmonary insufficiency (see under Precautions of Diazepam,
There are several types of opioid receptor and they are Methadone and buprenorphine are used in the treat- p.989), drugs such as diazepam, lorazepam, or midazolam may
distributed in distinct patterns through the central and ment of opioid dependence (see above). be helpful in patients with advanced cancer who have rapid shal-
peripheral nervous systems. The three main types in low respiration, especially when this is associated with anxie-
◊ References. ty.1-3 Levomepromazine is occasionally used as an alternative.
the CNS were originally designated μ (mu), κ (kappa),
1. Cherny NI. Opioid analgesics: comparative features and pre-
and δ (delta) although they have been reclassified as scribing guidelines. Drugs 1996; 51: 713–37. Opioids may relieve some forms of dyspnoea,2,4,5 such as those
OP3, OP2, and OP1, respectively. Activities attributed 2. Upton RN, et al. Pharmacokinetic optimisation of opioid treat- due to acute left ventricular failure, pulmonary oedema, and ma-
ment in acute pain therapy. Clin Pharmacokinet 1997; 33: lignant chest disease. Guidelines6 (based on the findings of sys-
to the stimulation of these receptors have been as fol- 225–44. tematic reviews7) issued for the management of dyspnoea in pal-
lows: 3. Walsh D. Advances in opioid therapy and formulations. Support liative care recommend that opioids should be considered in
Care Cancer 2005; 13: 138–44.
• μ—analgesia (mainly at supraspinal sites), respirato- 4. Hanks GW, Reid C. Contribution to variability in response to
patients with severe and unrelieved dyspnoea. The cause of dys-
pnoea should be established since the use of opioids is generally
ry depression, miosis, reduced gastrointestinal mo- opioids. Support Care Cancer 2005; 13: 145–52.
not advised, or only with extreme caution, in patients with ob-
tility, and euphoria; μ1 (supraspinal analgesia) and μ2 Action. Some references to opioid receptors. structive airways disease whose dyspnoea may be relieved by
(respiratory depression and gastrointestinal activity) 1. Pleuvry BJ. Opioid receptors and their ligands: natural and un- other means. In the UK, morphine and diamorphine are probably
subtypes have been postulated natural. Br J Anaesth 1991; 66: 370–80. the most commonly used opioids for dyspnoea, but dihydroco-
2. Pleuvry BJ. Opioid receptors and awareness of the Greek alpha- deine, hydrocodone, and oxymorphone have also been tried. It is
• κ—analgesia (mainly in the spinal cord); less intense bet. Br J Hosp Med 1992; 48: 678–81. unclear if all opioids are equally effective.5
miosis and respiratory depression, dysphoria and 3. Atcheson R, Lambert DG. Update on opioid receptors. Br J
Nebulised morphine, hydromorphone, or fentanyl have been
Anaesth 1994; 73: 132–4.
psychotomimetic effects 4. Dhawan BN, et al. International Union of Pharmacology. XII. tried for the management of dyspnoea, and there are anecdotal
• δ—less certain in man, but probably analgesia; se- Classification of opioid receptors. Pharmacol Rev 1996; 48: reports of benefit, especially in palliative care, but evidence from
567–86. controlled studies to date does not support such use.2-4,8-11 See
lective for enkephalins 5. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J also under Morphine, p.90.
• Other receptors include σ (sigma) and ε (epsilon) re- Pain 2002; 18 (4 suppl): S3–S13.
In patients with advanced cancer and intractable dyspnoea unre-
6. Gourlay GK. Advances in opioid pharmacology. Support Care
ceptors. The psychotomimetic effects of agonist-an- Cancer 2005; 13: 153–9. sponsive to the above measures, chlorpromazine may be useful
tagonists such as pentazocine that are poorly antago- to relieve air hunger and sedate dying patients who have unre-
Administration in children. See under Precautions, above. lieved distress;1 midazolam may be used as an alternative. Pro-
nised by naloxone have been thought by some to be
Administration in the elderly. See under Precautions, above. methazine has also been used. High doses of a corticosteroid
mediated by σ receptors such as dexamethasone may help to relieve dyspnoea in patients
Opioids act at one or more of these receptors as full or Anaesthesia. Opioid analgesics have been given intravenously with airways obstruction due to a tumour by reducing oedema
as supplements during general anaesthesia with inhalational or around the tumour.
partial agonists, or as antagonists. Morphine and simi- intravenous drugs. They have also been widely used as premed-
lar opioid agonists (sometimes called μ agonists) are ication before surgery to reduce anxiety, for smooth induction of 1. Walsh D. Dyspnoea in advanced cancer. Lancet 1993; 342:
450–1.
considered to act primarily at μ and perhaps at κ and δ anaesthesia, to reduce overall anaesthetic requirements, and to
2. Davis CL. ABC of palliative care: breathlessness, cough, and
receptors. Opioid agonist-antagonists such as pentazo- provide postoperative pain relief. Such use of opioids is now rare other respiratory problems. BMJ 1997; 315: 931–4.
and is restricted to patients already in pain or to those who will
cine appear to act as κ agonists and μ antagonists experience pain before induction of anaesthesia. Very high doses
3. American Thoracic Society. Dyspnea. Mechanisms, assess-
ment, and management: a consensus statement. Am J Respir
whereas buprenorphine is a partial agonist at μ recep- of morphine have been infused intravenously to produce anaes- Crit Care Med 1999; 159: 321–40. Also available at: http://
tors with some antagonist activity at κ receptors. The thesia for cardiac surgery, but shorter acting drugs such as fenta- www.thoracic.org/sections/publications/statements/pages/
respiratory-disease-adults/dyspnea1-20.html (accessed 26/06/08)
opioid antagonist naloxone acts at μ, κ, and δ receptors. nyl and related opioids are generally used now; some may prefer
4. Jennings AL, et al. Opioids for the palliation of breathlessness
agonist-antagonist opioids. Sedation and respiratory depression in terminal illness. Available in The Cochrane Database of Sys-
In addition to differing affinities for particular recep- may be prolonged necessitating assisted ventilation; reversal of tematic Reviews; Issue 3. Chichester: John Wiley; 2001 (ac-
tors the degree of activation once bound also differs. these effects can be achieved by opioid antagonists such as cessed 26/06/08).
 Opioid Analgesics/Oxaprozin 105
5. Kvale PA, et al. American College of Chest Physicians. Lung our. It should contain not less than 10% of anhydrous morphine, pre-operative sedation and as an adjunct to anaesthesia. Papaver-
cancer: palliative care. Chest 2003; 123 (suppl): 284S–311S. not less than 2% of anhydrous codeine, and not more than 3% of etum (BP 2008) 15.4 mg contains the equivalent of about 10 mg
Also available at: http://www.chestjournal.org/cgi/reprint/123/
1_suppl/284S.pdf (accessed 26/06/08) anhydrous thebaine. Protect from light. of the major component, anhydrous morphine.
6. Qaseem A, et al. Clinical Efficacy Assessment Subcommittee of Ph. Eur. 6.2 (Opium, Prepared; Opii Pulvis Normatus). Raw opi- • In the UK, papaveretum formerly contained the hydrochlo-
the American College of Physicians. Evidence-based interven- um powdered and dried at a temperature not exceeding 70°. It is rides of morphine, codeine, noscapine, and papaverine. How-
tions to improve the palliative care of pain, dyspnea, and depres- a yellowish-brown or dark brown powder and contains 9.8 to ever, because of concern over the potential genotoxicity of
sion at the end of life: a clinical practice guideline from the
American College of Physicians. Ann Intern Med 2008; 148: 10.2% of morphine and not less than 1.0% of codeine, calculated noscapine (p.1566) UK preparations containing papaveretum
141–6. Also available at: http://www.annals.org/cgi/reprint/ with reference to the dried drug. The content may be adjusted by were reformulated to exclude the noscapine component and
148/2/141.pdf (accessed 28/08/08) adding a suitable excipient or raw opium powder. the name papaveretum was redefined in the BP 1993 to reflect
7. Lorenz KA, et al. Evidence for improving palliative care at the USP 31 (Opium). The air-dried milky exudate obtained by in- this change of formulation. It is possible that in other countries
end of life: a systematic review. Ann Intern Med 2008; 148:
147–59. cising the unripe capsules of Papaver somniferum (Papaverace- the term papaveretum is still being used to describe a mixture
8. Chandler S. Nebulized opioids to treat dyspnea. Am J Hosp Pal- ae). Externally it is pale olive-brown or olive-grey; internally it is containing noscapine.
liat Care 1999; 16: 418–22. reddish-brown. It has a very characteristic odour and a very bitter Doses. Papaveretum is generally given by subcutaneous or intra-
9. Foral PA, et al. Nebulized opioids use in COPD. Chest 2004; taste. It yields not less than 9.5% of anhydrous morphine. muscular injection in doses of 7.7 to 15.4 mg every 4 hours if
125: 691–4. USP 31 (Powdered Opium). Opium dried at a temperature not
10. Brown SJ, et al. Nebulized morphine for relief of dyspnea due necessary. The initial dose in the elderly or debilitated patients
to chronic lung disease. Ann Pharmacother 2005; 39: 1088–92. exceeding 70°, and reduced to a very fine light brown or moder- should not exceed 7.7 mg.
11. Kallet RH. The role of inhaled opioids and furosemide for the ately yellowish-brown powder that yields not less than 10% and In the treatment of pain and as an adjunct in anaesthesia, papa-
treatment of dyspnea. Respir Care 2007; 52: 900–10. not more than 10.5% of anhydrous morphine. It may contain any veretum may also be given intravenously in doses of one-quarter
Pain. Opioid analgesics are used for the relief of acute and of the permitted diluents with the exception of starch. to one-half the corresponding subcutaneous or intramuscular
chronic pain (see Choice of Analgesic, p.2). Not every type of Profile dose. For pre-operative medication papaveretum is given intra-
pain responds; neuropathic pain, for example, may not be allevi- Opium is the air-dried latex obtained by incision from the unripe muscularly or subcutaneously sometimes with hyoscine hydro-
ated by opioid therapy. For further discussion of specific pain capsules of Papaver somniferum (Papaveraceae). It contains bromide.
states and the role of opioid analgesics in their treatment see p.5 morphine, codeine, and thebaine and a variable mixture of other For details of doses in children, see below.
onwards. alkaloids including noscapine and papaverine. The exuded latex Oral preparations containing papaveretum with aspirin have
There has also been interest in the local analgesic effects of opi- is dried and manipulated to form cakes of uniform composition, been given for the management of moderate to severe pain.
oids themselves.1,2 variously shaped according to the country of origin, and known
◊ Papaveretum has been confused with papaverine (p.2191) and
The use of opioid analgesics in opioid-dependent patients receiv- in commerce as Turkish, Indian, or European opium.
in one such case1 a patient became unconscious after self-injec-
ing maintenance treatment with an opioid is the subject of much Opium has the properties of opioid analgesics (p.101). Its anal- tion of papaveretum in mistake for papaverine.
debate; however, some consider such use to be appropriate in the gesic and sedative actions are due mainly to its content of mor- 1. Robinson LQ, Stephenson TP. Self injection treatment for impo-
management of acute pain in these patients and recommenda- phine (p.89). It acts less rapidly than morphine since opium ap- tence. BMJ 1989; 299: 1568.
tions have been issued.3 pears to be more slowly absorbed; the relaxing action of the
1. Thompson DF, Pierce DR. Local analgesia with opioid drugs. papaverine and noscapine on intestinal muscle makes it more Administration in children. Papaveretum may be given to
Ann Pharmacother 1995; 29: 189–90. constipating than morphine. children in the treatment of moderate to severe pain including
2. Stein C. The control of pain in peripheral tissue by opioids. N postoperative and severe chronic pain. It is also used for pre-op-
Engl J Med 1995; 332: 1685–90. Opium is intended only as the starting material for the manufac-
erative sedation and as an adjunct to anaesthesia. Papaveretum is
3. Alford DP, et al. Acute pain management for patients receiving ture of galenical preparations and is not dispensed as such. It is
generally given by subcutaneous or intramuscular injection eve-
maintenance methadone or buprenorphine therapy. Ann Intern used as Prepared Opium (Ph. Eur. 6.2), as Powdered Opium
ry 4 hours if necessary, according to age as follows:
Med 2006; 144: 127–34. (USP 31), as Opium Tincture (BP 2008 or USP 31), or as Cam-
phorated Opium Tincture (BP 2008) or Paregoric (USP 31) in • neonates: 115 micrograms/kg
HEADACHE. Opioid analgesics such as codeine are sometimes
various oral preparations. These have included Opiate Squill • 1 to 12 months: 154 micrograms/kg
included in oral compound analgesic preparations used in the
initial treatment of migraine (see p.616) or tension-type head- Linctus (BP 2008) (Gee’s linctus) for cough. • 1 to 6 years: 1.93 to 3.85 mg
ache (see p.617), but are best avoided, especially in patients Paregoric (USP 31) has been advocated in the USA for the treat- • 6 to 12 years: 3.85 to 7.7 mg
who experience frequent attacks. ment of neonatal abstinence syndrome. Older children may be given the usual adult dose (see above).
Restless legs syndrome. Some opioids may be beneficial in Abuse. Reports of squill-associated cardiac toxicity resulting In the treatment of pain and as an adjunct to anaesthesia papaver-
the treatment of restless legs syndrome (see Sleep-associated from the abuse of opiate squill linctus (Gee’s linctus).1,2 etum may also be given intravenously in doses of one-quarter to
Movement Disorders, p.958), although evidence is scanty. 1. Thurston D, Taylor K. Gee’s linctus. Pharm J 1984; 233: 63. one-half the corresponding subcutaneous or intramuscular dose.
2. Smith W, et al. Wenckebach’s phenomenon induced by cough Preparations
Sedation. In addition to their analgesic action opioids have linctus. BMJ 1986; 292: 868.
been used for their sedative properties. Mention of this use of BP 2008: Papaveretum Injection.
Preparations Proprietary Preparations (details are given in Part 3)
opioids can be found in the discussions of anaesthesia (p.1780),
BP 2008: Camphorated Opium Tincture; Concentrated Camphorated S.Afr.: Omnopon.
endoscopy (p.956), and intensive care (p.957). Opium Tincture; Opium Tincture;
Ph. Eur.: Opium Dry Extract, Standardised; Opium Tincture, Standardised; Multi-ingredient: UK: Aspav.
Tetanus. Opioid analgesics can be used to provide analgesia
USP 31: Opium Tincture; Paregoric.
and additional sedation in patients undergoing treatment for tet-
anus (p.196 and p.1901). Opioids such as fentanyl, morphine, Proprietary Preparations (details are given in Part 3)
Braz.: Elixir Paregorico. Oxaprozin (BAN, USAN, rINN)
and sufentanil have also been given to control the sympathetic
overactivity in such patients.1-3 Multi-ingredient: Braz.: Camomila; Elixir de Marinheiro†; Denm.: Pec-
tyl; Fin.: Tannopon; Fr.: Colchimax; Lamaline; Paregorique; Hong Kong: Oksaprotsiini; Oxaprozina; Oxaprozine; Oxaprozinum; Wy-
1. Rocke DA, et al. Morphine in tetanus—the management of sym- Brown Mixture; Israel: Davilla; Doveri; Mex.: Reglosedyl†; S.Afr.: Parago- 21743. 3-(4,5-Diphenyloxazol-2-yl)propionic acid.
pathetic nervous system overactivity. S Afr Med J 1986; 70: riese-Elikser; Tandpyndruppels; Spain: Digestovital†; Tanagel; Switz.: Bro-
666–8. mocod N; Pectocalmine; USA: B & O Supprettes No. 15A; B & O Sup-
Оксапрозин
2. Moughabghab AV, et al. Management of autonomic dysfunction prettes No. 16A; Venez.: Atrobel. C 18 H 15 NO 3 = 293.3.
in severe tetanus: the use of fentanyl. Can J Anaesth 1995; 42: C AS — 21256-18-8.
955. ATC — M01AE12.
3. Bhagwanjee S, et al. Management of sympathetic overactivity in ATC Vet — QM01AE12.
tetanus with epidural bupivacaine and sufentanil: experience Hydrochlorides of Mixed Opium Alkaloids
with 11 patients. Crit Care Med 1999; 27: 1721–5.
Alkaloidosum Opii Hydrochloridum; Extractum Concentratum
Opii; Mezclas de hidrocloruros de alcaloides del opio; Omnop-
onum; Opialum; Opium Concentratum. O
Opium Гидрохлориды Смешанных Алкалоидов Опия
Gum Opium; Nyers ópium; Opijus, žaliavinis; Opio; Opium brut; O
Pharmacopoeias. Preparations of the hydrochlorides of
Opium crudum; Opium surové; Raakaoopiumi; Råopium; Raw OH
mixed opium alkaloids are included in Jpn.
Opium. N
Опиум Papaveretum (BAN)
ATC — A07DA02; N02AA02.
ATC Vet — QA07DA02; QN02AA02. A mixture of 253 parts of morphine hydrochloride, 23 parts of
papaverine hydrochloride, and 20 parts of codeine hydrochlo-
NOTE. The following terms have been used as ‘street names’ (see
ride. Pharmacopoeias. In Chin., Jpn., and US.
p.vi) or slang names for various forms of opium:
Ah-pen-yen; Aunti; Aunti Emma; Big O; Black; Black pill; Папаверетум USP 31 (Oxaprozin). A white to yellowish-white, crystalline
Black shit; Black stuff; Black tar opium; Block; Boulette; Chan- C AS — 8002-76-4. powder. Store in airtight containers at a temperature of 20° to
doo; Chandu; China; Chinese molasses; Chinese tobacco; Choc- ATC — N02AA10. 25°. Protect from light.
olate; Cruz; Dopium; Dover’s deck; Dover’s powder; Dream ATC Vet — QN02AA10. Adverse Effects, Treatment, and Precautions
gum; Dream gun; Dream stick; Dreams; Dutch courage; Easing NOTE. Do not confuse papaveretum with papaverine (p.2191). As for NSAIDs in general, p.96.
powder; Fi-do-nie; Gee; God’s medicine; Goma; Gondola;
Gong; Goric; Great tobacco; Gum; Guma; Hard stuff; Hocus; Pharmacopoeias. In Br. Diagnosis and testing. False-positive results for testing of
Hop; Hops; Incense; Indonesian bud; Joy plant; Midnight oil; BP 2008 (Papaveretum). It contains 80.0 to 88.4% of anhydrous benzodiazepines in urine have been reported in patients taking
Mira; Mud; O; O.P.; Ope; O-Rock DC; Pen yan; Pin gon; Pin morphine hydrochloride, 8.3 to 9.2% of papaverine hydrochlor- oxaprozin.1 The manufacturer2 has commented that the interac-
yen; Pox; Skee; Tar; Toxy; Toys; When-shee; Ze; Zero. ide, and 6.6 to 7.4% of anhydrous codeine hydrochloride. A tion occurs with some immunoassay tests and that thin-layer
Pharmacopoeias. In Chin., Eur. (see p.vii), and US. white or almost white crystalline powder. Soluble in water, spar- chromatography can successfully discriminate between benzodi-
Chin., Eur., and US include a monograph for prepared or pow- ingly soluble in alcohol. A 1.5% solution in water has a pH of 3.7 azepines and oxaprozin. False-positive results for a fluorescence
dered opium. Eur. also contains monographs for standardised to 4.7. Protect from light. polarisation immunoassay for phenytoin have also been reported
opium dry extract or standardised opium tincture. Jpn includes Profile in patients receiving oxaprozin.3
prepared opium and a diluted opium powder containing 1% of The opium alkaloids are the prototypical opioid analgesics 1. Pulini M. False-positive benzodiazepine urine test due to oxa-
anhydrous morphine. (p.101). Mixtures of opium alkaloids such as papaveretum have prozin. JAMA 1995; 273: 1905.
2. Raphan H, Adams MH. False-positive benzodiazepine urine test
Ph. Eur. 6.2 (Opium, Raw; Opium BP 2008). The air-dried latex the analgesic and sedative properties of morphine (p.89) and are due to oxaprozin. JAMA 1995; 273: 1905–6.
obtained by incision from the unripe capsules of Papaver somni- used in the treatment of moderate to severe pain including post- 3. Patel T, et al. Assay interaction between oxaprozin and pheny-
ferum L. It has a characteristic odour and a blackish-brown col- operative and severe chronic pain. They may also be used for toin. Ann Pharmacother 1997; 31: 254.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
106 Analgesics Anti-inflammatory Drugs and Antipyretics
Effects on the liver. Fatal fulminant hepatitis occurred1 in a 56- NOTE. Compounded preparations of oxycodone may be repre- healthy adults. It was recommended that, when giving oxyco-
year-old woman who had received 600 to 1200 mg of oxaprozin sented by the following names: done to patients with end-stage liver disease, the dosing frequen-
daily for about 6 weeks. In another patient symptomatic hepatitis • Co-oxycodAPAP (PEN)—oxycodone and paracetamol. cy should be reduced and the dose lowered.
developing during oxaprozin use resolved on stopping the drug.2 1. Tallgren M, et al. Pharmacokinetics and ventilatory effects of
1. Purdum PP, et al. Oxaprozin-induced fulminant hepatitis. Ann
The following terms have been used as ‘street names’ (see p.vi) oxycodone before and after liver transplantation. Clin Pharma-
Pharmacother 1994; 28: 1159–61. or slang names for various forms of oxycodone: col Ther 1997; 61: 655–61.
2. Kethu SR, et al. Oxaprozin-induced symptomatic hepatotoxicity. 40; 40-bar; 80; Blue; Cotton; Hillbilly heroin; Kicker; OC; Os;
Ox; Oxy; Oxy Cotton; Oxycotton; Percs; Perks; Pills; Pink Porphyria. Oxycodone is considered to be unsafe in patients
Ann Pharmacother 1999; 33: 942–4. with porphyria because it has been shown to be porphyrinogenic
spoons; Rushbo.
Interactions in animals.
For interactions associated with NSAIDs, see p.99. Oxycodone Hydrochloride (BANM, USAN, rINNM) ⊗
Pharmacokinetics 7,8-Dihydro-14-hydroxycodeinone hydrochloride; Dihydrone
Interactions
Oxaprozin is slowly but extensively absorbed from the gastroin- Hydrochloride; Hidrocloruro de oxicodona; Oksikodonihy- For interactions associated with opioid analgesics, see
testinal tract; it is 99% bound to plasma proteins, mainly albu- drokloridi; Oksikodono hidrochloridas; Oxikodonhydroklorid; p.103.
min. Peak plasma concentrations are reached after about 2 to 3
Oxycodone, chlorhydrate d’; Oxycodoni hydrochloridum; Oxy- Antidepressants. For reference to possible cases of serotonin
hours. At steady state, the biological half-life is about 44 hours.
Oxaprozin is metabolised mainly in the liver by microsomal ox- cone Hydrochloride; Oxykodon-hydrochlorid; Thecodine. syndrome associated with use of oxycodone and SSRIs, see Opi-
idation and conjugation with glucuronic acid to form inactive Оксикодона Гидрохлорид oid Analgesics under Interactions of Fluoxetine, p.397.
metabolites which are excreted in the urine (65%) and faeces C 18 H 21NO 4 ,HCl = 351.8.
(35%). C AS — 124-90-3. Pharmacokinetics
ATC — N02AA05. Oxycodone is absorbed from the gastrointestinal tract;
◊ References. ATC Vet — QN02AA05.
1. Karim A. Inverse nonlinear pharmacokinetics of total and pro- oral bioavailability is about 60 to 87% due to lower
Pharmacopoeias. In Eur. (see p.vii) and US. Jpn includes the
tein unbound drug (oxaprozin): clinical and pharmacokinetic im-
trihydrate.
pre-systemic and/or first-pass metabolism compared
plications. J Clin Pharmacol 1996; 36: 985–97.
2. Karim A, et al. Oxaprozin and piroxicam, nonsteroidal antiin- Ph. Eur. 6.2 (Oxycodone Hydrochloride). A white or almost with other opioids. About 45% is bound to plasma pro-
flammatory drugs with long half-lives: effect of protein-binding white, hygroscopic, powder. Freely soluble in water; sparingly teins. It is metabolised to noroxycodone, via cyto-
differences on steady-state pharmacokinetics. J Clin Pharmacol soluble in dehydrated alcohol; practically insoluble in toluene. chrome P450 isoenzymes of the CYP3A family, and,
1997; 37: 267–78. Store in airtight containers. Protect from light.
3. Davies NM. Clinical pharmacokinetics of oxaprozin. Clin Phar- to a lesser extent, to oxymorphone (p.107) via
USP 31 (Oxycodone Hydrochloride). A white to off-white,
macokinet 1998; 35: 425–36.
odourless, hygroscopic crystals or powder. Soluble in water;
CYP2D6. Both metabolites undergo glucuronidation
Uses and Administration slightly soluble in alcohol. Store in airtight containers. and are excreted with unchanged drug in urine. The
Oxaprozin, a propionic acid derivative, is an NSAID (p.99). It is elimination half-life of oxycodone is reported to be 2 to
used in the treatment of osteoarthritis and rheumatoid arthritis in Oxycodone Terephthalate ⊗ 4 hours. Oxycodone crosses the placenta and is distrib-
a usual oral dose of 1.2 g given once daily, although in osteoar-
thritis, patients with low body-weight or mild disease should be Oxicodona, tereftalato de. 4,5α-Epoxy-14-hydroxy-3-methoxy- uted into breast milk.
given an initial dose of 600 mg once daily. The recommended 17-methylmorphinan-6-one 1,4-benzenedicarboxylate (2:1) salt. ◊ References.
maximum daily dose is 1.8 g or 26 mg/kg, whichever is the low- Оксикодона Терефталат 1. Pöyhiä R, et al. The pharmacokinetics of oxycodone after intra-
er. (C 18 H 21 NO 4 ) 2 ,C 8 H 6 O 4 = 796.9. venous injection in adults. Br J Clin Pharmacol 1991; 32:
For doses in patients with renal impairment and in children see C AS — 64336-55-6. 516–18.
2. Leow KP, et al. Single-dose and steady-state pharmacokinetics
below. Pharmacopoeias. In US. and pharmacodynamics of oxycodone in patients with cancer.
◊ References. USP 31 (Oxycodone Terephthalate). Store in airtight contain- Clin Pharmacol Ther 1992; 52: 487–95.
ers. 3. Mandema JW, et al. Characterization and validation of a pharma-
1. Miller LG. Oxaprozin: a once-daily nonsteroidal anti-inflamma- cokinetic model for controlled-release oxycodone. Br J Clin
tory drug. Clin Pharm 1992; 11: 591–603. Pharmacol 1996; 42: 747–56.
2. Anonymous. Oxaprozin for arthritis. Med Lett Drugs Ther 1993; Dependence and Withdrawal 4. Kaiko RF, et al. Pharmacokinetic-pharmacodynamic relation-
35: 15–16. As for Opioid Analgesics in general, p.101. ships of controlled-release oxycodone. Clin Pharmacol Ther
3. Dallegri F, et al. A review of the emerging profile of the anti- 1996; 59: 52–61.
inflammatory drug oxaprozin. Expert Opin Pharmacother 2005; Oxycodone has been subject to abuse (see under Ad- 5. Gammaitoni AR, Davis MW. Comparison of the pharmacokinet-
6: 777–85. verse Effects, Treatment, and Precautions, below). ics of oxycodone administered in three Percocet formulations.
J Clin Pharmacol 2002; 42: 192–7.
Administration in children. Oxaprozin is given orally in the ◊ Takotsubo-like cardiomyopathy developed in a 61-year-old 6. Lalovic B, et al. Pharmacokinetics and pharmacodynamics of
treatment of juvenile idiopathic arthritis (p.10) in children aged 6 woman when her dose of oxycodone was inadvertently and oral oxycodone in healthy human subjects: role of circulating ac-
years and over. Doses are expressed in terms of body-weight and greatly reduced 7 days after surgery for degenerative osteoarthri- tive metabolites. Clin Pharmacol Ther 2006; 79: 461–79.
may be given once daily: tis.1 The patient had a chronic history of opioid dependence and Children. The pharmacokinetics of oxycodone in children have
• 22 to 31 kg: 600 mg had been treated with oxycodone (80 mg daily) and hydromor- been studied1-4 and are generally considered similar to those in
• 32 to 54 kg: 900 mg phone (4 mg every 3 hours as needed) for several months before adults.2,4 However, pharmacokinetics may be more variable in
• 55 kg and over: 1200 mg surgery; postoperatively, her dose of oxycodone had been in- infants aged from 0 to 6 months, particularly those aged 2
creased to 120 mg daily with additional doses for breakthrough months and under.5
Administration in renal impairment. US licensed product pain. 1. Olkkola KT, et al. Pharmacokinetics and ventilatory effects of
information for oxaprozin recommends that the initial oral dose 1. Rivera JM, et al. "Broken heart syndrome" after separation (from intravenous oxycodone in postoperative children. Br J Clin
in patients with severe renal impairment or on dialysis is 600 mg OxyContin). Mayo Clin Proc 2006; 81: 825–8. Pharmacol 1994; 38: 71–6.
once daily. The dose may be increased to 1.2 g once daily, if nec- 2. Kokki H, et al. Pharmacokinetics of oxycodone after intrave-
essary. Adverse Effects, Treatment, and Precau- nous, buccal, intramuscular and gastric administration in chil-
dren. Clin Pharmacokinet 2004; 43: 613–22.
Preparations tions 3. El-Tahtawy A, et al. Population pharmacokinetics of oxycodone
USP 31: Oxaprozin Tablets. As for Opioid Analgesics in general, p.102. in children 6 months to 7 years old. J Clin Pharmacol 2006; 46:
433–42.
Proprietary Preparations (details are given in Part 3) UK licensed product information contra-indicates the 4. Kokki H, et al. Comparison of oxycodone pharmacokinetics af-
Austria: Zakoprosin; Belg.: Duraprox; Canad.: Daypro; Chile: Duraprox; ter buccal and sublingual administration in children. Clin Phar-
Walix; Cz.: Dayrun; Ger.: Danoprox†; Dayrun†; Gr.: Duraprox; Misaf; Ni- use of oxycodone in patients with moderate to severe
macokinet 2006; 45: 745–54.
said; Oxapron; Trimelot; Ital.: Walix; Jpn: Alvo; S.Afr.: Deflam; USA: Day- hepatic impairment or severe renal impairment; how- 5. Pokela ML, et al. Marked variation in oxycodone pharmacoki-
pro.
ever, product information in the USA permits its cau- netics in infants. Paediatr Anaesth 2005; 15: 560–565.
tious use in patients with severe hepatic or severe renal
impairment although doses may need to be reduced. Uses and Administration
Oxycodone (BAN, USAN, rINN) ⊗ Abuse. Oxycodone hydrochloride modified-release tablets
Oxycodone, a phenanthrene derivative, is an opioid
have been subject to abuse.1-3 The crushed tablets have been in-
analgesic (p.104). Oxycodone hydrochloride is given
Dihydrone; 14-Hydroxydihydrocodeinone; NSC-19043; Ok- orally or by subcutaneous or intravenous injection for
sikodoni; Oxicodona; Oxikodon; Oxycodonum. 6-Deoxy-7,8-di- haled or injected by addicts and in some cases this has resulted in
hydro-14-hydroxy-3-O-methyl-6-oxomorphine; (−)-(5R,6S,14S)- fatalities. the relief of moderate to severe pain.
1. Wolf BC, et al. One hundred seventy two deaths involving the A usual oral starting dose for opioid-naive patients in
4,5-Epoxy-14-hydroxy-3-methoxy-9a-methylmorphinan-6-one. use of oxycodone in Palm Beach County. J Forensic Sci 2005;
Оксикодон 50: 192–5. severe pain is 5 mg every 4 to 6 hours increased there-
C 18 H 21 NO 4 = 315.4. 2. Cicero TJ, et al. Trends in abuse of OxyContin and other opioid after as necessary according to response. For patients
analgesics in the United States: 2002-2004. J Pain 2005; 6:
C AS — 76-42-6. 662–72. who have been receiving a strong opioid analgesic the
ATC — N02AA05. 3. Adlaf EM, et al. Use of OxyContin by adolescent students. Can initial dose of oxycodone should be based on the daily
Med Assoc J 2006; 174: 1303.
ATC Vet — QN02AA05. opioid requirement; UK licensed product information
Effects on the respiratory system. References1,2 to respira- suggests that 10 mg of oral oxycodone is equivalent to
tory depression occurring in children given oxycodone.
about 20 mg of oral morphine. Most patients do not re-
H3CO 1. Olkkola KT, et al. Pharmacokinetics and ventilatory effects of
intravenous oxycodone in postoperative children. Br J Clin quire more than 400 mg daily. Preparations containing
Pharmacol 1994; 38: 71–6. oxycodone hydrochloride and aspirin, ibuprofen, or
2. Kalso E. Pharmacokinetics and ventilatory effects of intravenous
oxycodone in postoperative children. Br J Clin Pharmacol 1995; paracetamol are also used. Oxycodone hydrochloride
O OH 39: 214. may also be given orally as a modified-release prepa-
NCH3 Hepatic impairment. The clearance and elimination of oxy- ration every 12 hours.
codone were prolonged in 6 women with end-stage liver cirrho- For details of doses in children, see below.
sis awaiting liver transplantations.1 Significant ventilatory de-
O pression also occurred. Pharmacokinetic values after successful Intravenous doses of oxycodone hydrochloride range
transplantation were similar to those previously reported for from 1 to 10 mg, given over 1 to 2 minutes, and repeat-
 Oxycodone/Oxyphenbutazone 107
ed not more often than every 4 hours; a dose of Endocodone†; ETH-Oxydose; Oxycontin; Oxyfast; OxyIR; Percolone†; based on the daily opioid requirement; licensed product informa-
Roxicodone; Venez.: Oxycontin. tion suggests that 10 mg of oral oxymorphone is equivalent to
2 mg/hour is the recommended starting dose as an in-
Multi-ingredient: Arg.: Oxinovag Complex; Canad.: Endocet; Endo- about 30 mg of oral morphine and recommends giving half the
travenous infusion. The intravenous route may also be dan; Percocet; Percodan; ratio-Oxycocet; ratio-Oxycodan; Israel: Percocet; calculated equivalent dose of oxymorphone initially. Oxymor-
used for patient-controlled analgesia. When given sub- Percodan; Ital.: Depalgos; USA: Combunox; Endocet; Magnacet; Narvox; phone hydrochloride may also be given orally as a modified-
Percocet; Percodan; Perloxx; Roxicet; Roxilox; Roxiprin†; Tylox.
cutaneously, the starting dose is 5 mg every 4 hours; release preparation every 12 hours. Oral preparations of oxymor-
subcutaneous infusions should be started at 7.5 mg dai- phone should be taken on an empty stomach.
ly in opioid-naive patients. When transferring between Oxymorphone hydrochloride is given by intramuscular or sub-
oral and parenteral oxycodone, UK licensed product Oxymorphone Hydrochloride (BANM, rINNM) ⊗ cutaneous injection in initial doses of 1 to 1.5 mg, repeated every
7,8-Dihydro-14-hydroxymorphinone hydrochloride; Hidro- 4 to 6 hours as necessary; 500 micrograms may be given by in-
information advises that, as a guide, 2 mg of oral oxy- travenous injection. The usual dose for analgesia during labour is
codone is equivalent to about 1 mg of parenteral oxy- cloruro de oximorfona; Oximorphone Hydrochloride; Oxymor-
0.5 to 1 mg intramuscularly. When transferring between oral and
codone. phone, Chlorhydrate d’; Oxymorphoni Hydrochloridum. 6-De- parenteral oxymorphone, licensed product information advises
oxy-7,8-dihydro-14-hydroxy-6-oxomorphine hydrochloride; (− that, as a guide, 10 mg of oral oxymorphone is equivalent to
Oxycodone has been given rectally as suppositories )-(5R,6S,14S)-4,5-Epoxy-3,14-dihydroxy-9a-methylmorphinan-6- about 1 mg of parenteral oxymorphone.
containing 30 mg of oxycodone (as the pectinate) or 10 one hydrochloride. Oxymorphone hydrochloride is also given rectally as a supposi-
or 20 mg of oxycodone hydrochloride; the dose may Оксиморфона Гидрохлорид tory in a dose of 5 mg every 4 to 6 hours.
be repeated every 6 to 8 hours. C 17 H 19 NO 4 ,HCl = 337.8. ◊ References.
C AS — 76-41-5 (oxymorphone); 357-07-3 (oxymorphone 1. Prommer E. Oxymorphone: a review. Support Care Cancer
For doses in patients with hepatic or renal impairment, hydrochloride). 2006; 14: 109–15.
see below. 2. Chamberlin KW, et al. Oral oxymorphone for pain management.
Ann Pharmacother 2007; 41: 1144–52.
Oxycodone terephthalate is also used orally. HO
Administration in hepatic impairment. Advice on the use
Administration in children. Although oxycodone hydro- of oxymorphone in patients with hepatic impairment is conflict-
chloride is not licensed in the UK for use in children under 18 ing. Licensed product information for one range of preparations
years old, the BNFC suggests that it may be given for the treat- (Opana and Opana ER tablets; Endo, USA) recommends cau-
ment of moderate to severe pain in palliative care. Those aged O OH tion in patients with mild hepatic impairment; these patients
from 1 month to 12 years may be given initial oral doses of NCH3 should be started on the lowest oral dose and titrated slowly
200 micrograms/kg (up to 5 mg) every 4 to 6 hours increased thereafter. In addition, it is stated that oxymorphone is contra-
thereafter as necessary according to response; older children may indicated in those with moderate or severe impairment. Howev-
be given the usual adult dose (see above). Oxycodone hydrochlor- O er, licensed information for another oxymorphone preparation
ide may also be given orally as a modified-release preparation (Numorphan injection and suppositories; Endo, USA) only rec-
every 12 hours to those aged 8 years and older. (oxymorphone) ommends caution in hepatic disease although lower doses (un-
specified) are advised in those patients with severe impairment.
Administration in hepatic or renal impairment. The Pharmacopoeias. In US.
plasma concentrations of oxycodone may be increased in pa- Administration in renal impairment. In patients with mod-
USP 31 (Oxymorphone Hydrochloride). A white or slightly off- erate to severe renal impairment, the bioavailability of oxymor-
tients with hepatic or renal impairment and consequently dosage white odourless powder, darkening on exposure to light. Its
adjustment may be necessary in such patients. In the UK, li- phone was found to increase by over 50%; consequently, it is
aqueous solutions are slightly acidic. Soluble 1 in 4 of water, 1 in recommended that oxymorphone is given with caution and in re-
censed product information recommends that the oral starting 100 of alcohol, and 1 in 25 of methyl alcohol; very slightly solu-
dose for adult patients with mild hepatic impairment or mild to duced doses (unspecified) to those with a creatinine clearance of
ble in chloroform and in ether. Store in airtight containers at a less than 50 mL/minute.
moderate renal impairment should be 2.5 mg given every 6
temperature of 25°, excursions permitted between 15° and 30°.
hours; it contra-indicates the use of oxycodone in those with Preparations
Protect from light.
moderate to severe hepatic impairment or severe renal impair- USP 31: Oxymorphone Hydrochloride Injection; Oxymorphone Hydro-
ment. US product information permits the cautious use of oxyco- Dependence and Withdrawal chloride Suppositories.
done in adult patients with severe hepatic or severe renal impair- As for Opioid Analgesics in general, p.101. Proprietary Preparations (details are given in Part 3)
ment.
Adverse Effects, Treatment, and Precautions Canad.: Numorphan†; USA: Numorphan; Opana.
Pain. References. As for Opioid Analgesics in general, p.102.
1. Sunshine A, et al. Analgesic efficacy of controlled-release oxy- For details on the use of oxymorphone in patients with hepatic or
codone in postoperative pain. J Clin Pharmacol 1996; 36: renal impairment see below. Oxyphenbutazone (BAN, rINN)
595–603.
Interactions G-27202; Hydroxyphenylbutazone; Oksifenbutatsoni; Oxifenb-
2. Curtis GB, et al. Relative potency of controlled-release oxyco-
done and controlled-release morphine in a postoperative pain For interactions associated with opioid analgesics, see p.103. utazon; Oxifenbutazona; Oxyphenbutazonum. 4-Butyl-1-(4-hy-
model. Eur J Clin Pharmacol 1999; 55: 425–9. Licensed product information for a modified-release preparation droxyphenyl)-2-phenylpyrazolidine-3,5-dione monohydrate.
3. Gimbel JS, et al. Controlled-release oxycodone for pain in dia- of oxymorphone hydrochloride (Opana ER; Endo, USA) states Оксифенбутазон
betic neuropathy: a randomized controlled trial. Neurology that patients must not ingest alcohol, including alcohol-contain-
2003; 60: 927–34. C 19 H 20 N 2 O 3 ,H 2 O = 342.4.
ing medicines, at the same time due to the risk of increased plas-
C AS — 129-20-4 (anhydrous oxyphenbutazone); 7081-
4. Gammaitoni AR, et al. Randomized, double-blind, placebo- ma concentrations and a potentially fatal overdose of oxymor- 38-1 (oxyphenbutazone monohydrate).
controlled comparison of the analgesic efficacy of oxycodone phone.
10 mg/acetaminophen 325 mg versus controlled-release oxyco- ATC — M01AA03; M02AA04; S01BC02.
done 20 mg in postsurgical pain.J Clin Pharmacol 2003; 43: Pharmacokinetics ATC Vet — QM01AA03; QM02AA04; QS01BC02.
296–304. Oxymorphone hydrochloride is absorbed from the gastrointesti-
5. Oldfield V, Perry CM. Oxycodone/ibuprofen combination tab- nal tract after oral doses, but bioavailability is only about 10%
let: a review of its use in the management of acute pain. Drugs because of first-pass metabolism. Absorption is increased after a
2005; 65: 2337–54.
high-fat meal. About 10% is bound to plasma proteins. Oxymor-
6. Kalso E. Oxycodone. J Pain Symptom Manage 2005; 29 (sup- phone is extensively metabolised in the liver by glucuronidation
pl): S47–S56. OH
and less than 1% of a dose appears in the urine and faeces as
7. Bercovitch M, Adunsky A. High dose controlled-release oxyco- unchanged drug. With regard to its major metabolites between
done in hospice care. J Pain Palliat Care Pharmacother 2006; 33 and 38% of a dose is excreted in the urine as oxymorphone- N
20: 33–9. O N
3-glucuronide and less than 1% as 6-OH-oxymorphone. Oxy-
8. Reid CM, et al. Oxycodone for cancer-related pain: meta-anal- morphone crosses the placenta.
ysis of randomized controlled trials. Arch Intern Med 2006; H 3C
166: 837–43. Correction. ibid.; 2387. ◊ References. O
9. Portenoy RK, et al. Long-term use of controlled-release oxyco- 1. Adams MP, Ahdieh H. Pharmacokinetics and dose-proportional-
done for noncancer pain: results of a 3-year registry study. Clin ity of oxymorphone extended release and its metabolites: results
J Pain 2007; 23: 287–99. Profile
of a randomized crossover study. Pharmacotherapy 2004; 24: Oxyphenbutazone, a metabolite of phenylbutazone (p.117), is an
10. Pan H, et al. Efficacy and tolerability of oxycodone hydrochlo- 468–76.
ride controlled-release tablets in moderate to severe cancer pain.
NSAID (p.96). It has been applied topically to the eye as an anti-
2. Adams MP, Ahdieh H. Single- and multiple-dose pharmacoki-
Clin Drug Invest 2007; 27: 259–67. netic and dose-proportionality study of oxymorphone immedi-
inflammatory ointment in conditions such as episcleritis. Oxy-
ate-release tablets. Drugs R D 2005; 6: 91–9. phenbutazone was used systemically in disorders such as anky-
Preparations losing spondylitis, osteoarthritis, and rheumatoid arthritis but
Uses and Administration such use is no longer considered justified because of the risk of
USP 31: Oxycodone and Acetaminophen Capsules; Oxycodone and Oxymorphone hydrochloride, a phenanthrene derivative, is an severe haematological adverse effects (see also Effects on the
Acetaminophen Tablets; Oxycodone and Aspirin Tablets; Oxycodone Hy- opioid analgesic (p.101) with actions and uses similar to those of
drochloride Extended-Release Tablets; Oxycodone Hydrochloride Oral Blood, under Phenylbutazone, p.117).
morphine (p.86), apart from a lack of cough suppressant activity.
Solution; Oxycodone Hydrochloride Tablets. The piperazine salt has also been used.
Oxymorphone is given orally, parenterally, or rectally for the re-
Proprietary Preparations (details are given in Part 3) lief of moderate to severe pain, including pain in obstetrics, and Porphyria. Oxyphenbutazone has been associated with acute
Arg.: Oxicalmans; Oxinovag; Oxycontin; Austral.: Endone; Oxycontin; is reported to provide analgesia for 3 to 6 hours. It may also be attacks of porphyria and is considered unsafe in porphyric pa-
Oxynorm; Proladone; Austria: Oxycontin; Oxynorm; Belg.: Oxycontin; used parenterally for premedication, as an adjunct to anaesthesia, tients.
Braz.: Oxycontin; Canad.: Oxy IR; Oxycontin; Supeudol; Chile: Oxycon- and to relieve dyspnoea due to pulmonary oedema resulting from
tin; Cz.: Oxycontin; Denm.: Oxycontin; Oxynorm; Fin.: Oxanest; Oxy- left ventricular failure. Preparations
contin; Oxynorm; Fr.: Eubine†; Oxycontin; Oxynorm; Ger.: Oxygesic; Proprietary Preparations (details are given in Part 3)
Hung.: Oxycontin; Irl.: Oxycontin; Oxynorm; Israel: Oxycod; Oxycontin; A usual oral starting dose for opioid-naive patients is 10 to
Ital.: Oxycontin; Jpn: Oxycontin; Malaysia: Oxycontin; Mex.: Oxycon- India: Sioril†; Mex.: Edefen†; Redolet†.
20 mg of oxymorphone hydrochloride every 4 to 6 hours adjust-
tin†; Neth.: Oxycontin; Oxynorm; Norw.: Oxycontin; Oxynorm; NZ: Ox- ed thereafter as necessary; some patients may be started on lower Multi-ingredient: Braz.: Algi Peralgin†; Algiflamanil; Analtrix†; Febupen;
ycontin; Oxynorm; Philipp.: Oxycontin; Port.: Oxycontin; Singapore: Flamanan; Reumazine†; Mex.: Dartrizon.
Oxycontin; Oxynorm; Spain: Oxycontin; Oxynorm; Swed.: Oxycontin; doses of 5 mg. For patients who have been receiving a strong
Oxynorm; Switz.: Oxycontin; Oxynorm; UK: Oxycontin; Oxynorm; USA: opioid analgesic the initial dose of oxymorphone should be
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
108 Analgesics Anti-inflammatory Drugs and Antipyretics
Paracetamol (BAN, rINN) 2. McKeever TM, et al. The association of acetaminophen, aspirin,
and ibuprofen with respiratory disease and lung function. Am J
Prompt treatment is essential, even when there are no obvious
symptoms, and all patients should be admitted to hospital; full
Acetaminofeno; Acetaminophen; N-Acetyl-p-aminophenol; Respir Crit Care Med 2005; 171: 966–71. supportive measures should also be instituted.
3. Eneli I, et al. Acetaminophen and the risk of asthma: the epide-
Asetaminofen; Paracétamol; Paracetamolis; Paracetamolum; Par- miologic and pathophysiologic evidence. Chest 2005; 127: • Activated charcoal may be used to reduce gastrointestinal ab-
asetamol; Parasetamoli. 4′-Hydroxyacetanilide; N-(4-Hydroxy- 604–12. sorption, if it can be given within 1 hour of the overdose, and
phenyl)acetamide. 4. Nuttall SL, et al. Does paracetamol cause asthma? J Clin Pharm if more than 150 mg/kg of paracetamol has been ingested.
Ther 2003; 28: 251–7. However, if acetylcysteine or methionine is to be given by
Парацетамол
Hypersensitivity. Reactions characterised by urticaria, dysp- mouth the charcoal is best cleared from the stomach to prevent
C 8 H 9 NO 2 = 151.2. it reducing the absorption of the antidote.
C AS — 103-90-2. noea, and hypotension have occurred after use of paracetamol in
adults1-4 and children.5,6 Angioedema has also been reported.7 • There is little evidence that gastric lavage is of benefit in those
ATC — N02BE01. Fixed drug eruptions, confirmed by rechallenge, have been de- who have overdosed solely with paracetamol.
ATC Vet — QN02BE01. scribed,8-11 and toxic epidermal necrolysis has occurred.12 • The plasma-paracetamol concentration should be determined
1. Stricker BHC, et al. Acute hypersensitivity reactions to para- as soon as possible, but not within 4 hours of ingestion, to en-
cetamol. BMJ 1985; 291: 938–9. sure that peak concentrations are recorded. The risk of liver
HO 2. Van Diem L, Grilliat JP. Anaphylactic shock induced by para- damage is determined by comparison with a nomogram refer-
O cetamol. Eur J Clin Pharmacol 1990; 38: 389–90. ence line on a plot of plasma-paracetamol concentration
3. Kumar RK, Byard I. Paracetamol as a cause of anaphylaxis. against hours after ingestion. A semi-logarithmic plot or a lin-
Hosp Med 1999; 60: 66–7.
N CH3 4. Bachmeyer C, et al. Acetaminophen (paracetamol)-induced an-
ear plot may be used, see Figure 1 (p.109) and Figure 2
H aphylactic shock. South Med J 2002; 95: 759–60. (p.109). Generally, antidote treatment is required if the pa-
5. Ellis M, et al. Immediate adverse reactions to acetaminophen in tient’s plasma-paracetamol concentration is higher than the
children: evaluation of histamine release and spirometry. J appropriate line (but see below).
NOTE. Compounded preparations of paracetamol may be repre- Pediatr 1989; 114: 654–6.
sented by the following names: • Patients receiving enzyme-inducing drugs such as car-
6. Bousetta K, et al. Hypersensitivity reactions to paracetamol in
children: a study of 25 cases. Allergy 2005; 60: 1174–7. bamazepine, phenytoin, phenobarbital, rifampicin, and St
• Co-bucafAPAP (PEN)—butalbital, paracetamol, and caffeine 7. Idoko JA, et al. Angioneurotic oedema following ingestion of John’s wort, or those with malnutrition or a history of alcohol
• Co-codamol x/y (BAN)—where x and y are the strengths in paracetamol. Trans R Soc Trop Med Hyg 1986; 80: 175. abuse, are considered at high risk, and should receive an anti-
milligrams of codeine phosphate and paracetamol respective- 8. Thomas RHM, Munro DD. Fixed drug eruption due to paraceta- dote even if their plasma-paracetamol concentrations are up to
ly mol. Br J Dermatol 1986; 115: 357–9. 50% below the standard reference line.
9. Cohen HA, et al. Fixed drug eruption caused by acetaminophen. • Plasma-paracetamol concentrations measured more than 15
• Co-codAPAP (PEN)—paracetamol and codeine phosphate Ann Pharmacother 1992; 26: 1596–7.
10. Harris A, Burge SM. Vasculitis in a fixed drug eruption due to hours after ingestion are not reliable indicators of hepatic tox-
• Co-dydramol (BAN)—dihydrocodeine tartrate 1 part and pa- paracetamol. Br J Dermatol 1995; 133: 790–1. icity. Furthermore, the nomogram may not be suitable for use
racetamol 50 parts (w/w) 11. Hern S, et al. Bullous fixed drug eruption due to paracetamol when patients have taken modified-release preparations of pa-
• Co-hycodAPAP (PEN)—hydrocodone tartrate and paraceta- with an unusual immunofluorescence pattern. Br J Dermatol racetamol.16-18 Some suggestions for modified strategies for
1998; 139: 1129–31. the use of the Rumack-Matthew nomogram in the face of
mol 12. Halevi A, et al. Toxic epidermal necrolysis associated with overdosage with modified-release preparations have been
• Co-methiamol x/y (BAN)—where x and y are the strengths in acetaminophen ingestion. Ann Pharmacother 2000; 34: 32–4.
made.19-21
milligrams of DL-methionine and paracetamol, respectively Overdosage. Acute oral overdosage with paracetamol, wheth- • Plasma-paracetamol concentrations and the Rumack-
• Co-oxycodAPAP (PEN)—oxycodone and paracetamol er accidental or deliberate, is relatively common and can be Matthew nomogram are also of little value in patients who
extremely serious because of the narrow margin between thera- have taken repeated supratherapeutic doses or multiple over-
• Co-proxamol (BAN)—dextropropoxyphene hydrochloride 1 peutic and toxic doses. Ingestion of as little as 10 to 15 g of
part and paracetamol 10 parts (w/w) doses of paracetamol over a short period of time: such patients
paracetamol by adults may cause severe hepatocellular necrosis should be considered at serious risk and given antidote treat-
• Co-proxAPAP (PEN)—dextropropoxyphene napsilate and and, less often, renal tubular necrosis. Patients should be consid- ment.
paracetamol. ered at risk of severe liver damage if they have ingested more • Deaths from liver failure have occurred in patients presenting
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and than 150 mg/kg of paracetamol or 12 g or more in total, which- with plasma-paracetamol concentrations below the treatment
Viet. ever is the smaller. The risk of severe toxicity after acute para- line: suggested explanations include inadequate patient histo-
Ph. Eur. 6.2 (Paracetamol). A white or almost white, crystalline cetamol overdose appears to be less in children than in adults at ries and a need for a lower treatment threshold.22
powder. Sparingly soluble in water; freely soluble in alcohol; comparable doses; however, chronic use of supratherapeutic
doses in children has resulted in unintentional overdoses and se- • If there is any doubt about timing or the need to treat, then a
very slightly soluble in dichloromethane. Protect from light. patient should be treated with an antidote. In some centres,
USP 31 (Acetaminophen). A white odourless crystalline pow- vere hepatotoxicity.1,2
patients who have ingested 150 mg/kg or more of paracetamol
der. Soluble 1 in 20 of boiling water, 1 in 10 of alcohol, and 1 in Patients receiving enzyme-inducing drugs or those with a history are treated regardless of plasma-paracetamol concentra-
15 of 1N sodium hydroxide. Store in airtight containers. Protect of alcohol abuse are at special risk of hepatic damage, as may be tions.23
from light. Protect from moisture and heat. patients suffering from malnutrition such as those with anorexia
• Antidote treatment should be started as soon as possible after
or AIDS. It has also been suggested that fasting may predispose
suspected paracetamol ingestion and should not be delayed
to hepatotoxicity.3
Adverse Effects and Treatment while awaiting the results of plasma assays. Once the results
Adverse effects of paracetamol are rare and usually Early signs of overdosage (very commonly nausea and vomiting become available, treatment may be stopped if the initial con-
although they may also include lethargy and sweating) usually centration was below the nomogram reference line. However,
mild, although haematological reactions including settle within 24 hours. Abdominal pain may be the first indica- if the initial concentration is above the reference line, the full
thrombocytopenia, leucopenia, pancytopenia, neutro- tion of liver damage, which is not usually apparent for 24 to 48 course of antidote must be given and should not be stopped
penia, and agranulocytosis have been reported. Skin hours and sometimes may be delayed for up to 4 to 6 days after when subsequent plasma concentrations fall below the refer-
rashes and other hypersensitivity reactions occur occa- ingestion. Liver damage is generally at a maximum 72 to 96 ence line.
hours after ingestion. Hepatic failure, encephalopathy, coma, and Choice of antidote. Acetylcysteine (p.1548) is usually the anti-
sionally. Hypotension has been reported rarely with death may result. Complications of hepatic failure include acido-
parenteral use. dote of choice but the route of administration varies, and the best
sis, cerebral oedema, haemorrhage, hypoglycaemia, hypoten- protocol has yet to be determined.6,24 Intravenous use has been
Overdosage with paracetamol can result in severe liver sion, infection, and renal failure. Prothrombin time increases associated with anaphylactic reactions but is the preferred route
damage and sometimes acute renal tubular necrosis. with deteriorating liver function and some recommend that it be in the UK because of fears that oral absorption might be reduced
measured regularly. However, as both paracetamol 4 and by vomiting or activated charcoal. However, in the USA the oral
Prompt treatment with acetylcysteine or methionine is acetylcysteine5 can independently affect prothrombin time in the
essential and is discussed under Overdosage, below. route is also used, and is clearly effective. The use of methionine
absence of hepatic injury, the use of prothrombin time as a mark- (p.1450) by mouth is licensed in the UK, despite the same risks
◊ References. er for hepatotoxicity has been questioned and it has been recom- of impaired absorption due to vomiting or activated charcoal. It
mended that treatment decisions are based on the entire liver bi- is cheaper and easier to give than intravenous acetylcysteine and
1. Graham GG, et al. Tolerability of paracetamol. Drug Safety
2005; 28: 227–40.
ochemistry.6 may be used in situations where a patient cannot be transferred
Acute renal failure with acute tubular necrosis may develop, to hospital, provided it is given within 10 to 12 hours of the over-
Effects on the kidneys. For reference to evidence that abuse even in the absence of severe liver damage. Other non-hepatic
or prolonged excessive use of analgesics, including paracetamol, dose and the patient is not vomiting.
symptoms that have been reported following paracetamol over- Acetylcysteine is most effective when given during the first 8
can produce nephropathy, see under NSAIDs, p.98. dosage include myocardial abnormalities and pancreatitis. hours after taking the overdose and the effect diminishes pro-
See also under Overdosage, below. The mechanism of toxicity in overdosage with paracetamol is gressively thereafter. It used to be believed that starting treatment
Effects on the respiratory tract. The results of a case-con- thought to be the production of a minor but highly reactive more than 15 hours after overdosage was of no benefit and might
trol study1 have suggested that the frequent (daily or weekly) use metabolite, N-acetyl-p-benzoquinoneimine (NABQI) by cyto- aggravate the risk of hepatic encephalopathy. However, late
of paracetamol may be associated with asthma. However, the chrome P450 isoenzymes (mainly CYP2E1 and CYP3A4)2 in treatment was subsequently shown to be safe,25 and studies of
UK CSM has commented that the results of this study do not the liver and kidney. The amount of NABQI produced after nor- patients treated up to 36 hours after ingestion suggest that benefit
alter any advice regarding the use of paracetamol and that it re- mal doses of paracetamol is usually completely detoxified by may be obtained up to and possibly beyond 24 hours.26,27 Fur-
mains a safe and effective pain killer for many patients including conjugation with glutathione and excreted as mercaptopurine thermore, giving intravenous acetylcysteine to patients who had
asthmatics. and cysteine conjugates. In paracetamol overdosage, tissue already developed fulminant hepatic failure has been shown to
Subsequently, a further study and a review have found an in- stores of glutathione become depleted, allowing NABQI to accu- reduce morbidity and mortality.28
crease in the prevalence of asthma2,3 and COPD2 with frequent mulate and bind to sulfhydryl groups within hepatocytes causing • An initial dose of 150 mg/kg of acetylcysteine in 200 mL of
(daily or weekly) use of paracetamol. A link between paraceta- cell damage. Substances capable of replenishing depleted stores glucose 5% is given intravenously over 15 minutes in the UK,
mol use in pregnancy and asthma in children has also been sug- of glutathione, such as acetylcysteine or methionine, are there- or over 60 minutes in the USA. This is followed by an intra-
gested (see Pregnancy under Precautions, below). However, fore used as antidotes in paracetamol overdosage. Acetylcysteine venous infusion of 50 mg/kg in 500 mL of glucose 5% over
another review4 stated that there have been very few actual re- may also be involved in the repair of damaged tissue. the next 4 hours and then 100 mg/kg in one litre over the next
ports of paracetamol causing asthma; furthermore, bronchos- Treatment of oral paracetamol overdosage. The management 16 hours. Sodium chloride 0.9% may be used where glucose
pasm is not a recognised feature of paracetamol overdosage. The of paracetamol overdosage as practised in the UK and US has 5% is unsuitable. The volume of intravenous fluids should be
review concluded that a strong link between paracetamol use and been the subject of numerous reviews.3,6-13 Guidelines have also modified for children. If an anaphylactoid reaction develops,
asthma was unlikely. been issued in the UK by the Paracetamol Information Centre.14 the infusion should be stopped and an antihistamine given; it
1. Shaheen SO, et al. Frequent paracetamol use and asthma in Separate consensus guidelines have also been issued by clinical may be possible to continue the acetylcysteine infusion at a
adults. Thorax 2000; 55: 266–70. toxicologists in Australia and New Zealand.15 slower rate.
 Paracetamol 109
Figure 1. A semi-logarithmic plot of plasma-paracetamol concentration against Figure 2. A linear plot of plasma-paracetamol concentration against hours
hours after ingestion. after ingestion.

500

200
150

Plasma-paracetamol concentration (mmol/L)

Plasma-paracetamol concentration (μg/mL)

Plasma-paracetamol concentration (mg/L)

100
Probable hepatic toxicity Normal treatment line

50

10
Possible hepatic toxicity

25%
5
50%

High-risk treatment line

1
4 8 12 16 20 24

Time (hours) Time (hours)

Adapted from Rumack BH, Matthew HJ. Acetaminophen poisoning and toxicity. Courtesy of P A Routledge.
Pediatrics 1975; 55: 871–6.
Notes for the use of this chart:
Notes for the use of this chart: 1. The time coordinates refer to time after ingestion.
1. The time coordinates refer to time after ingestion. 2. Plasma-paracetamol concentrations drawn before 4 hours may not represent peak
2. Plasma-paracetamol concentrations drawn before 4 hours may not represent peak concentrations.
concentrations. 3. The graph should be used only in relation to a single acute ingestion.
3. The graph should be used only in relation to a single acute ingestion. 4. Patients whose plasma-paracetamol concentrations are above the normal treatment line
4. The solid line 25% below the standard nomogram is included to allow for possible should be treated.
errors in plasma assays and estimated time from ingestion of an overdose. 5. Patients on enzyme-inducing drugs or with malnutrition or a history of alcohol abuse
5. The solid line 50% below the standard nomogram is to assess the possible hepatic should be treated if their plasma-paracetamol concentrations are above the high-risk
toxicity in patients receiving enzyme-inducing drugs or with malnutrition or a history treatment line.
of alcohol abuse. 6. The value of such charts is uncertain if the patient is first seen 15 hours or more after
6. The value of such charts is uncertain if the patient is first seen 15 hours or more after ingestion, or has taken modified release preparations of paracetamol.
ingestion, or has taken modified release preparations of paracetamol.

• In the USA, acetylcysteine may also be given orally as an al- overdosage may occur. However, the issue of whether methio- treatment should be based on the total administered dose of para-
ternative to parenteral treatment. It is given as an initial dose nine should be routinely added to paracetamol preparations is cetamol and/or any resultant hepatic impairment.
of 140 mg/kg as a 5% solution followed by 70 mg/kg every 4 contentious for medical and ethical reasons. 1. Miles FK, et al. Accidental paracetamol overdosing and fulmi-
hours for an additional 17 doses. Some29 have suggested in- Histamine H2-antagonists. It has been suggested that since cime- nant hepatic failure in children. Med J Aust 1999; 171: 472–5.
creasing the loading dose of oral acetylcysteine when it is giv- tidine blocks the hepatic cytochrome P450 mixed function oxi- 2. American Academy of Pediatrics Committee on Drugs. Aceta-
en after activated charcoal, whereas others30 have found that minophen toxicity in children. Pediatrics 2001; 108: 1020–4.
dase system, it might be of use as an adjunct to acetylcysteine for 3. Whitcomb DC, et al. Association of acetaminophen hepatotox-
the efficacy of acetylcysteine is not reduced by use of activat- patients whose production of the toxic metabolite of paracetamol icity with fasting and ethanol use. JAMA 1994; 272: 1845–50.
ed charcoal beforehand and consider a larger acetylcysteine is increased due to enzyme induction. Although there have been 4. Whyte IM, et al. Acetaminophen causes an increased Interna-
dose unnecessary. several anecdotal reports claiming benefit for cimetidine in pa- tional Normalized Ratio by reducing functional factor VII. Ther
Methionine, like acetylcysteine, is most effective when given as tients with paracetamol poisoning, there is no current evidence to Drug Monit 2000; 22: 742–8.
early as possible after paracetamol overdosage. However, it is support these claims.6,10,11,34 5. Schmidt LE, et al. Effect of acetylcysteine on prothrombin in-
dex in paracetamol poisoning without hepatocellular injury.
not as effective if treatment is delayed31-33 and hepatic damage is Liver transplantation may be considered as a last recourse in Lancet 2002; 360: 1151–2.
more frequent and severe if treatment with methionine is started some patients. 6. Brok J et al. Interventions for paracetamol (acetaminophen)
more than 10 hours after ingestion; it may also precipitate hepatic overdoses. Available in The Cochrane Database of Systematic
encephalopathy. After maternal overdosage during pregnancy fetal metabolism Reviews; Issue 2. Chichester: John Wiley; 2006 (accessed
of paracetamol that crosses the placenta can produce sufficient 23/10/06).
• The usual oral dose of methionine in adults and children over hepatotoxic metabolites to cause fetal hepatotoxicity. Limited 7. Routledge P, et al. Paracetamol (acetaminophen) poisoning.
6 years is 2.5 g every 4 hours for 4 doses starting less than 10 data from case reports and a case series suggest that early treat- BMJ 1998; 317: 1609–10.
to 12 hours after ingestion of the paracetamol and provided the ment with oral or intravenous acetylcysteine can be safe and ef- 8. Makin AJ, et al. Management of severe cases of paracetamol
patient is not vomiting. Children under 6 years should be giv- overdosage. Br J Hosp Med 1994; 52: 210–13.
fective in such cases.35
en 1 g every 4 hours for 4 doses. It has also been given intra- 9. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poison-
There is little information available on overdosage when para- ing. Lancet 1995; 346: 547–52.
venously. 10. Prescott LF. Paracetamol overdose. In: Paracetamol (acetami-
cetamol is given as an intravenous infusion. The standard nom-
The literature relating to the use of methionine in paracetamol ogram may not be appropriate in determining treatment from nophen): a critical bibliographic review. London: Taylor &
Francis, 1996: 401–73.
poisoning is, in general, imprecise as to the form of methionine plasma-paracetamol concentrations after intravenous overdose, 11. Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose.
used. In the UK, the doses quoted above refer to DL-methionine. as it is based on data from acute paracetamol ingestion rather Am J Health-Syst Pharm 1999; 56: 1081–91.
Preparations containing both methionine and paracetamol (co- than intravenous administration. The National Poisons Informa- 12. Kozer E, Koren G. Management of paracetamol overdose: cur-
methiamol) have been formulated for use in situations where tion Service in the UK recommends that the need for antidote rent controversies. Drug Safety 2001; 24: 503–12.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
110 Analgesics Anti-inflammatory Drugs and Antipyretics
13. Dart RC, et al. Acetaminophen poisoning: an evidence-based Hepatic impairment. A short review1 concluded that there Pharmacokinetics
consensus guideline for out-of-hospital management. Clin Tox- was evidence that paracetamol could be and had been used safely
icol 2006; 44: 1–18. Paracetamol is readily absorbed from the gastrointesti-
in patients with liver disease. Studies had also shown that al-
14. Paracetamol Information Centre. Guidelines for the manage-
though the half-life of paracetamol was prolonged in such pa- nal tract with peak plasma concentrations occurring
ment of acute paracetamol overdosage (revised 2007). Also
available at: http://www.pharmweb.net/pwmirror/pwy/ tients, glutathione concentrations in those taking recommended about 10 to 60 minutes after oral doses. Paracetamol is
paracetamol/chart.html (accessed 23/07/08) doses were not depleted to the critical levels that would enable distributed into most body tissues. It crosses the pla-
15. Daly FF, et al. Panel of Australian and New Zealand clinical accumulation of paracetamol’s hepatotoxic metabolite. The BNF
toxicologists. Guidelines for the management of paracetamol centa and is present in breast milk. Plasma-protein
poisoning in Australia and New Zealand—explanation and warns that large doses should be avoided. binding is negligible at usual therapeutic concentra-
elaboration: a consensus statement from clinical toxicologists 1. Benson GD, et al. The therapeutic use of acetaminophen in pa-
consulting to the Australasian poisons information centres. Med tients with liver disease. Am J Ther 2005; 12: 133–41.
tions but increases with increasing concentrations. The
J Aust 2008; 188: 296–301. elimination half-life of paracetamol varies from about
Also available at: http://www.mja.com.au/public/issues/ Pregnancy. Paracetamol is generally considered to be the anal- 1 to 3 hours.
188_05_030308/dal10916_fm.html (accessed 13/08/08) gesic of choice in pregnant patients. However, the frequent use
16. Graudins A, et al. Overdose of extended-release acetami- of paracetamol (defined as most days or daily use) in late preg- Paracetamol is metabolised mainly in the liver and ex-
nophen. N Engl J Med 1995; 333: 196.
17. Vassallo S, et al. Use of the Rumack-Matthew nomogram in cas- nancy may be associated with an increased risk of persistent creted in the urine mainly as the glucuronide and sul-
es of extended-release acetaminophen toxicity. Ann Intern Med wheezing in the infant1 which may persist into childhood2 (but fate conjugates. Less than 5% is excreted as unchanged
1996; 125: 940. see also Effects on the Respiratory Tract, above). The authors
18. Dart RC, et al. The safety profile of sustained release paraceta- emphasised that the number of pregnant women taking frequent paracetamol. A minor hydroxylated metabolite (N-
mol during therapeutic use and following overdose. Drug Safety doses was very small and they recommended that infrequent pa- acetyl-p-benzoquinoneimine), is usually produced in
2005; 28: 1045–56.
19. Temple AR, Mrazik TJ. More on extended-release acetami- racetamol should remain the analgesic of choice in pregnancy. very small amounts by cytochrome P450 isoenzymes
nophen. N Engl J Med 1995; 333: 1508. 1. Shaheen SO, et al. Paracetamol use in pregnancy and wheezing (mainly CYP2E1 and CYP3A4) in the liver and kid-
20. Graudins A, et al. More on extended-release acetaminophen. N in early childhood. Thorax 2002; 57: 958–63.
Engl J Med 1995; 333: 1508–9. ney. It is usually detoxified by conjugation with glu-
2. Shaheen SO, et al. Prenatal paracetamol exposure and risk of
21. Cetaruk EW, et al. Extended-release acetaminophen overdose. asthma and elevated immunoglobulin E in childhood. Clin Exp tathione but may accumulate after paracetamol over-
JAMA 1996; 275: 686.
22. Bridger S, et al. Deaths from low dose paracetamol poisoning.
Allergy 2005; 35: 18–25. dosage and cause tissue damage.
BMJ 1998; 316: 1724–5. Renal impairment. Caution is recommended when giving pa-
23. Aujla KS, et al. Nomogram does not show absolute concentra- ◊ References.
tion for treatment. BMJ 1998; 317: 1655.
racetamol to patients with renal impairment. Plasma concentra-
1. van der Marel CD, et al. Paracetamol and metabolite pharmacok-
24. Kanter MZ. Comparison of oral and i.v. acetylcysteine in the tions of paracetamol and its glucuronide and sulfate conjugates inetics in infants. Eur J Clin Pharmacol 2003; 59: 243–51.
treatment of acetaminophen poisoning. Am J Health-Syst are increased in patients with moderate renal failure and in pa-
Pharm 2006; 63: 1821–7. tients on dialysis.1-3 It has been suggested that paracetamol itself Absorption. The absorption of paracetamol was slow and in-
25. Parker D, et al. Safety of late acetylcysteine treatment in para- may be regenerated from these metabolites.1,2 There are conflict- complete in vegetarian subjects compared with non-vegetarian
cetamol poisoning. Hum Exp Toxicol 1990; 9: 25–7. ing data on whether the conjugates of paracetamol accumulate in subjects.1
26. Smilkstein MJ, et al. Efficacy of oral N-acetylcysteine in the
treatment of acetaminophen overdose: analysis of the National patients with renal impairment receiving multiple doses.2,3 1. Prescott LF, et al. Impaired absorption of paracetamol in vege-
Multicenter Study (1976 to 1985). N Engl J Med 1988; 319: 1. Prescott LF, et al. Paracetamol disposition and metabolite kinet- tarians. Br J Clin Pharmacol 1993; 36: 237–40.
1557–62. ics in patients with chronic renal failure. Eur J Clin Pharmacol
27. Harrison PM, et al. Improved outcome of paracetamol-induced 1989; 36: 291–7.
fulminant hepatic failure by late administration of acetyl- Uses and Administration
2. Martin U, et al. The disposition of paracetamol and the accumu-
cysteine. Lancet 1990; 335: 1572–3. lation of its glucuronide and sulphate conjugates during multiple Paracetamol, a para-aminophenol derivative, has
28. Keays R, et al. Intravenous acetylcysteine in paracetamol in-
duced fulminant hepatic failure: a prospective controlled trial.
dosing in patients with chronic renal failure. Eur J Clin Pharma- analgesic and antipyretic properties and weak anti-
col 1991; 41: 43–6.
BMJ 1991; 303: 1026–9.
3. Martin U, et al. The disposition of paracetamol and its conju-
inflammatory activity. Paracetamol is given orally or as
29. Chamberlain JM, et al. Use of activated charcoal in a simulated
poisoning with acetaminophen: a new loading dose for N-ace- gates during multiple dosing in patients with end-stage renal fail- a rectal suppository for mild to moderate pain and for
tylcysteine? Ann Emerg Med 1993; 22: 1398–1402. ure maintained on haemodialysis. Eur J Clin Pharmacol 1993; fever (p.10). It may also be given by intravenous infu-
30. Spiller HA, et al. A prospective evaluation of the effect of acti- 45: 141–5.
vated charcoal before oral N-acetylcysteine in acetaminophen sion for the short-term treatment of moderate pain, par-
overdose. Ann Emerg Med 1994; 23: 519–23.
Interactions ticularly after surgery, and of fever. Paracetamol is of-
31. Vale JA, et al. Intravenous N-acetylcysteine: the treatment of ten the analgesic or antipyretic of choice, especially in
choice in paracetamol poisoning? BMJ 1979; 2: 1435–6. The risk of paracetamol toxicity may be increased in
32. Vale JA, et al. Treatment of acetaminophen poisoning: the use
patients receiving other potentially hepatotoxic drugs the elderly and in patients in whom salicylates or other
of oral methionine. Arch Intern Med 1981; 141: 394–6. NSAIDs are contra-indicated. Such patients include
33. Tee LGB, et al. N-Acetylcysteine for paracetamol overdose. or drugs that induce liver microsomal enzymes. The
Lancet 1986; i: 331–2. absorption of paracetamol may be accelerated by drugs asthmatics, those with a history of peptic ulcer, and
34. Kaufenberg AJ, Shepherd MF. Role of cimetidine in the treat- children.
ment of acetaminophen poisoning. Am J Health-Syst Pharm such as metoclopramide. Excretion may be affected
1998; 55: 1516–19. and plasma concentrations altered when given with The usual oral dose is 0.5 to 1 g every 4 to 6 hours up
35. Wilkes JM, et al. Acetaminophen overdose in pregnancy. South
Med J 2005; 98: 1118–22. probenecid. Colestyramine reduces the absorption of to a maximum of 4 g daily. Paracetamol may also be
Pancreatitis. Drug-induced pancreatitis associated with para- paracetamol if given within 1 hour of paracetamol. given as suppositories in a rectal dose of 0.5 to 1 g
cetamol was reported1 to be a rare reaction only occurring in pa- every 4 to 6 hours, up to 4 times daily.
◊ Reviews.
tients taking more than recommended doses. In a retrospective Paracetamol is also given by intravenous infusion
study of data from 814 patients who had taken paracetamol over- 1. Toes MJ, et al. Drug interactions with paracetamol. Am J Ther
doses, hyperamylasaemia was detected in 246, and was more
2005; 12: 56–66. over 15 minutes; dosage may be calculated by weight
common and more severe in patients transferred to a specialist Antibacterials. The plasma-paracetamol concentrations con- as follows:
unit because of more severe poisoning.2 However, acute pancre- sidered an indication for antidote treatment (see under Overdos- • patients weighing over 50 kg, single doses of 1 g
atitis was diagnosed only in 33 cases. age, above) should be halved in patients receiving enzyme-in-
1. Underwood TW, Frye CB. Drug-induced pancreatitis. Clin ducing drugs such as rifampicin. Severe hepatotoxicity at
every 4 or more hours, to a maximum of 4 g daily
Pharm 1993; 12: 440–8. therapeutic doses or moderate overdoses of paracetamol has • from 33 to 50 kg, single doses of 15 mg/kg every 4
2. Schmidt LE, Dalhoff K. Hyperamylasaemia and acute pancreati- been reported in patients receiving isoniazid, alone1-3 or with or more hours, to a maximum of 60 mg/kg or 3 g
tis in paracetamol poisoning. Aliment Pharmacol Ther 2004; 20: other drugs for tuberculosis.4
173–9. daily (whichever is less)
For the effects of paracetamol on chloramphenicol, see p.241.
For doses in children or in renal impairment, see below.
Precautions 1. Murphy R, et al. Severe acetaminophen toxicity in a patient re-
Paracetamol should be given with care to patients with ceiving isoniazid. Ann Intern Med 1990; 113: 799–800. ◊ References.
2. Moulding TS, et al. Acetaminophen, isoniazid, and hepatic tox-
impaired kidney or liver function. It should also be giv- icity. Ann Intern Med 1991; 114: 431. 1. Prescott LF. Paracetamol (acetaminophen): a critical biblio-
graphic review. London: Taylor & Francis, 1996.
en with care to patients with alcohol dependence. 3. Crippin JS. Acetaminophen hepatotoxicity: potentiation by iso-
niazid. Am J Gastroenterol 1993; 88: 590–2. 2. Bannwarth B, Péhourcq F. Bases pharmacologiques de l’emploi
Breast feeding. No adverse effects have been seen in breast- du paracétamol: aspects pharmacocinétiques et pharmacody-
4. Nolan CM, et al. Hepatotoxicity associated with acetaminophen namiques. Drugs 2003; 63 (suppl 2): 5–13.
fed infants whose mothers were receiving paracetamol, and the usage in patients receiving multiple drug therapy for tuberculo-
American Academy of Pediatrics considers1 that it is therefore sis. Chest 1994; 105: 408–11. 3. Prescott LF. Nouvelles perspectives avec le paracétamol. Drugs
2003; 63 (suppl 2): 51–6.
usually compatible with breast feeding. The BNF also considers
that the amount of paracetamol distributed into breast milk is too Anticoagulants. For the effects of paracetamol on oral antico-
agulants, see under Warfarin, p.1427. Administration in children. In the UK, the licensed oral dos-
small to be harmful to a breast-fed infant. es in children are:
Pharmacokinetic studies in 12 nursing mothers given a single Antiepileptics. The plasma-paracetamol concentrations con- • 3 months to 1 year: 60 to 120 mg
dose of paracetamol showed that peak paracetamol concentra- sidered an indication for antidote treatment (see under Overdos-
tions in breast milk of 10 to 15 micrograms/mL were achieved in age, above) should be halved in patients receiving enzyme-in- • 1 to 5 years: 120 to 250 mg
1 to 2 hours. Plasma concentrations were determined in 2 ducing drugs such as carbamazepine, phenobarbital, phenytoin, • 6 to 12 years: 250 to 500 mg
mothers; a breast milk/plasma ratio of about 1 was reported.2 or primidone. These doses may be given every 4 to 6 hours when necessary up
Similar findings have been reported from other studies.3,4 For the effects of paracetamol on lamotrigine, see p.486. to a maximum of 4 doses in 24 hours.
1. American Academy of Pediatrics. The transfer of drugs and oth-
er chemicals into human milk. Pediatrics 2001; 108: 776–89. Antivirals. For reports of adverse effects on the liver associated In younger children the BNFC suggests the following doses:
Correction. ibid.; 1029. Also available at: with use of paracetamol with antiviral drugs, see under Interferon • neonates 28 to 32 weeks postmenstrual age (gestational age at
http://aappolicy.aappublications .org/cgi/ content/full/ Alfa, p.888 and Zidovudine, p.915. birth plus chronological age): 20 mg/kg as a single dose then
pediatrics%3b108/3/776 (accessed 19/10/06) 10 to 15 mg/kg every 8 to 12 hours if necessary up to a maxi-
2. Berlin CM, et al. Disposition of acetaminophen in milk, saliva, Probenecid. Pretreatment with probenecid can decrease para-
and plasma of lactating women. Pediatr Pharmacol 1980; 1: mum of 30 mg/kg daily
cetamol clearance and increase its plasma half-life.1 Although
135–41. • neonates over 32 weeks postmenstrual age: 20 mg/kg as a
urinary excretion of the sulfate and glucuronide conjugates of pa-
3. Hurden EL, et al. Excretion of paracetamol in human breast single dose then 10 to 15 mg/kg every 6 to 8 hours if necessary
milk. Arch Dis Child 1980; 55: 969–72. racetamol are reduced, that of paracetamol is unchanged.
up to a maximum of 60 mg/kg daily
4. Bitzén P-O, et al. Excretion of paracetamol in human breast 1. Kamali F. The effect of probenecid on paracetamol metabolism
milk. Eur J Clin Pharmacol 1981; 20: 123–5. and pharmacokinetics. Eur J Clin Pharmacol 1993; 45: 551–3. • 1 to 3 months of age: 30 to 60 mg every 8 hours if necessary
 Paracetamol/Parecoxib Sodium 111
The BNFC also suggests higher doses for use in children with treatment before NSAIDs are tried. Paracetamol is useful for the Acet; Biogesic; Calpol; Childrens Panadol Drops for Infants; Dhamol; Fibrex-
more severe symptoms: relief of acute low back pain (p.7). in; Milidon†; Napa; Naprex; Pacemol†; Panadol; Panamol; Paximol; Poro;
Rapidol; Remedol; Tylenol; Spain: Acertol; Actron†; Antidol; Apiretal; Ban-
• 1 to 3 months: 20 mg/kg as a single dose followed by 15 to Dependence and tolerance are not a problem with non-opioid an- dol†; Bolidol; Calmanticold†; Cupanol; Dafalgan; Dolgesic; Dolostop; Duor-
20 mg/kg every 6 to 8 hours if necessary up to a maximum of algesics such as paracetamol, but there is a ceiling of efficacy, ol; Efetamol; Efferalgan; Febrectal; Gelocatil; Melabon Infantil; Panadol;
60 mg/kg daily above which increasing the dose has no further therapeutic ef- Parafludeten; Pediapirin†; Perfalgan; Resakal†; Resolvebohm; Sinmol; Talgo;
Temperal†; Termalgin; Termocatil; Tylenol; Xumadol; Swed.: Alvedon;
• older children: 20 mg/kg every 6 hours to a maximum of fect. Curadon; Panodil; Perfalgan; Reliv; Switz.: Acetalgine; Becetamol; Ben-u-
90 mg/kg daily for 48 hours or longer if necessary followed by ron; Contre-Douleurs P; Dafalgan; Democyl†; Demogripal†; DoloStop
15 mg/kg every 6 hours. Usual adult maximum doses (see
Preparations nouvelle formule†; Dolprone; Influbene N; Kafa; Malex; Nina†; Osa Sup-
above) should not be exceeded BP 2008: Co-codamol Capsules; Co-codamol Tablets; Co-dydramol Tab- positoires contre douleurs et fievre; Panadol; Perfalgan; Pharmacard Family
lets; Co-proxamol Tablets; Dispersible Paracetamol Tablets; Effervescent Douleurs & Fievre†; Rivodol†; Seranex N; Siniphen Nouvelle formule; Tre-
For post-immunisation pyrexia, a dose of 60 mg has been rec- Co-codamol Tablets; Paediatric Paracetamol Oral Solution; Paracetamol upel Dolo Paracetamol; Treuphadol; Tylenol; Zolben; Thai.: A-Mol; Aceta-
ommended for children 2 to 3 months of age. If necessary a sec- Capsules; Paracetamol Oral Suspension; Paracetamol Suppositories; Para- P†; Acetasil; Algogen; Biogesic; Calpol; Cemol; Daga; Denamol; Depyret;
ond dose may be given after six hours; if the pyrexia persists after cetamol Tablets; Soluble Paracetamol Tablets; Detamol†; Fenn; Icolid Plus; Kit; Lotemp; Mypara; Nasa; Nutamol†; Panadol;
USP 31: Acetaminophen and Aspirin Tablets; Acetaminophen and Caffeine Para GDEK; Para-G; Paracap; Paracet; Paragin; Paramol; Paramol TP;
that dose, medical advice should be sought. Paranal-L; Paranal†; Parat; Paratol; Partamol; Pemol; Pyracon; Pyretal†; Ram-
Tablets; Acetaminophen and Codeine Phosphate Capsules; Acetami-
UK licensed rectal doses, which may be given to children every nophen and Codeine Phosphate Oral Solution; Acetaminophen and Co- ol; Sara†; Tempra; Tumdi; Tylenol; Tymol; Umeda Para-J; Unicap; Unimol;
4 to 6 hours, up to 4 times daily are: deine Phosphate Oral Suspension; Acetaminophen and Codeine Phos- Uracet; Vemol†; Xebramol; Turk.: A-Per; Asomal; Babinoks; Berko-Seta-
phate Tablets; Acetaminophen and Diphenhydramine Citrate Tablets; mol; Calpol; Efferalgan; Efpa; Ekosetol; Geralgine; Gripin; Minafen; Minoset;
• 1 to 5 years: 125 to 250 mg Acetaminophen and Pseudoephedrine Hydrochloride Tablets; Acetami- Noral; Panadol; Para-Nox; Paracet; Parasedol; Parol; Paroma; Pirofen; Pol-
• 6 to 12 years: 250 to 500 mg nophen Capsules; Acetaminophen Extended-Release Tablets; Acetami- mofen; Sedalon; Setamol; Tamol; Tempo; Termacet; Termalgine; Tylol; Ver-
nophen for Effervescent Oral Solution; Acetaminophen Oral Solution; midon; Volpan; UAE: Adol; UK: Abdine Cold Relief; Alvedon; Anadin Pa-
The BNFC suggests the following rectal doses in younger chil- racetamol; Boots Pain Relief Suspension 6 Years Plus; Calpol; Disprol;
dren: Acetaminophen Oral Suspension; Acetaminophen Suppositories; Acetami-
nophen Tablets; Acetaminophen, Aspirin, and Caffeine Tablets; Acetami- Fennings Childrens Cooling Powders; Galpamol; Hedex; Infadrops; Manda-
• neonates 28 to 32 weeks postmenstrual age: 20 mg/kg as a nophen, Chlorpheniramine Maleate, and Dextromethorphan Hydrobro- nol; Medinol; Miradol; Obimol; Paldesic; Panadol; Panaleve; Paracets; Para-
clear; Parapaed; Perfalgan; Salzone; USA: Acephen; Aceta; Apacet; Apap;
single dose then 15 mg/kg every 12 hours if necessary to a mide Tablets; Acetaminophen, Dextromethorphan Hydrobromide,
Apra; Arthritis Pain Formula Aspirin Free; Aspirin Free Anacin; Aspirin Free
maximum of 30 mg/kg daily Doxylamine Succinate, and Pseudoephedrine Hydrochloride Oral Solution;
Acetaminophen, Diphenhydramine Hydrochloride, and Pseudoephedrine Pain Relief; Bromo Seltzer; Childrens Dynafed Jr†; Childrens Mapap; Com-
• neonates over 32 weeks postmenstrual age: 30 mg/kg as a trex Maximum Strength Sore Throat; Dolono; Dynafed EX†; Feverall; Ge-
Hydrochloride Tablets; Butalbital, Acetaminophen, and Caffeine Capsules; napap; Genebs; Halenol; Infantaire; Liquiprin; Mapap; Maranox; Meda†;
single dose then 20 mg/kg every 8 hours if necessary to a max- Butalbital, Acetaminophen, and Caffeine Tablets; Hydrocodone Bitartrate Oraphen-PD; Panadol; Panitone; Redutemp; Ridenol; Silapap; Tapanol†;
imum of 60 mg/kg daily and Acetaminophen Tablets; Isometheptene Mucate, Dichloralphenazone, Tempra; Tylenol; Tylenol Sore Throat Daytime; UN-Aspirin; Uni-Ace; Ven-
and Acetaminophen Capsules; Oxycodone and Acetaminophen Capsules; ez.: Acetafen; Acetalis; Aceval; Agurin; Alivax; Amifen; Ananty; Apiret; Apy-
• 1 to 3 months of age: 30 to 60 mg every 8 hours Oxycodone and Acetaminophen Tablets; Propoxyphene Hydrochloride rene; Atamel; Brexin; Cadafen†; Colprin†; Menpirin†; Paracor; Parstelin†;
• 3 to 12 months of age: 60 to 125 mg every 4 to 6 hours if nec- and Acetaminophen Tablets; Propoxyphene Napsylate and Acetami- Tachipirin; Tempra; Tylenol; Tylex; Vestax; Winadol†.
essary to a maximum of 4 doses in 24 hours nophen Tablets.
Multi-ingredient: numerous preparations are listed in Part 3.
The BNFC also suggests higher rectal doses for use in children Proprietary Preparations (details are given in Part 3)
with more severe symptoms: Arg.: Acetolit; Alikal Dolor; Apracur Antifebril; Bio Grip-T; Causalon; Cus-
todial†; Dirox; Doxidol; Dristancito†; Fiebrol†; Fiebrolito; Flash; Guemusin†;
• 1 to 3 months: 30 mg/kg as a single dose followed by Inmunogrip T Caliente; Invernosan†; Itedal; Mejoral; Multifebrin†; Nodipir;
20 mg/kg every 8 hours to a maximum of 60 mg/kg daily Nodolex†; Novo Asat; Para Z Mol†; Parageniol; Paratral; Parclen; PH 4 Parecoxib Sodium (BANM, USAN, rINNM)
• older children: 40 mg/kg as a single dose followed by Plus†; Plovacal; Predualito†; Qura Plus; Tafirol; Termofren; Tetradox; Tyle- Natrii Parecoxibum; Parecoxib sódico; Parécoxib Sodique; SC-
nol†; Vick Vitapyrena; Viclor; Austral.: Chemists Own Pain & Fever; Child-
20 mg/kg every 4 to 6 hours to a maximum of 90 mg/kg daily rens Panadol; Dymadon; Febridol; Lemsip; Ordov Febrigesic†; Panadol; Pan- 69124A. N-{[p-(5-Methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl}-
for 48 hours or longer, if necessary, before reducing to amax; Parahexal; Paralgin; Perfalgan; Setamol†; Tylenol†; Austria: propionamide sodium.
15 mg/kg every 6 hours. Usual adult maximum doses (see Becetamol; Ben-u-ron; Duaneo; Enelfa; Gewamol; Grippostad; Kratofin sim- Натрий Парекоксиб
above) should not be exceeded plex; Mexalen; Momentum; OSA; Parakapton; Paraspeed; Peinfort; Perfal-
gan; Belg.: Algostase Mono; Curpol; Dafalgan; Dolol-Instant; Dolprone; C 19 H 17 N 2 NaO 4 S = 392.4.
Doses by intravenous infusion in children, given over 15 min- Lemsip; Panadol; Pe-Tam; Perdolan; Perfusalgan; Sanicopyrine; Braz.: Aceta- C AS — 198470-84-7 (parecoxib); 197502-82-2
utes, are: mil; Acetofen; Anatyl; Cefabrina; Cetafrin†; Cetynol†; Contradol†; Cyfenol; (parecoxib sodium).
Dorfen; Dorib†; Dorico; Dorsanol; Dorvan†; Emsgrip; Febralgin†; Fervex; ATC — M01AH04.
• full-term neonates and other children below 10 kg: single dos- Gripeonil†; Gripotermon; Pacemol†; Paracemil†; Paracen; Paralgen; Pa-
es of 7.5 mg/kg every 4 or more hours, to a maximum of ratermol†; Piramin; Pyrimel; Sonridor; Termo-Ped†; Termol; Tilekin; Trifen; ATC Vet — QM01AH04.
30 mg/kg daily; intravenous paracetamol has not been studied Tyflen†; Tylalgin†; Tyleflan†; Tylenol; Tylephen; Tylidol; Unigrip; Canad.:
in premature neonates Abenol; Acet; Alsiphene†; Artritol; Atasol; Cephanol; Childrens Feverhalt;
Multi-gesic; Novo-Gesic; Pain Aid Free; Panadol; Pediatrix; Robigesic†; Tan-
• between 10 and 33 kg: single doses of 15 mg/kg every 4 or taphen; Tempra; Tylenol; Chile: Acamol; Asafen Nueva Formula†; Cotibin O O O
more hours, to a maximum of 60 mg/kg or 2 g daily (which- Compuesto; Cryogenine Plus†; Daimeton†; Fibrimol†; Geniol-P; Kitadol;
ever is less) Panadol; Panagesic; Parox Meltab; Rapidol; Supracalm; Tapsin Infantil; Tapsin S CH3
SC; Winasorb; Xumadol; Zolben; Cz.: Ben-u-ron; Calpol; Daleron; Effect N
• from 33 to 50 kg: single doses of 15 mg/kg every 4 or more Comfort; Efferalgan; Gelocatil†; Medipyrin; Mexalen; Panadol; Paralen; Par-
hours, to a maximum of 60 mg/kg or 3 g daily (whichever is amax Rapid; Perfalgan; Denm.: Pamol; Panam; Panodil; Paratabs; Perfalgan;
H
less) Pinex; Fin.: Pamol; Panadol; Para-Suppo; Para-Tabs; Paraceon; Paramax
• over 50 kg: usual adult doses (see above) Rap; Perfalgan; Fr.: Claradol; Dafalgan; Doliactic; Doliprane; Dolitabs; Dolko; N
Dolotec; Efferalgan; Efferalganodis; Expandox; Febrectol†; Geluprane; Pana-
The intravenous solution may be diluted to a minimum strength dol; Paralyoc; Perfalgan; Ger.: Ben-u-ron; Captin; Contac Erkaltungs-Trunk; O
of one-tenth of its original concentration in sodium chloride Doloreduct†; Dorocoff-Paracetamol†; Enelfa; Fensum; Grippostad Heissge- CH3
0.9% or glucose 5%; the diluted solution should be used within trank†; Mono Praecimed; Paedialgon; Parapaed; PCM; Perfalgan; Pyromed†;
RubieMol†; Sinpro N; Togal; Gr.: Apotel; Calmodor; Cetinject†; Dalmi- (parecoxib)
1 hour of preparation. nette†; Depon; Depon Maximum; Depon Odis; Dolal; Genspir†; Lonarid
It has been suggested1 that the recommended doses of paraceta- Aplo; Panadol; Par; Perfalgan; protAlgon; Tunelzin†; Hong Kong: Afebrin†;
mol for children may result in subtherapeutic blood concentra- Angenol; Arfen; Ben-u-ron; Biogesic; Calpol†; Children’s Tylenol†; Christa- Incompatibility. Parecoxib sodium should not be mixed with
mol; Cortal for Children; Dhamol; Europain; Fortolin†; Infant’s Tylenol†; Jun-
tions, and that an initial loading dose should be given, followed ior Strength Tylenol†; Panadol; Parcemol; Parmol; Progesic; Serimol; Seta- products other than those recommended in licensed product in-
by regular doses up to the recommended maximum daily dose. mol; Tiffy; Tylenol†; Uni-Febrin; Hung.: Ben-u-ron; Efferalgan; Febrilin; formation (see Uses and Administration, below). In particular,
However, the appropriate maximum daily dose remains contro- Grippostad; Mexalen; Panadol; Paramax Rapid; Perfalgan; Rubophen; India: the use of lactated Ringer’s solution with or without glucose will
versial, and there is obvious concern given the risks of overdos- Calpol; Crocin; Disprin Paracetamol; Doliprane†; Febridol; Febrinil; Jagcin; cause parecoxib to precipitate. Parecoxib should also not be giv-
Malidens; Pacimol; Paracin; Paracip; Parafizz†; Pyrexon; Pyrigesic; Ultragin;
age. Indon.: Afebrin; Alphamol; Biogesic; Bodrex Forte; Calapol; Contratemp; en in the same syringe as opioids. The use of sterile water for
1. Zacharias M, Watts D. Pain relief in children. BMJ 1998; 316: Cupanol; Dapyrin; Dumin; Erphamol; Farmadol; Fevrin; Grafadon; Gunace- injection is not recommended as the resulting solution is not iso-
1552. ta; Itamol; Lanamol; Maganol; Naprex; Nasamol; Nufadol; Ottopan; Pamol; tonic.
Panadol; Paracetol; Praxion; Progesic; Propyretic; Pyrex; Pyrexin; Pyridol;
Administration in renal impairment. In patients with a cre- Sanmol; Sumagesic; Tempra; Termorex; Turpan; Xepamol; Irl.: Anadin Pa- Adverse Effects, Treatment, and Precautions
atinine clearance of 30 mL/minute or less it is recommended that racetamol; Calpol; Disprol; Hedex; Lemsip Children’s Cold Relief; Panadol; As for NSAIDs in general, p.96.
the interval between each intravenous paracetamol dose is in- Paralief; Paralink; Parapaed; Paratabs; Perfalgan; Tylenol†; Israel: Abrol; Ab-
rolet; Acamol; Acamoli; Aldolor; Dexamol; Dexamol Kid; Efferalgan†; Pana- Hypersensitivity reactions, including anaphylaxis and angioede-
creased to 6 hours. dol; Paramol; Paramolan; Rokamol; Sensamol; Supramol†; Vimoli; Ital.: ma and serious skin reactions, have been reported with valdecox-
Headache. Non-opioid analgesics such as paracetamol, aspi- Acetamol; Efferalgan; Levadol; Minofen; Normaflu†; Panadol; Perfalgan; ib and may therefore occur with parecoxib, a prodrug of val-
Piros; Puernol†; Sanipirina; Tachipirina; Malaysia: Acet†; Arfen; Biogesic; decoxib (see also p.132). Parecoxib should be stopped at the first
rin, and other NSAIDs are often tried first for the symptomatic Dhamol; Dumin†; Hoemal; Naprex†; Panadol; Parafizz; Partamol; Poro;
treatment of various types of headache including migraine (see Rapidol; Serimol†; Setromol†; Uphamol; Mex.: Abatem; Ac-Fast; Acetafen; signs of hypersensitivity. Some of these reactions occurred in pa-
p.616) and tension-type headache (see p.617). These drugs given Acetif; Alpirex; Amolgen; Analphen; Andopan†; Andox; Antidol; Biofer; tients with a history of allergic reactions to sulfonamides and the
at the onset of symptoms can successfully treat an acute attack of Bremotel†; Calinofen; Coriver; Datril; Dismifen; Dolgan Flash; Dolotemp†; use of parecoxib is contra-indicated in such patients.
Doluvital; Dolviran; Farpik; Febran†; Ferridal; Filanc; Frilen; Ginol†; Icetazol;
migraine. However, absorption may be poor due to gastric stasis Ifutemp†; Infalgina; Magnidol; Magnidol-Plus; Mejoral Acti-Rapido; Mejoral- Parecoxib should be avoided in patients with severe hepatic im-
which is commonly present in migraine. For this reason dispers- ito; Minofen; Neodol; Neodolito†; Nordinet Infantil; Notem; Panofen; Phar- pairment (Child-Pugh score of 10 or more), inflammatory bowel
ible and effervescent preparations and compound preparations macen; Piralgina; Piralgina 650; Piralyn; Piremol; Precifen; Prosedal; Quitadol; disease, and moderate to severe heart failure (NYHA class II to
containing drugs such as metoclopramide which relieve gastric Resfin; Sedalito; Sinedol; Soltadol; Sons Piral; Sudis; Tafirol; Temperal; Tem- IV). It should not be used in patients with ischaemic heart dis-
pire; Tempofin; Tempra; Tempre†; Temprin; Temzzard; Termotrin†; Tylenol;
stasis have been advocated. Tylex; Ulpafie; Winasorb; Neth.: Daro; Democyl; Finimal Junior†; Hedex; ease, peripheral arterial disease, or cerebrovascular disease. It
Pain. Paracetamol is used in the management of mild to moder- Kinder Finimal†; Lagalgin†; Momentum; Panadol; Perfalgan; Sinaspril-Para- should also not be used after coronary artery bypass graft surgery
ate pain (see Choice of Analgesic, p.2). It is of similar potency to
cetamol; Tylenol; Vicks Paracetamol; Norw.: Pamol; Panodil; Paracet; Perfal- as there may be an increased risk of adverse effects such as myo-
gan; Pinex; NZ: Disprol†; Lemsip Cold & Flu Original, Cold & Flu Max; cardial infarction, deep-vein thrombosis, pulmonary embolism,
aspirin, but with weak anti-inflammatory activity. Paracetamol Pacimol; Pamol; Panadol; Paracare; Parapaed; Perfalgan; Philipp.: Acet;
may also be used as an adjunct to opioids in the management of Acetadol; Aeknil; Alvedon; Baropyrine; Biogesic; Calpol; Cloxina; Corgic; stroke, renal impairment, deep surgical infections, and sternal
severe pain such as cancer pain (p.5). Paracetamol is the pre- Crocin; Detramol; Dolexpel; Febrinil; Gendol; Gifaril P; Lexalgin; Medgenol; wound complications. This may apply especially in obese pa-
ferred choice for pain in children (p.3) because of the association
Naprex; Nektol; Neo-Kiddielets; Opigesic; Para-4-Kids; Parvid; Rexidol; Rib- tients or those with a history of cerebrovascular disease. Parecox-
er; Saridon; Tempain; Tempra; Tylenol; Ultragesic; Zestagesic; Zydinol; Pol.: ib should be used with caution in patients with significant risk
of aspirin with Reye’s syndrome in this age group (see p.22). In Acenol; Apap; Calpol; Codipar; Efferalgan; Grippostad; Novo-Gesic; Pana-
the treatment of rheumatic disorders, a weak anti-inflammatory dol; Perfalgan; Tazamol; Port.: Anti-Gripe Asclepius; Atralidon; Beluron; factors for cardiovascular disease such as hypertension, hyperli-
effect limits the role of paracetamol. However, it may be of ben- Ben-u-ron; Calpol†; Cofedron; Dafalgan; Efferalgan; Fludeten†; Gelocatil; pidaemia, and diabetes mellitus. Caution is also recommended
Katagrip; Neogrip; Panadol; Panasorbe; Pantadolor; Paracetol; Paramolan; when using parecoxib in dehydrated patients; rehydration may
efit for simple pain control in rheumatoid arthritis (p.11) and an- Parsel; Perdolan Mono†; Perfalgan; Singrips; Supofen; Takiprina; Tylenol; Zar-
kylosing spondylitis (see under Spondyloarthropathies, p.13), al- be advisable before giving parecoxib.
amol†; Rus.: Calpol (Калпол); Cefecon D (Цефекон Д); Daleron
though these patients usually require the additional anti- (Далерон); Dolomol (Доломол); Flutabs (Флютабс); Panadol (Панадол); Effects on the cardiovascular system. There have been
inflammatory effects provided by NSAIDs. Synovial inflamma- Perfalgan (Перфалган); S.Afr.: Anadin-3; Antalgic; Brunomol†; Calpol; Do- concerns about the adverse cardiovascular effects of selective
lorol; Empaped; Fevamol; Go-Pain P; Junior Disprin†; Medpramol; Merck-
tion is usually only a minor component of osteoarthritis (p.11), Gesic†; Micro-Gesic; Napamol; Pacimol; Painamol; Panado; Paradco; Par- cyclo-oxygenase-2 (COX-2) inhibitors after the general world-
and paracetamol is generally recommended as first choice of amed; Perfalgan; Prolief; Pyradol; Tylenol; Varipan; Winpain†; Singapore: wide withdrawal of rofecoxib (see p.121). The short-term use of
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
112 Analgesics Anti-inflammatory Drugs and Antipyretics
parecoxib after coronary artery bypass graft surgery has been as- with half the usual dose, repeated to a maximum of 40 mg daily. USP 31 (Pentazocine Hydrochloride). A white crystalline pow-
sociated with an increased risk of adverse effects such as myo- Doses may need to be reduced in hepatic impairment, see below. der. It exhibits polymorphism, one form melting at about 254°
cardial infarction, deep-vein thrombosis, pulmonary embolism, Parecoxib should be reconstituted with either sodium chloride and the other at about 218°. Soluble 1 in 30 of water, 1 in 20 of
and stroke.1 When compared with patients in the placebo group, 0.9%, glucose 5%, or sodium chloride 0.45% with glucose 5%; alcohol, and 1 in 4 of chloroform; very slightly soluble in acetone
the risk of such effects was almost 4 times greater in those given no other solvents are recommended in licensed product informa- and in ether; practically insoluble in benzene. Store in airtight
intravenous parecoxib for 3 days followed by oral valdecoxib for tion. In addition the reconstituted solution may only be injected containers. Protect from light.
the next 7 days. into intravenous lines delivering sodium chloride 0.9%, glucose
For discussion and advice on the use of selective COX-2 inhibi- 5%, sodium chloride 0.45% with glucose 5%, or lactated Ring- Pentazocine Lactate (BANM, USAN, rINNM) ⊗
tors in patients with cardiovascular or cerebrovascular disease, er’s solution. (See above for details on incompatibilities.)
Lactato de pentazocina; Pentatsosiinilaktaatti; Pentazocine, lac-
see under Celecoxib, p.34. ◊ References. tate de; Pentazocini lactas; Pentazocinlaktat; Pentazocin-laktát;
1. Nussmeier NA, et al. Complications of the COX-2 inhibitors 1. Cheer SM, Goa KL. Parecoxib (parecoxib sodium). Drugs 2001;
parecoxib and valdecoxib after cardiac surgery. N Engl J Med Pentazocino laktatas.
61: 1133–41.
2005; 352: 1081–91. Пентазоцина Лактат
2. Amabile CM, Spencer AP. Parecoxib for parenteral analgesia in
Effects on the gastrointestinal tract. It is generally accept- postsurgical patients. Ann Pharmacother 2004; 38: 882–6. C 19 H 27NO,C 3 H 6 O 3 = 375.5.
ed that the inhibition of cyclo-oxygenase-1 (COX-1) plays a role 3. Mehlisch DR, et al. The analgesic efficacy of intramuscular C AS — 17146-95-1.
in the adverse gastrointestinal effects of the NSAIDs, and that the parecoxib sodium in postoperative dental pain. J Am Dent Assoc
2004; 135: 1578–90. Pharmacopoeias. In Eur. (see p.vii). US includes only Penta-
selective inhibition of the other isoform, COX-2, by NSAIDs 4. Malan TP, et al. The cyclooxygenase-2-specific inhibitor zocine Lactate Injection.
such as parecoxib may cause less gastrotoxicity than that seen parecoxib sodium is as effective as 12 mg of morphine adminis- Ph. Eur. 6.2 (Pentazocine Lactate). A white or almost white
with the non-selective inhibition of the traditional NSAIDs. tered intramuscularly for treating pain after gynecologic laparot- powder. Sparingly soluble in water; slightly soluble in dichlo-
However, licensed product information reports that upper gas- omy surgery. Anesth Analg 2005; 100: 454–60. romethane; freely soluble in methyl alcohol. A 1% solution in
trointestinal perforation, ulceration, and bleeds have occurred 5. Beaussier M, et al. A randomized, double-blind comparison be-
tween parecoxib sodium and propacetamol for parenteral post- water has a pH of 5.5 to 6.5. Protect from light.
with parecoxib treatment and therefore it should be used with operative analgesia after inguinal hernia repair in adult patients. BP 2008 (Pentazocine Lactate). A white to pale cream powder.
caution in patients with a history of such events. Anesth Analg 2005; 100: 1309–15. Sparingly soluble in water, in alcohol, and in chloroform; freely
Effects on the kidneys. Increasing evidence of the renal tox- 6. Sindhvananda W, et al. Parecoxib versus tramadol for post-ap- soluble in methyl alcohol. A 1% solution in water has a pH of 5.5
pendectomy pain. J Med Assoc Thai 2005; 88: 1557–62. to 6.5.
icity of the selective cyclo-oxygenase-2 (COX-2) inhibitors such 7. Gajraj NM. COX-2 inhibitors celecoxib and parecoxib: valuable
as parecoxib suggests that such NSAIDs appear to have effects options for postoperative pain management. Curr Top Med Chem Incompatibility. Commercial injections of pentazocine lactate
on renal function similar to those of the non-selective NSAIDs 2007; 7: 235–49. are reported to be incompatible with soluble barbiturates and oth-
(see p.98). er alkaline substances including sodium bicarbonate. Diazepam
Administration in hepatic impairment. Licensed product
Up to June 2004, the Australian Adverse Drug Reactions Advi- information in the UK states that no dosage adjustment is gener- and chlordiazepoxide have also been reported to be incompati-
sory Committee had received 20 reports of adverse reactions as- ally necessary for parecoxib in patients with mild hepatic impair- ble, as have glycopyrronium bromide1 and nafcillin sodium.2
sociated with parecoxib.1 Of these, 13 mentioned renal impair- ment (Child-Pugh score 5 or 6). For those with moderate impair- 1. Ingallinera TS, et al. Compatibility of glycopyrrolate injection
ment with raised creatinine levels and/or oliguria; acute renal ment (Child-Pugh score 7 to 9) parecoxib should be given at half with commonly used infusion solutions and additives. Am J
failure was reported in 4 of the 13 cases and multiple doses of the usual dose (see above), repeated to a maximum dose of Hosp Pharm 1979; 36: 508–10.
parecoxib had been given in 6 cases. (In Australia, parecoxib was 2. Jeglum EL, et al. Nafcillin sodium incompatibility with acidic
40 mg daily. Use in patients with severe impairment (Child-Pugh solutions. Am J Hosp Pharm 1981; 38: 462, 464.
approved for single-dose use only because of safety concerns score 10 and over) is not recommended as there is no clinical
about multiple doses.) experience in such patients. Dependence and Withdrawal
1. Adverse Drug Reactions Advisory Committee (ADRAC). As for Opioid Analgesics, p.101.
Parecoxib—one shot only. Aust Adverse Drug React Bull 2004; Preparations
Pentazocine is subject to abuse.
23: 10–11. Also available at: http://www.tga.gov.au/adr/aadrb/ Proprietary Preparations (details are given in Part 3)
aadr0406.pdf (accessed 08/11/07) Austral.: Dynastat; Austria: Dynastat; Belg.: Dynastat; Chile: Pro-Bextra; ◊ Pentazocine does produce physical dependence, but withdraw-
Interactions Cz.: Dynastat; Denm.: Dynastat; Fin.: Dynastat; Fr.: Dynastat; Ger.: Dyn- al symptoms are substantially less severe than with morphine. It
astat; Gr.: Dynastat; Hong Kong: Dynastat; Hung.: Dynastat; India: Bio- does not typically produce drug-seeking behaviour of the same
For interactions associated with NSAIDs, see p.99. val-P†; Valcox; Valdixx; Valdone-P; Valus-P†; Vorth-P; Indon.: Dynastat; Irl.:
Dynastat; Ital.: Dynastat; Mex.: Dynastat; Neth.: Dynastat; Norw.: Dyna- degree or intensity as morphine or other prototypic μ agonists,
Parecoxib is rapidly hydrolysed to its active metabolite, val-
stat; NZ: Dynastat; Port.: Dynastat; Rus.: Dynastat (Династат); S.Afr.: nor does it substitute for morphine in dependent subjects.1 Pen-
decoxib; the metabolism of valdecoxib is mainly mediated by the Rayzon; Spain: Dynastat; Swed.: Dynastat; Switz.: Bextra†; Thai.: Dyna- tazocine injection has been abused,2 but street abuse, especially
cytochrome P450 isoenzymes CYP3A4 and CYP2C9. Conse- stat; UK: Dynastat; Venez.: Dynastat†. in the USA, has more often involved the intravenous use of
quently, caution is recommended when using parecoxib with in-
crushed tablets of pentazocine and tripelennamine (‘T’s and
hibitors of such isoenzymes. Licensed product information ad-
Blues’).3-5 A decreased incidence of pentazocine abuse in the
vises that the dose of parecoxib should be reduced if given with
fluconazole, a CYP2C9 inhibitor; however, dose adjustment of Pentazocine (BAN, USAN, rINN) ⊗ USA appeared to coincide with the introduction of oral tablets
incorporating naloxone,1 the rationale being that naloxone antag-
parecoxib is not generally necessary when giving with ketocona- NIH-7958; NSC-107430; Pentatsosiini; Pentazocin; Pentazocina; onises the effect of pentazocine if illicitly injected, but has no
zole, a CYP3A4 inhibitor, despite increased plasma concentra- Pentazocinas; Pentazocinum; Win-20228. (2R*,6R*,11R*)-1,2,- effect when taken orally. Some continued to abuse the new pen-
tions of valdecoxib. The effects of enzyme inducers such as car- 3,4,5,6-Hexahydro-6,11-dimethyl-3-(3-methylbut-2-enyl)-2,6- tazocine/naloxone formulation;6 intravenous abuse in one wom-
bamazepine, dexamethasone, phenytoin, and rifampicin have methano-3-benzazocin-8-ol. an, who was unaware of the reformulation, resulted in opioid
not been studied; theoretically, the metabolism of valdecoxib
Пентазоцин withdrawal symptoms and severe hypertension.7 A 1989 report
may be increased by these drugs.
C 19 H 27NO = 285.4. from the WHO committee1 rated the likelihood of abuse of pen-
Valdecoxib has been noted to increase the plasma levels of dex- tazocine as moderate, based on its pharmacological profile, de-
tromethorphan, a CYP2D6 substrate, and therefore caution is C AS — 359-83-1.
ATC — N02AD01. pendence potential, and actual abuse. The committee considered
recommended when giving parecoxib with drugs that are metab- that it should continue to be scheduled as a psychotropic sub-
olised via CYP2D6 and that have a narrow therapeutic index. ATC Vet — QN02AD01.
stance rather than a narcotic drug.
Such drugs include flecainide, metoprolol, and propafenone. 1. WHO. WHO expert committee on drug dependence: twenty-
Valdecoxib may also affect the plasma levels of drugs that are fifth report. WHO Tech Rep Ser 775 1989. Also available at:
H CH3
metabolised via CYP2C19: an increase in the plasma levels of http://libdoc.who.int/trs/WHO_TRS_775.pdf (accessed 27/06/08)
omeprazole was seen in patients using valdecoxib. 2. Hunter R, Ingram IM. Intravenous pentazocine abuse by a nurse.
N CH3 Lancet 1983; ii: 227.
Pharmacokinetics H 3. Poklis A, Whyatt PL. Current trends in the abuse of pentazocine
On intravenous or intramuscular injection, parecoxib is rapidly and tripelennamine: the metropolitan St. Louis experience. J Fo-
hydrolysed in the liver to its active metabolite, valdecoxib, and CH3 rensic Sci 1980; 25: 72–8.
HO
propionic acid; the plasma half-life of parecoxib is about 22 min- 4. Senay EC. Clinical experience with T’s and B’s. Drug Alcohol
utes. Plasma protein binding is about 98%. Valdecoxib is also H 3C Depend 1985; 14: 305–11.
extensively metabolised in the liver; pathways involved include 5. Jackson C, et al. Fatal intracranial hemorrhage associated with
phenylpropanolamine, pentazocine, and tripelennamine over-
those via the cytochrome P450 isoenzymes CYP3A4 and Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. dose. J Emerg Med 1985; 3: 127–32.
CYP2C9, and glucuronidation. Another active metabolite has Ph. Eur. 6.2 (Pentazocine). A white or almost white powder. It 6. Reed DA, Schnoll SH. Abuse of pentazocine-naloxone combina-
been identified but it is not considered to contribute a significant shows polymorphism. Practically insoluble in water; soluble in tion. JAMA 1986; 256: 2562–4.
clinical effect. Excretion is mainly via the urine with about 70% alcohol; freely soluble in dichloromethane. Protect from light. 7. Reinhart S, Barrett SM. An acute hypertensive response after in-
of a dose appearing as inactive metabolites. Less than 5% of a USP 31 (Pentazocine). A white or very pale, tan-coloured pow- travenous use of a new pentazocine formulation. Ann Emerg Med
dose appears as unchanged valdecoxib in the urine. No 1985; 14: 591–3.
der. Practically insoluble in water; soluble 1 in 11 of alcohol, 1 in
unchanged parecoxib is found in the urine with only trace 2 of chloroform, and 1 in 42 of ether; soluble in acetone; sparing- Adverse Effects
amounts in the faeces. The elimination half-life of valdecoxib is ly soluble in ethyl acetate and in benzene. Store in airtight con- As for Opioid Analgesics in general, p.102.
about 8 hours. tainers. Protect from light. Pentazocine may cause hallucinations and other psychotomimet-
◊ References. ic effects such as nightmares and thought disturbances. High dos-
1. Karim A, et al. A pharmacokinetic study of intramuscular (IM) Pentazocine Hydrochloride (BANM, USAN, rINNM) ⊗ es may result in hypertension and tachycardia; increased aortic
parecoxib sodium in normal subjects. J Clin Pharmacol 2001; Hidrocloruro de pentazocina; Pentatsosiinihydrokloridi; Pentazo- and pulmonary artery pressure with an increase in cardiac work
41: 1111–19. has followed intravenous use in patients with myocardial infarc-
cine, chlorhydrate de; Pentazocin-hidroklorid; Pentazocin-hydro-
Uses and Administration tion. Like morphine it causes respiratory depression, but penta-
chlorid; Pentazocinhydroklorid; Pentazocini hydrochloridum; zocine is said to have a ‘ceiling’ effect and the depth of respira-
Parecoxib is an NSAID (p.99) reported to be a selective inhibitor Pentazocino hidrochloridas.
of cyclo-oxygenase-2 (COX-2). It is a prodrug of valdecoxib tory depression does not increase proportionately with higher
(p.132) and is used for the short-term treatment of postoperative Пентазоцина Гидрохлорид doses.
pain in patients aged 18 years and over. Parecoxib is given as the C 19 H 27NO,HCl = 321.9. Rare adverse effects with pentazocine have included agranulocy-
sodium salt although doses are expressed as the base; 42.4 mg of C AS — 2276-52-0; 64024-15-3. tosis and serious skin reactions such as erythema multiforme and
parecoxib sodium is equivalent to about 40 mg of parecoxib. The Pharmacopoeias. In Eur. (see p.vii) and US. toxic epidermal necrolysis.
recommended dose is 40 mg given by intravenous or slow intra- Ph. Eur. 6.2 (Pentazocine Hydrochloride). A white or almost Pentazocine injections may be painful. Local tissue damage may
muscular injection; this may be followed by 20 or 40 mg every 6 white powder. It shows polymorphism. Sparingly soluble in wa- occur at injection sites particularly after subcutaneous injection
to 12 hours as required. The maximum daily dose is 80 mg. Eld- ter and in dichloromethane; soluble in alcohol. A 1% solution in or multiple doses; there have been reports of muscle fibrosis as-
erly patients weighing less than 50 kg should begin treatment water has a pH of 4.0 to 6.0. Protect from light. sociated with intramuscular injections.
 Pentazocine/Pethidine Hydrochloride 113
Effects on the blood. There have been reports of agranulocy- repeated every 3 to 4 hours; it should not be necessary to exceed with cefoperazone sodium or mezlocillin sodium; with nafcillin
tosis associated with pentazocine.1-3 360 mg daily. Also if frequent injections are needed, the intra- sodium an immediate cloudy appearance cleared on agitation.
1. Marks A, Abramson N. Pentazocine and agranulocytosis. Ann muscular route should be used rather than the subcutaneous Incompatibility has also been seen between pethidine hydrochlo-
Intern Med 1980; 92: 433. route, and the injection sites should be varied. In obstetric ride and aciclovir sodium, imipenem, furosemide,3 liposomal
2. Haibach H, et al. Pentazocine-induced agranulocytosis. Can analgesia 30 mg may be given as a single dose by intramuscular doxorubicin hydrochloride,4 and idarubicin.5 Solutions of ce-
Med Assoc J 1984; 130: 1165–6. injection during labour; alternatively, 20 mg may be given by in- fazolin sodium6 and pethidine hydrochloride mixed in 5% glu-
3. Sheehan M, et al. Pentazocine-induced agranulocytosis. Can travenous injection as soon as contractions occur at regular inter- cose injection turned light yellow after storage for 5 days at 25°;
Med Assoc J 1985; 132: 1401.
vals and repeated 2 or 3 times at intervals of 2 to 3 hours if nec- the admixture was stable for at least 20 days at 4°.
Effects on the CNS. Oculogyric crisis has been associated essary. 1. Patel JA, Phillips GL. A guide to physical compatibility of intra-
with the use of pentazocine.1 For details of doses in children, see below. venous drug admixtures. Am J Hosp Pharm 1966; 23: 409–11.
1. Burstein AH, Fullerton T. Oculogyric crisis possibly related to 2. Nieves-Cordero AL, et al. Compatibility of narcotic analgesic
pentazocine. Ann Pharmacother 1993; 27: 874–6. Pentazocine is given rectally in suppositories usually in a dose
solutions with various antibiotics during simulated Y-site injec-
equivalent to pentazocine 50 mg up to 4 times daily. tion. Am J Hosp Pharm 1985; 42: 1108–9.
Effects on the skin. Toxic epidermal necrolysis in a 62-year- As a deterrent to abuse a combined oral preparation of pentazo-
old man was attributed to pentazocine;1 he had taken 50 to 75 mg 3. Pugh CB, et al. Visual compatibility of morphine sulfate and
cine hydrochloride and naloxone hydrochloride is available in meperidine hydrochloride with other injectable drugs during
every 4 hours for 8 days. His severe uraemia was attributed to some countries. simulated Y-site injection. Am J Hosp Pharm 1991; 48: 123–5.
fluid loss through the skin. 4. Trissel LA, et al. Compatibility of doxorubicin hydrochloride li-
1. Hunter JAA, Davison AM. Toxic epidermal necrolysis associat- Administration in children. In the UK, pentazocine is li- posome injection with selected other drugs during simulated Y-
ed with pentazocine therapy and severe reversible renal failure. censed for the relief of moderate to severe pain in children and site administration. Am J Health-Syst Pharm 1997; 54: 2708–13.
Br J Dermatol 1973; 88: 287–90. doses may be repeated every 3 to 4 hours if necessary. Those 5. Turowski RC, Durthaler JM. Visual compatibility of idarubicin
Treatment of Adverse Effects aged 6 to 12 years may be given a usual oral dose of 25 mg. Chil- hydrochloride with selected drugs during simulated Y-site injec-
As for Opioid Analgesics in general, p.102. dren aged 1 to 12 years may be given doses of up to 1 mg/kg tion. Am J Hosp Pharm 1991; 48: 2181–4.
by subcutaneous or intramuscular injection or up to 6. Lee DKT, et al. Stability of cefazolin sodium and meperidine
As pentazocine has both opioid agonist and antagonist activity its hydrochloride. Am J Health-Syst Pharm 1996; 53: 1608–10.
500 micrograms/kg by intravenous injection.
effects may not be completely reversed by naloxone, but use of
the latter is still recommended in pentazocine overdosage. Preparations Stability. Pethidine hydrochloride injection 100 mg/mL was
BP 2008: Pentazocine Capsules; Pentazocine Injection; Pentazocine Sup- stable1 for at least 24 hours at room temperature when diluted to
Precautions a concentration of 300 mg/litre in glucose 5% and 4% and in so-
positories; Pentazocine Tablets;
As for Opioid Analgesics in general, p.103. USP 31: Pentazocine and Aspirin Tablets; Pentazocine and Naloxone Tab- dium chloride injection (0.9%) and sodium chloride injection
Pentazocine has weak opioid antagonist actions and may precip- lets; Pentazocine Injection. (0.9%) diluted 1 in 5.
itate withdrawal symptoms if given to patients who are physical- Proprietary Preparations (details are given in Part 3)
ly dependent on opioids. It should generally be avoided after Accelerated stability studies using elevated temperatures and hu-
Austral.: Fortral†; Austria: Fortral; Belg.: Fortal; Canad.: Talwin; Cz.:
myocardial infarction and in patients with heart failure or arterial Fortral; Denm.: Fortral†; Fr.: Fortal†; Ger.: Fortral; Gr.: Fortal; India: midities to simulate tropical conditions classified pethidine hy-
or pulmonary hypertension. Fortwin; Pentawin; Israel: Rafazocine†; Talwin NX†; Talwin†; Ital.: Talwin; drochloride as a ‘less stable drug substance’.2 It was suggested
Jpn: Peltazon†; Pentagin†; Sosegon†; Neth.: Fortral; Norw.: Fortralin†; that during quality assurance of preparations containing pethi-
When frequent injections are needed, pentazocine should be giv- NZ: Fortral†; Port.: Sosegon†; S.Afr.: Ospronim; Sosenol; Spain: Soseg- dine hydrochloride particular attention should be paid to their
en intramuscularly rather than subcutaneously and the injection on; Switz.: Fortalgesic†; Thai.: Fortwin†; Pangon; Sosegon†; UK: Fortral; stability.
sites should be varied. USA: Talwin; Talwin NX.
Multi-ingredient: India: Expergesic; Foracet; Irl.: Fortagesic†; USA: 1. Rudd L, Simpson P. Pethidine stability in intravenous solutions.
Abuse. See under Dependence and Withdrawal, above. Emergent-Ez; Talacen; Talwin Compound†. Med J Aust 1978; 2: 34.
2. WHO. WHO expert committee on specifications for pharmaceu-
Porphyria. Pentazocine has been associated with acute attacks tical preparations: thirty-first report. WHO Tech Rep Ser 790
of porphyria and is considered unsafe in porphyric patients. 1990. Also available at: http://libdoc.who.int/trs/WHO_TRS_
Interactions 790.pdf (accessed 26/06/08)
For interactions associated with opioid analgesics, see p.103.
Pethidine Hydrochloride
Tobacco smoking. Smokers metabolised about 40% more
⊗
(BANM, rINNM) Dependence and Withdrawal
pentazocine than non-smokers, although there was large inter- Hidrocloruro de petidina; Meperidine Hydrochloride; Péthidine, As for Opioid Analgesics, p.101.
subject variation;1 tobacco smoking might induce liver enzymes chlorhydrate de; Pethidin-hydrochlorid; Pethidini hydrochlori- Doses of pethidine as large as 3 or 4 g daily have been
responsible for drug oxidation. dum; Petidiinihydrokloridi; Petidin Hidroklorür; Petidin-hidroklor- taken by addicts. As tolerance to the CNS stimulant
1. Vaughan DP, et al. The influence of smoking on the inter-subject id; Petidinhydroklorid; Petidino hidrochloridas; Petydyny chlo-
variation in pentazocine elimination. Br J Clin Pharmacol 1976; and antimuscarinic effects is not complete with these
3: 279–83. rowodorek. Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate hy- very large doses, muscle twitching, tremor, mental
drochloride.
Pharmacokinetics confusion, dilated pupils, and sometimes convulsions
Pentazocine is well absorbed from the gastrointestinal tract; after Петидина Гидрохлорид
may be present.
an oral dose, peak plasma concentrations occur in 1 to 3 hours C 15 H 21 NO 2 ,HCl = 283.8.
and the half-life is reported to be about 2 to 3 hours. After intra- C AS — 57-42-1 (pethidine); 50-13-5 (pethidine hydro- Withdrawal symptoms appear more rapidly than with
muscular injection, peak plasma concentrations are reached in 15 chloride). morphine and are of shorter duration.
minutes to 1 hour and the half-life is about 2 to 5 hours. About 50 ATC — N02AB02.
to 75% has been reported to be bound to plasma proteins. Penta-
For the abuse of pethidine analogues, see under Pre-
ATC Vet — QN02AB02. cautions, below.
zocine undergoes extensive first-pass metabolism in the liver;
oral bioavailability is low with only about half of a dose reaching
the systemic circulation. Metabolites and a small amount of Adverse Effects and Treatment
unchanged drug are excreted in the urine. It crosses the placenta CH3
and is distributed into breast milk.
As for Opioid Analgesics in general, p.102.
N The effects on smooth muscle may be relatively less
Hepatic impairment. Clearance of pentazocine was signifi-
cantly reduced and terminal half-life and oral bioavailability in- intense than with morphine and constipation occurs
creased in cirrhotic patients when compared with healthy sub- less frequently. Local reactions often follow injection
jects.1 of pethidine; general hypersensitivity reactions occur
O
1. Neal EA, et al. Enhanced bioavailability and decreased clear- CH3 rarely. Pethidine given intravenously may increase the
ance of analgesics in patients with cirrhosis. Gastroenterology
1979; 77: 96–102. O heart rate. After overdosage, symptoms are generally
Uses and Administration similar to those of morphine poisoning. However,
Pentazocine, a benzomorphan derivative, is an opioid analgesic (pethidine) stimulation of the CNS and convulsions may also oc-
(p.104) that has mixed opioid agonist and antagonist actions. cur, especially in tolerant individuals or after toxic oral
Agonist activity is thought to be mainly at κ opioid receptors doses; these have been attributed mainly to the metab-
(with possibly some σ receptor activity); it acts as a weak antag- NOTE. The following terms have been used as ‘street names’ (see
onist or partial agonist at μ receptors. Pentazocine is used for the p.vi) or slang names for various forms of pethidine: olite norpethidine.
relief of moderate to severe pain including the pain of labour. Bam; Peth.
Incidence of adverse effects. The incidence of adverse ef-
Combined preparations with paracetamol or aspirin may also be Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and fects in hospitalised patients receiving pethidine was monitored
used in the treatment of moderate pain. It may also be used for Viet. by the Boston Collaborative Drug Surveillance Program.1 Ad-
pre-operative sedation and as an adjunct to anaesthesia. Its anal- Ph. Eur. 6.2 (Pethidine Hydrochloride). A white or almost white, verse reactions to oral pethidine were reported in 16 of 366 pa-
gesic effect declines more rapidly than that of morphine. crystalline powder. Very soluble in water; freely soluble in alco- tients and mainly involved the gastrointestinal tract. After pethi-
Pentazocine is given orally as the hydrochloride; doses may be hol. Store in airtight containers. Protect from light. dine by injection 102 of 3268 patients had adverse effects, the
expressed as either the base or the salt. Pentazocine is also given USP 31 (Meperidine Hydrochloride). A fine white odourless CNS being involved in 38.
parenterally and rectally as the lactate; doses are expressed in crystalline powder. Very soluble in water; soluble in alcohol;
sparingly soluble in ether. pH of a 5% solution in water is about More recently, 20 adverse reactions were identified in a chart re-
terms of the base. Pentazocine 100 mg is equivalent to about view of 141 patients given pethidine and considered to be at high
112.8 mg of pentazocine hydrochloride or 131.6 mg of pentazo- 5. Protect from light.
risk of developing toxicity;2 high-risk patients were defined as
cine lactate. Incompatibility. Solutions of pethidine hydrochloride are acid- those with renal impairment (creatinine clearance 50 mL/minute
A usual oral dose is the equivalent of 50 to 100 mg of pentazoc- ic. They are incompatible with barbiturate salts and loss of clarity or less), those receiving patient-controlled analgesia (PCA) with
ine or pentazocine hydrochloride every 3 to 4 hours after food, to was also seen in an early additive study1 with other drugs includ- pethidine, and those given intravenous pethidine in doses of over
a maximum of 600 mg daily. ing aminophylline, heparin sodium, meticillin sodium, morphine 200 mg daily for several days. The most common adverse reac-
The usual initial dose by subcutaneous, intramuscular, or intrave- sulfate, nitrofurantoin sodium, phenytoin sodium, sodium io- tions were confusion and anxiety; other reported adverse effects
nous injection is the equivalent of pentazocine 30 mg as a single dide, sulfadiazine sodium, and sulfafurazole diolamine. Colour included nervousness, seizures, and hallucinations. Patients who
dose. Thereafter, the dose may be adjusted according to re- change from pale yellow to light green occurred when solutions developed adverse reactions were significantly older, more likely
sponse; in some patients 45 to 60 mg by subcutaneous or intra- of minocycline hydrochloride or tetracycline hydrochloride were to be taking a benzodiazepine, and had longer hospital stays than
muscular injection may be required. In the USA single intrave- mixed with pethidine hydrochloride in 5% glucose injection.2 In those without adverse effects. Out of the 20 reports, 16 adverse
nous doses of not more than 30 mg are advised. Doses may be the same study an immediate precipitate occurred on admixture effects were noted in the 123 patients who received pethidine via
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
114 Analgesics Anti-inflammatory Drugs and Antipyretics
a PCA pump; cumulative doses for patients using PCA were suppressed by labetalol.1 Like other histamine-releasing opioids, Barbiturates. Opioid analgesics and barbiturates can be ex-
found to be a significant risk factor in the development of adverse pethidine should be used with caution in such patients. pected to have additive CNS depressant effects. Prolonged seda-
effects. 1. Lawrence CA. Pethidine-induced hypertension in phaeochromo- tion with pethidine in the presence of phenobarbital has also
1. Miller RR, Jick H. Clinical effects of meperidine in hospitalized cytoma. BMJ 1978; 1: 149–50. been attributed to induction of N-demethylation of pethidine, re-
medical patients. J Clin Pharmacol 1978; 18: 180–9. sulting in the enhanced formation of the potentially neurotoxic
2. Seifert CF, Kennedy S. Meperidine is alive and well in the new Pregnancy and the neonate. Pethidine has been widely used
for analgesia during labour. It rapidly crosses the placenta and metabolite norpethidine.1,2
millennium: evaluation of meperidine usage patterns and fre-
quency of adverse drug reactions. Pharmacotherapy 2004; 24: like other opioid analgesics may cause respiratory depression in 1. Stambaugh JE, et al. A potentially toxic drug interaction be-
776–83. tween pethidine (meperidine) and phenobarbitone. Lancet 1977;
the neonate, although perhaps less so than morphine. Respiratory i: 398–9.
Effects on the cardiovascular system. Histamine release depression varies according to the timing and size of the maternal 2. Stambaugh JE, et al. The effect of phenobarbital on the metabo-
was more frequent after pethidine than after morphine, fentanyl, dose. lism of meperidine in normal volunteers. J Clin Pharmacol
or sufentanil given intravenously for the induction of anaesthe- Fetal depression was not apparent when delivery occurred within 1978; 18: 482–90.
sia.1 Increased plasma-histamine concentrations occurred in 5 of 1 hour of giving pethidine, but was present in 6 of 24 infants Histamine H2-antagonists. See under Opioid Analgesics,
16 patients given pethidine in a mean dose of 4.3 mg/kg and delivered 1 to 3 hours after injection and in all of 5 infants deliv- p.103.
were generally accompanied by hypotension, tachycardia, ery- ered 3 to 6 hours after injection.1 However, higher blood concen-
thema, and increased plasma-adrenaline concentrations. Only 1 trations of pethidine were seen in infants delivered within 1 hour MAOIs. Some of the most serious interactions involving pethi-
of 10 given morphine and none of those receiving fentanyl or of an intramuscular dose of pethidine compared with those deliv- dine have been with non-selective MAOIs and have been mani-
sufentanil showed evidence of histamine release. All of the his- ered 1 to 4 hours after injection. The role of pethidine metabolites fest as enhanced depressant effects or hyperexcitability (see In-
tamine releasers were young women. was uncertain. It has also been reported2 that depressed neonatal teractions, above). However, a life-threatening interaction has
1. Flacke JW, et al. Histamine release by four narcotics: a double- responses persisted for the first 2 days of life; depression was also been reported between pethidine and selegiline, a selective
blind study in humans. Anesth Analg 1987; 66: 723–30. dose-related being greatest with the highest dose of pethidine (75 monoamine oxidase type B inhibitor.1 Also, symptoms sugges-
Effects on the nervous system. CNS excitatory effects of to 150 mg within 4 hours of delivery). Neonates appear able to tive of a mild serotonin syndrome developed in a 73-year-old
pethidine such as tremors, muscle twitches, and convulsions metabolise pethidine, although probably more slowly than woman taking moclobemide (a reversible inhibitor of monoam-
have been associated with toxic doses and have been attributed adults.3 The amounts of pethidine and norpethidine excreted by ine oxidase type A), nortriptyline, and lithium after she was giv-
to the metabolite norpethidine. Accumulation of norpethidine the neonate increased significantly with the maternal dose-deliv- en pethidine intravenously.2
may occur if large doses of pethidine are repeated at short inter- ery interval for intervals of up to 5 hours and most of the placen- Use of the antibacterial isoniazid with pethidine led to a drop in
vals (including for patient-controlled analgesia) and is especially tally transferred pethidine should be excreted by the third day. blood pressure and lethargy in a 54-year-old man.3 Serotonin
likely when renal function is impaired.1-13 Elimination of pethidine took up to 6 days in the neonates in syndrome developed in a 27-year-old man after the use of pethi-
1. Kaiko RF, et al. Central nervous system excitatory effects of another study.4 dine with linezolid;4 symptoms resolved when pethidine was
meperidine in cancer patients. Ann Neurol 1983; 13: 180–5. Further references on the transplacental transfer of pethidine can stopped. The authors of both studies attributed the interaction to
2. Lieberman AN, Goldstein M. Reversible parkinsonism related be found in Pregnancy under Pharmacokinetics, below. the inhibitory action of isoniazid and linezolid on monoamine
to meperidine. N Engl J Med 1985; 312: 509. oxidase.
3. Mauro VF, et al. Meperidine-induced seizure in a patient with- Neither psychological nor physical effects were found in 5-year-
out renal dysfunction or sickle cell anemia. Clin Pharm 1986; 5: olds born to mothers who had received pethidine during labour.5 1. Zornberg GL, et al. Severe adverse interaction between pethi-
837–9. Neonatal behaviour does not appear to have been affected signif- dine and selegiline. Lancet 1991; 337: 246. Correction. ibid.;
4. Morisy L, Platt D. Hazards of high-dose meperidine. JAMA 440.
1986; 255: 467–8.
icantly by pethidine, although it has been acknowledged that the
2. Gillman PK. Possible serotonin syndrome with moclobemide
5. Armstrong PJ, Bersten A. Normeperidine toxicity. Anesth Analg relationship between maternal analgesia in labour and subse- and pethidine. Med J Aust 1995; 162: 554.
1986; 65: 536–8. quent infant behaviour is by no means simple.6 The results of 3. Gannon R, et al. Isoniazid, meperidine, and hypotension. Ann
6. Eisendrath SJ, et al. Meperidine-induced delirium. Am J Psychi- early studies that suggested an excess of cases of cancer in chil- Intern Med 1983; 99: 415. Correction. ibid.; 740.
atry 1987; 144: 1062–5. dren whose mothers received pethidine during labour have been
7. Kyff JV, Rice TL. Meperidine-associated seizures in a child. 4. Das PK, et al. Serotonin syndrome after concomitant treatment
Clin Pharm 1990; 9: 337–8. refuted by a later and larger study.7 with linezolid and meperidine. Clin Infect Dis 2008; 46: 264–5.
8. Pryle BJ, et al. Toxicity of norpethidine in sickle cell crisis. BMJ 1. Morrison JC, et al. Metabolites of meperidine related to fetal de-
1992; 304: 1478–9. pression. Am J Obstet Gynecol 1973; 115: 1132–7. Phenothiazines. Prochlorperazine prolonged the respiratory
9. Hagmeyer KO, et al. Meperidine-related seizures associated 2. Hodgkinson R, et al. Double-blind comparison of the neurobe- depressant effect of pethidine in healthy subjects.1 Enhanced
with patient-controlled analgesia pumps. Ann Pharmacother haviour of neonates following the administration of different CNS depression and hypotension were reported when healthy
1993; 27: 29–32. doses of meperidine to the mother. Can Anaesth Soc J 1978; 25: subjects were given chlorpromazine in addition to pethidine;
10. Stone PA, et al. Norpethidine toxicity and patient controlled an- 405–11. there was evidence of increased N-demethylation of pethidine.2
algesia. Br J Anaesth 1993; 71: 738–40. 3. Hogg MIJ, et al. Urinary excretion and metabolism of pethidine
11. Marinella MA. Meperidine-induced generalized seizures with 1. Steen SN, Yates M. Effects of benzquinamide and prochlorpera-
and norpethidine in the newborn. Br J Anaesth 1977; 49: 891–9. zine, separately and combined with meperidine, on the human
normal renal function. South Med J 1997; 90: 556–8.
12. McHugh GJ. Norpethidine accumulation and generalized sei- 4. Cooper LV, et al. Elimination of pethidine and bupivacaine in the respiratory center. Clin Pharmacol Ther 1972; 13: 153.
zure during pethidine patient-controlled analgesia. Anaesth In- newborn. Arch Dis Child 1977; 52: 638–41. 2. Stambaugh JE, Wainer IW. Drug interaction: meperidine and
tensive Care 1999; 27: 289–91. 5. Buck C. Drugs in pregnancy. Can Med Assoc J 1975; 112: 1285. chlorpromazine, a toxic combination. J Clin Pharmacol 1981;
13. Hubbard GP, Wolfe KR. Meperidine misuse in a patient with 6. Anonymous. To measure life. Lancet 1981; ii: 291–2. 21: 140–6.
sphincter of Oddi dysfunction. Ann Pharmacother 2003; 37: 7. Golding J, et al. Childhood cancer, intramuscular vitamin K, and
534–7. pethidine given during labour. BMJ 1992; 305: 341–6. Phenytoin. The hepatic metabolism of pethidine appears to be
enhanced by phenytoin; use together resulted in reduced half-life
Renal impairment. Caution is necessary when pethidine is and bioavailability in healthy subjects; blood concentrations of
Precautions given to patients with renal impairment; UK licensed product in-
As for Opioid Analgesics in general, p.103. norpethidine were increased.1
formation recommends that it should be avoided in those with
1. Pond SM, Kretschzmar KM. Effect of phenytoin on meperidine
Pethidine should also be given cautiously to patients severe impairment, whereas US product information suggests to clearance and normeperidine formation. Clin Pharmacol Ther
with a history of convulsive disorders or supraventricu- use reduced doses. Evidence of CNS excitation, including sei- 1981; 30: 680–6.
zures and twitches, in 2 patients with renal insufficiency given
lar tachycardias. multiple doses of pethidine was attributed to accumulation of the
m e t a b o l i t e n o r p e t h i d i n e; b o t h p a t i e n t s h a d h i g h
Pharmacokinetics
Abuse. A synthetic analogue of pethidine, MPPP (1-methyl-4-
phenyl-4-propionoxypiperidine), manufactured illicitly for rec- norpethidine : pethidine plasma concentration ratios.1 Pethidine hydrochloride is absorbed from the gastroin-
reational use, achieved notoriety when it was accidentally con- See also under Pharmacokinetics, below. testinal tract, but only about 50% of the drug reaches
taminated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropy- 1. Szeto HH, et al. Accumulation of normeperidine, an active me- the systemic circulation because of first-pass metabo-
ridine) leading to an epidemic of parkinsonism among tabolite of meperidine, in patients with renal failure or cancer. lism. Absorption after intramuscular injection is varia-
intravenous drug abusers.1 WHO has also identified another Ann Intern Med 1977; 86: 738–41.
ble. Peak plasma concentrations have been reported 1
analogue, PEPAP (1-phenylethyl-4-phenyl-4-acetoxypiperidine)
as being liable to abuse.2 Interactions to 2 hours after oral doses. It is about 60 to 80% bound
1. Buchanan JF, Brown CR. ‘Designer drugs’: a problem in clinical For interactions associated with opioid analgesics, see to plasma proteins.
toxicology. Med Toxicol 1988; 3: 1–17.
2. WHO. WHO expert committee on drug dependence: twenty- p.103. Pethidine is metabolised in the liver by hydrolysis to
fourth report. WHO Tech Rep Ser 761 1988. Also available at:
Very severe reactions, including coma, severe respira- pethidinic acid (meperidinic acid) or demethylation to
http://libdoc.who.int/trs/WHO_TRS_761.pdf (accessed norpethidine (normeperidine) and hydrolysis to nor-
26/06/08) tory depression, cyanosis, and hypotension have oc-
curred in patients receiving MAOIs (including mo- pethidinic acid (normeperidinic acid), followed by par-
Breast feeding. No adverse effects have been seen in breast-
feeding infants whose mothers were given pethidine, and the clobemide and selegiline) and given pethidine. There tial conjugation with glucuronic acid. Norpethidine is
American Academy of Pediatrics considers1 that it is therefore are also reports of hyperexcitability, convulsions, tachy- pharmacologically active and its accumulation may re-
usually compatible with breast feeding.
cardia, hyperpyrexia, and hypertension. Pethidine sult in toxicity. Pethidine is reported to have a plasma
1. American Academy of Pediatrics. The transfer of drugs and oth-
should not be given to patients receiving MAOIs or elimination half-life of about 3 to 6 hours in healthy
er chemicals into human milk. Pediatrics 2001; 108: 776–89.
Correction. ibid.; 1029. Also available at: within 14 days of their discontinuation. Use of pethi- subjects; the metabolite norpethidine is eliminated
http://aappolicy.aappublications .org/cgi/ content/full/
dine with phenothiazines has produced severe hypo- more slowly, with a half-life reported to be up to about
pediatrics%3b108/3/776 (accessed 26/06/08)
tensive episodes and may prolong the respiratory de- 20 hours. Both pethidine and norpethidine appear in
The elderly. Pethidine had a slower elimination rate in elderly the CSF. At the usual values of urinary pH or if the
compared with young patients and a reduction in total daily dose pression due to pethidine.
might be necessary in elderly patients receiving repeated doses
urine is alkaline, only a small amount of pethidine is
Plasma concentrations of norpethidine are increased by excreted unchanged; urinary excretion of pethidine and
of pethidine.1 Another study concluded that age-related changes
in disposition were not sufficient to warrant modification of
ritonavir, with a resultant risk of toxicity; use together norpethidine is enhanced by acidification of the urine.
pethidine dosage regimens.2 should be avoided (see also p.103). Pethidine crosses the placenta and is distributed into
1. Holmberg L, et al. Comparative disposition of pethidine and nor- Antibacterials. See MAOIs below for interactions between breast milk.
pethidine in old and young patients. Eur J Clin Pharmacol 1982;
pethidine and isoniazid and linezolid.
22: 175–9. ◊ Reviews.
2. Herman RJ, et al. Effects of age on meperidine disposition. Clin Antidepressants. For reference to possible cases of serotonin
Pharmacol Ther 1985; 37: 19–24. 1. Edwards DJ, et al. Clinical pharmacokinetics of pethidine: 1982.
syndrome associated with use of pethidine and SSRIs, see Opioid Clin Pharmacokinet 1982; 7: 421–33.
Phaeochromocytoma. Pethidine provoked episodes of hy- Analgesics under Interactions of Fluoxetine, p.397. See also 2. Moore RA, et al. Opiate metabolism and excretion. Baillieres
pertension in a patient with phaeochromocytoma; the effect was MAOIs, below. Clin Anaesthesiol 1987; 1: 829–58.
 Pethidine Hydrochloride/Phenacetin 115
Administration. The elimination half-life of pethidine was be repeated after 1 to 3 hours if necessary up to a max- more effective for acute pain. For reference to use by other routes
prolonged and plasma clearance decreased when given perioper- imum of 400 mg in 24 hours. see Administration, above.
atively compared with postoperatively.1 1. Mather LE, Glynn CJ. The minimum effective analgesic blood
During labour the pharmacokinetics of pethidine may depend on For premedication 25 to 100 mg may be given intra- concentration of pethidine in patients with intractable pain. Br J
muscularly about 1 hour before surgery. It may also be Clin Pharmacol 1982; 14: 385–90.
how it is given. In a comparison of intramuscular injection at dif- 2. Edwards DJ, et al. Clinical pharmacokinetics of pethidine: 1982.
ferent sites, absorption of pethidine from the gluteus muscle was given subcutaneously in similar doses. As an adjunct Clin Pharmacokinet 1982; 7: 421–33.
impaired and the deltoid muscle was preferred.2 to anaesthesia 10 to 25 mg may be given by slow in- SICKLE-CELL CRISIS. Concern has been expressed over the con-
No statistically significant differences were found in pharmacok- travenous injection. tinued use of pethidine for analgesia in painful crises in sick-
inetic parameters for deltoid and gluteal intramuscular injections le-cell disease. Control of pain may be inadequate and doses
in elderly postoperative patients.3 However, substantial interpa- For details of doses in children, see below.
commonly used to manage crises may lead to accumulation of
tient variability was noted for both sites, and the authors suggest- Administration. In addition to the conventional routes pethi- the neuroexcitatory metabolite of pethidine and precipitate
ed that more rapid and predictable routes such as intravenous in- dine has been given epidurally,1-4 intraperitoneally,5,6 and intrath- seizures.1,2 See also Effects on the Nervous System, above.
jection may be more appropriate for postoperative use in the ecally.7-9 It has also been given by various routes as a patient- 1. Pryle BJ, et al. Toxicity of norpethidine in sickle cell crisis. BMJ
elderly. controlled system.10-13 However, some consider that the use of 1992; 304: 1478–9.
1. Tamsen A, et al. Patient-controlled analgesic therapy, part 1: pethidine should be avoided for patient-controlled analgesia be- 2. Harrison JFM, et al. Pethidine in sickle cell crisis. BMJ 1992;
pharmacokinetics of pethidine in the per- and postoperative pe- cause of the increased risk of norpethidine-induced seizures14 305: 182.
riods. Clin Pharmacokinet 1982; 7: 149–63.
(see also Incidence of Adverse Effects and Effects on the Nerv- Sedation. Some references to the use of pethidine for endosco-
2. Lazebnik N, et al. Intravenous, deltoid, or gluteus administration
of meperidine during labor? Am J Obstet Gynecol 1989; 160: ous System, above). py are given below.
1184–9. 1. Perriss BW. Epidural pethidine in labour: a study of dose re- 1. Bahal-O’Mara N, et al. Sedation with meperidine and mida-
3. Erstad BL, et al. Site-specific pharmacokinetics and pharmaco- quirements. Anaesthesia 1980; 35: 380–2. zolam in pediatric patients undergoing endoscopy. Eur J Clin
dynamics of intramuscular meperidine in elderly postoperative 2. Husemeyer RP, et al. A study of pethidine kinetics and analgesia Pharmacol 1994; 47: 319–23.
patients. Ann Pharmacother 1997; 31: 23–8. in women in labour following intravenous, intramuscular and 2. Diab FH, et al. Efficacy and safety of combined meperidine and
epidural administration. Br J Clin Pharmacol 1982; 13: 171–6. midazolam for EGD sedation compared with midazolam alone.
Hepatic impairment. The terminal half-life of pethidine was 3. Perriss BW, et al. Analgesia following extradural and im pethi- Am J Gastroenterol 1996; 91: 1120–5.
prolonged to about 7 hours in cirrhotic patients compared with 3 dine in post-caesarean section patients. Br J Anaesth 1990; 64: 3. Laluna L, et al. The comparison of midazolam and topical lido-
hours in healthy subjects, which was attributed to impairment of 355–7. caine spray versus the combination of midazolam, meperidine,
4. Blythe JG, et al. Continuous postoperative epidural analgesia and topical lidocaine spray to sedate patients for upper endosco-
the drug-metabolising activity of the liver.1 Another study con- for gynecologic oncology patients. Gynecol Oncol 1990; 37: py. Gastrointest Endosc 2001; 53: 289–93.
cluded that although impaired hepatic metabolism might confer 307–10.
relative protection from norpethidine toxicity in patients with cir- 5. Colbert ST, et al. An assessment of the value of intraperitoneal LYTIC COCKTAILS. Lytic cocktails consisting of chlorprom-
rhosis, there might be an increased risk of cumulative toxicity meperidine for analgesia postlaparoscopic tubal ligation. Anesth azine, pethidine, and/or promethazine have been given intra-
because of slow elimination of the metabolite.2 Analg 2000; 91: 667–70. venously in some countries for the management of pre-ec-
6. O’Hanlon DM, et al. Intraperitoneal pethidine versus intramus- lampsia and imminent eclampsia. However, the use of pheno-
1. Klotz U, et al. The effect of cirrhosis on the disposition and elim- cular pethidine for the relief of pain after laparoscopic cholecys-
ination of meperidine in man. Clin Pharmacol Ther 1974; 16: tectomy: randomized trial. World J Surg 2002; 26: 1432–6. thiazines is generally not recommended late in pregnancy,
667–75. 7. Acalovschi I, et al. Saddle block with pethidine for perineal op- and other treatments are preferred for hypertension (see Hy-
2. Pond SM, et al. Presystemic metabolism of meperidine to erations. Br J Anaesth 1986; 58: 1012–16. pertension in Pregnancy, under Hypertension, p.1171); the
normeperidine in normal and cirrhotic subjects. Clin Pharmacol 8. Yu SC, et al. Addition of meperidine to bupivacaine for spinal management of eclampsia, which is the convulsive phase, is
Ther 1981; 30: 183–8. anaesthesia for caesarean section. Br J Anaesth 2002; 88:
379–83.
discussed on p.470.
Pregnancy. Some references to the pharmacokinetics of pethi- 9. Vranken JH, et al. Plasma concentrations of meperidine and Lytic cocktails have also been used for sedation and analgesia in
dine during labour are given below. normeperidine following continuous intrathecal meperidine in children, by intramuscular or occasionally intravenous injection.
1. Tomson G, et al. Maternal kinetics and transplacental passage of patients with neuropathic cancer pain. Acta Anaesthesiol Scand However, there is a high rate of therapeutic failure as well as se-
pethidine during labour. Br J Clin Pharmacol 1982; 13: 653–9. 2005; 49: 665–70.
10. Striebel HW, et al. Patient-controlled intranasal analgesia (PCI-
rious adverse effects with such combinations, and the American
2. Kuhnert BR, et al. Disposition of meperidine and normeperidine
following multiple doses during labor: I mother. Am J Obstet NA) for the management of postoperative pain: a pilot study. J Academy of Pediatrics1 had recommended that alternative seda-
Gynecol 1985; 151: 406–9. Clin Anesth 1996; 8: 4–8. tives and analgesics should be considered. Lytic cocktails are not
3. Kuhnert BR, et al. Disposition of meperidine and normeperidine 11. Kee N, et al. Comparison of patient-controlled epidural analge- the most appropriate means of sedation for short procedures
following multiple doses during labor: II fetus and neonate. Am sia with patient-controlled intravenous analgesia using pethi- since patients must be monitored for about 1 hour before the pro-
J Obstet Gynecol 1985; 151: 410–15. dine or fentanyl. Anaesth Intensive Care 1997; 25: 126–32.
12. Sharma SK, et al. Cesarean delivery: a randomized trial of epi-
cedure while the drugs take effect, and for even longer during the
Renal impairment. Plasma protein binding of pethidine was dural versus patient-controlled meperidine analgesia during la- recovery period.2
reported to be decreased in renal disease and ranged from 58.2% bor. Anesthesiology 1997; 87: 487–94. 1. American Academy of Pediatrics Committee on Drugs. Reap-
in healthy subjects to 31.8% in anuric patients.1 The same work- 13. Chen PP, et al. Patient-controlled pethidine after major upper praisal of Lytic cocktail/Demerol, Phenergan, and Thorazine
abdominal surgery: comparison of the epidural and intravenous (DPT) for the sedation of children. Pediatrics 1995; 95:
ers also reported prolonged elimination of pethidine in patients routes. Anaesthesia 2001; 56: 1106–12. 598–602.
with renal dysfunction.2 14. Hagmeyer KO, et al. Meperidine-related seizures associated 2. Barst SM, et al. A comparison of propofol and Demerol-Phener-
See also under Precautions, above. with patient-controlled analgesia pumps. Ann Pharmacother gan-Thorazine for brief, minor, painful procedures in a pediatric
1993; 27: 29–32. hematology-oncology clinic. Int J Pediatr Hematol/Oncol 1995;
1. Chan K, et al. Plasma protein binding of pethidine in patients
Administration in children. Pethidine is used for the relief of 1: 587–91.
with renal disease. J Pharm Pharmacol 1983; 35: 94P.
2. Chan K, et al. Pharmacokinetics of low-dose intravenous pethi- moderate to severe acute pain and for premedication in children. Shivering. For reference to the use of pethidine in the manage-
dine in patients with renal dysfunction. J Clin Pharmacol 1987; For the relief of pain, the BNFC suggests that children aged 2 ment of shivering associated with anaesthesia, see under Ad-
27: 516–22. verse Effects of General Anaesthetics, p.1779. Pethidine has also
months to 12 years may be given pethidine hydrochloride 0.5 to
2 mg/kg orally or by subcutaneous or intramuscular injection been used to treat amphotericin B-induced shaking chills.1
Uses and Administration every 4 to 6 hours if necessary; older children up to 18 years of 1. Burks LC, et al. Meperidine for the treatment of shaking chills
Pethidine, a phenylpiperidine derivative, is a synthetic age may be given 50 to 100 mg orally, or 25 to 100 mg intramus- and fever. Arch Intern Med 1980; 140: 483–4.
opioid analgesic (p.104) that acts mainly as a μ opioid cularly or subcutaneously, every 4 to 6 hours if necessary. Injec- Preparations
agonist. Pethidine is used for the relief of most types of tion solutions may be given orally if needed, to achieve a suitable BP 2008: Pethidine Injection; Pethidine Tablets;
dose. Pethidine may also be given by intravenous injection in USP 31: Meperidine Hydrochloride Injection; Meperidine Hydrochloride
moderate to severe acute pain including the pain of la- doses of 0.5 to 1 mg/kg to neonates and children up to 12 years Syrup; Meperidine Hydrochloride Tablets.
bour. It is more lipid soluble than morphine and has a of age, repeated every 10 to 12 hours if necessary in those up to Proprietary Preparations (details are given in Part 3)
less potent and shorter lasting analgesic effect; analge- 2 months of age and every 4 to 6 hours if necessary in older chil- Arg.: Cluyer; Meperol; Austria: Alodan; Belg.: Dolantine; Braz.: Dolanti-
dren; those aged 12 to 18 years may be given the usual adult na; Dolosal; Dornot; Canad.: Demerol; Chile: Demerol†; Cz.: Dolsin;
sia usually lasts for 2 to 4 hours. Its short duration of Ger.: Dolantin; Hung.: Dolargan; Israel: Dolestine; Philipp.: Demerol;
action and accumulation of its potentially neurotoxic intravenous dose (see above) repeated every 4 to 6 hours if Pol.: Dolargan; Dolcontral; Spain: Dolantina; Turk.: Aldolan; USA: De-
necessary. An intravenous injection of 1 mg/kg as a loading merol; Venez.: Demerol†; Dispadol†.
metabolite norpethidine on repeated dosage make it dose followed by continuous intravenous infusion of 100 to Multi-ingredient: Austral.: Marcain with Pethidine†; UK: Pamergan
unsuitable for the management of chronic pain. Pethi- 400 micrograms/kg per hour adjusted according to response may P100.
dine has a weaker action on smooth muscle than mor- also be given to those aged 1 month and over.
phine and its lower potential to increase biliary pres- For premedication, UK licensed product information recom-
sure may make it a more suitable opioid analgesic for mends that 1 to 2 mg/kg is given intramuscularly about 1 hour Phenacetin (rINN)
before surgery.
pain associated with biliary colic and pancreatitis (but Aceto-p-phenetidide; Acetophenetidin; Acetylphenetidin; Fen-
See also Lytic Cocktails, below.
see Biliary-tract Disorders, p.103). It is also used for acetin; Fenacetina; Fenasetiini; Paracetophenetidin; Phénacétine;
premedication and as an adjunct to anaesthesia. It has Eclampsia and pre-eclampsia. See Lytic Cocktails under Se- Phenacetinum. p-Acetophenetidide; 4′-Ethoxyacetanilide; N-(4-
dation, below. Ethoxyphenyl)acetamide.
been given with phenothiazines such as promethazine
to achieve basal narcosis. Pethidine has little effect on Pain. Pethidine produces prompt but short-lasting analgesia, and Фенацетин
may be preferred to morphine when rapid control of acute pain is C 10 H 13 NO 2 = 179.2.
cough or on diarrhoea. required. It has been widely used in obstetrics to control the pain C AS — 62-44-2.
For the relief of pain, pethidine hydrochloride is given of labour (although the BNF notes that morphine or other opioids ATC — N02BE03.
in oral doses of 50 to 150 mg every 4 hours if neces- are often preferred for obstetric pain), and for postoperative pain ATC Vet — QN02BE03.
sary. It may also be given by intramuscular or subcuta- relief after caesarean section or other surgical procedures.
neous injection in doses of 25 to 100 mg and by slow In a study of patients with intractable pain the minimum effect-
ive analgesic blood concentration ranged from 100 to H
intravenous injection in doses of 25 to 50 mg repeated 820 nanograms/mL (median 250 nanograms/mL) in 15 of 16; N CH3
after 4 hours. For postoperative pain, the BNF suggests the remaining patient failed to obtain analgesia with pethidine.
that the subcutaneous or intramuscular doses may be Additional measures were considered necessary1 if the minimum O
given every 2 to 3 hours if necessary. effective concentration exceeded 400 nanograms/mL. H 3C O
Pethidine has traditionally been given by intermittent intramus-
In obstetric analgesia 50 to 100 mg may be given by cular injection in the treatment of acute pain, but inconsistent Adverse Effects and Precautions
intramuscular or subcutaneous injection as soon as pain relief can be expected because of fluctuating blood-pethi- Phenacetin may cause methaemoglobinaemia, sulfhaemoglobi-
contractions occur at regular intervals. This dose may dine concentrations;2 continuous intravenous infusion might be naemia, and haemolytic anaemia.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
116 Analgesics Anti-inflammatory Drugs and Antipyretics
Prolonged use of large doses of analgesic mixtures containing Hypersensitivity. Immediate allergic reactions to phenazone
phenacetin has been associated with the development of renal have been reported.1,2 In one patient leucopenia was detected 8
papillary necrosis (see Effects on the Kidneys, p.98) and transi- weeks later.1 H 2N N NH2
tional-cell carcinoma of the renal pelvis. 1. Kadar D, Kalow W. Acute and latent leukopenic reaction to anti-
pyrine. Clin Pharmacol Ther 1980; 28: 820–22.
Porphyria. Phenacetin is considered to be unsafe in patients 2. McCrea JB, et al. Allergic reaction to antipyrine, a marker of
with porphyria because it has been shown to be porphyrinogenic hepatic enzyme activity. DICP Ann Pharmacother 1989; 23:
N N
in animals. 38–40.
Uses and Administration Porphyria. Phenazone is considered to be unsafe in patients
Phenacetin, a para-aminophenol derivative, has analgesic and with porphyria because it has been shown to be porphyrinogenic
antipyretic properties. It was usually given with aspirin, caffeine, in animals.
or codeine but is now little used because of adverse haematolog- (phenazopyridine)
ical effects and nephrotoxicity.
Interactions
Phenazone affects the metabolism of some other drugs and its
Preparations own metabolism is affected by other drugs that increase or re- Pharmacopoeias. In Pol. and US.
duce the activity of liver enzymes. USP 31 (Phenazopyridine Hydrochloride). A light or dark red to
Proprietary Preparations (details are given in Part 3)
dark violet crystalline powder. Is odourless or with a slight odour.
Multi-ingredient: Cz.: Dinyl†; Mironal†; Hung.: Antineuralgica; Dolor. Pharmacokinetics Soluble 1 in 300 of cold water, 1 in 20 of boiling water, 1 in 59
Phenazone is absorbed from the gastrointestinal tract and peak of alcohol, 1 in 331 of chloroform, and 1 in 100 of glycerol; very
plasma concentrations are obtained within 1 to 2 hours of inges- slightly soluble in ether. Store in airtight containers.
Phenazone (BAN, rINN) tion. It is distributed throughout the body fluids with concentra-
tions in the saliva and breast milk reaching about the same levels Removal of stains. Phenazopyridine stains may be removed
Analgésine; Antipyrin; Antipyrine; Azophenum; Fenatsoni; Fena- as those in plasma. Less than 10% is bound to plasma proteins from fabric by soaking in a 0.25% solution of sodium dithionite.
zon; Fenazona; Fenazonas; Phénazone; Phenazonum; Phenyld- and it has an elimination half-life of about 12 hours. Phenazone
imethylpyrazolone. 1,5-Dimethyl-2-phenyl-4-pyrazolin-3-one.
Adverse Effects
is metabolised in the liver to 3 major metabolites 3-hy- Phenazopyridine hydrochloride has caused gastrointestinal ad-
Феназон droxymethylphenazone, 4-hydroxyphenazone, and norphena- verse effects, headache, and rashes. Hepatotoxicity, haemolytic
C 11 H 12 N 2 O = 188.2. zone. Phenazone, 3-hydroxymethylphenazone, and glucuroni- anaemia, methaemoglobinaemia, and acute renal failure have
C AS — 60-80-0. dated metabolites are all excreted in the urine. A small portion also been reported, generally associated with overdosage or with
ATC — N02BB01. may be eliminated via the bile. therapeutic doses in patients with renal impairment. Crystal de-
ATC Vet — QN02BB01. Uses and Administration posits of phenazopyridine have formed in the urinary tract.
Phenazone is an NSAID (p.99) and has been given orally; phen- Abnormal coloration of body tissues or fluids may occur. Urine
azone and caffeine citrate and phenazone salicylate have similar- is tinged either orange or red and underclothes are apt to be
ly been given orally as analgesics. stained.
Solutions containing about 5% of phenazone have been used top-
Effects on the CNS. A case of aseptic meningitis, with distinct
ically as ear drops in disorders such as acute otitis media (but see
episodes of fever and confusion, was associated with the use of
below).
phenazopyridine.1
O N CH3 Phenazone is used as a test for the activity of drug-metabolising
1. Herlihy TE. Phenazopyridine and aseptic meningitis. Ann Intern
N enzymes in the liver. Med 1987; 106: 172–3.
Diagnosis and testing. A review1 of normal plasma-phena- Overdosage. Report of a 2-year-old child who developed cya-
CH3 zone pharmacokinetics, urinary metabolite disposition, and total nosis and methaemoglobinaemia after ingesting at most three
body clearances of phenazone in the presence of cirrhosis, fatty 200-mg tablets of phenazopyridine hydrochloride.1
liver, hepatitis, and cholestatis.
Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. 1. Gold NA, Bithoney WG. Methemoglobinemia due to ingestion
Ph. Eur. 6.2 (Phenazone). White or almost white crystalline 1. St Peter JV, Awni WM. Quantifying hepatic function in the pres- of at most three pills of pyridium in a 2-year-old: case report and
ence of liver disease with phenazone (antipyrine) and its metab- review. J Emerg Med 2003; 25: 143–8.
powder or colourless crystals. Very soluble in water, in alcohol, olites. Clin Pharmacokinet 1991; 20: 50–65.
and in dichloromethane. Protect from light. Precautions
USP 31 (Antipyrine). Colourless crystals or white crystalline Otitis media. There appears to be no justification1 for the in-
Phenazopyridine hydrochloride is contra-indicated in patients
powder. Is odourless. Very soluble in water; freely soluble in al- clusion of phenazone in topical preparations used in treating
with renal impairment or severe hepatitis and should be used
cohol and in chloroform; sparingly soluble in ether. Solutions are acute otitis media (p.182). It is presumably included in such
with caution in those with G6PD deficiency. Treatment should
neutral to litmus. Store in airtight containers. preparations because it is believed to have a local anti-inflamma-
be stopped if the skin or sclerae become discoloured; this may
tory and, therefore, analgesic action. It would, however, seem
indicate accumulation as a result of impaired renal excretion.
unlikely that phenazone would have any action on the skin of the
Phenazone and Caffeine Citrate Phenazopyridine may interfere with urinalysis based on colour
intact tympanic membrane and, therefore, on the pain which is
Antipyrino-Coffeinum Citricum; Fenazona y citrato de cafeína; reactions or spectrometry.
due primarily to the stretching and distention of the membrane.
Migrenin; Phenzone and Caffeine Citrate. 1. Carlin WV. Is there any justification for using phenazone in a Staining of contact lenses may occur.
Феназон и Кофеина Цитрат local application prescribed for the treatment of acute otitis me- Pharmacokinetics
dia? BMJ 1987; 294: 1333.
Phenazopyridine hydrochloride is absorbed from the gastrointes-
Description. Phenazone and caffeine citrate is a powder usual- Preparations
ly containing phenazone 90%, caffeine 9%, and citric acid tinal tract. It is excreted mainly in the urine; up to 65% may be
monohydrate 1%. USP 31: Antipyrine and Benzocaine Otic Solution; Antipyrine, Benzocaine, excreted as unchanged phenazopyridine and 18% as paraceta-
and Phenylephrine Hydrochloride Otic Solution. mol.
Pharmacopoeias. In Jpn. Proprietary Preparations (details are given in Part 3)
Austral.: Erasol; Ger.: Aequiton-P†; Migrane-Kranit; Mono Migranin; Hong Uses and Administration
Phenazone Salicylate Kong: Tropex; Irl.: Tropex; Pol.: Antotalgin; S.Afr.: Aurone; Oto-Phen; Phenazopyridine is an azo dye that exerts an analgesic effect on
Venez.: Otamina. the mucosa of the urinary tract and is used to provide symptomat-
Antipyrin Salicylate; Fenatsonisalisylaatti; Fenazona salicilato; Multi-ingredient: Arg.: Aqua Lent Colirio; Bajumol†; Bideon; Ceros- ic relief of pain and irritability in conditions such as cystitis and
Fenazonsalicylat; Phenazoni Salicylas; Salipyrin. porin GS†; Clarisoft; Coliria; Cristalomicina; Irix; Kalopsis; Leroid†; Otalex prostatitis (see p.2178 and p.2181, respectively), and urethritis
Феназона Салицилат G; Otocalmia Biotic; Otocerol; Otocuril; Otonorthia; Sincerum; Usualix; (p.199). Phenazopyridine hydrochloride has been given in usual
Vislus; Austral.: Auralgan; Austria: Asthma Efeum; Coffo Selt; Otalgan;
C 11 H 12 N 2 O,C 7 H 6 O 3 = 326.3. Spalt†; Belg.: Hemorhinol; Otocalmine; Ouate Hemostatique; Tympal- oral doses of about 200 mg three times daily after food. If given
C AS — 520-07-0. gine†; Braz.: Anestesiol†; Espasmalgon†; Osmotil†; Otovix†; Canad.: Au- with an antibacterial for the treatment of urinary-tract infections
Pharmacopoeias. In Fr. ralgan; Cz.: Otipax; Denm.: Koffisal; Fr.: Brulex; HEC; Otipax; Ger.: Cof- (p.199), treatment should usually not exceed 2 days, although
feemed N†; Migranin†; Otalgan; Hung.: Otipax; India: Tytin; Israel: lower doses have been given as part of a combined preparation
Adverse Effects and Precautions Anaesthetic Ear Drops; Otidin; Ital.: Otalgan; Otomidone; Otopax; Neth.: for at least a week.
Spalt N; Norw.: Antineuralgica; Fanalgin; NZ: Auralgan; Degest 2†;
Phenazone is liable to give rise to skin eruptions and in suscepti- Philipp.: Auralgan; Port.: Otocalma†; Profrin-A†; Rus.: Otipax
ble individuals even small doses may have this effect. Hypersen- Urinary-tract infections. There is currently no well-substan-
(Отипакс); S.Afr.: Auralyt; Aurasept; Aurone Forte; Covancaine; Ilvico;
sitivity reactions and nephrotoxicity have been reported. Large Otised; Oto-Phen Forte; Universal Earache Drops; Singapore: HEC†; tiated role for phenazopyridine in the treatment of urinary-tract
oral doses may cause nausea, drowsiness, coma, and convul- Tropex; Spain: AB FE†; Epistaxol; Otalgan†; Otosedol; Pomada Heridas†; infections and its adverse effects are potentially serious.1
Quimpedor; Tabletas Quimpe; Swed.: Doleron†; Koffazon; Switz.: Otal- 1. Zelenitsky SA, Zhanel GG. Phenazopyridine in urinary tract in-
sions. gan; Otipax; Otosan; Otothricinol; Seranex sans codeine†; Spedralgin sans fections. Ann Pharmacother 1996; 30: 866–8.
Effects on the blood. Phenazone can cause haemolytic anae- codeine†; Thai.: Auralgan†; USA: Allergen; Auralgan; Auroguard Otic; Au-
mia in certain individuals with a deficiency of G6PD.1 Episodes roto†; Cy-Gesic; Otocalm†; Tympagesic†; Venez.: Audocaina†; Otan; Ota- Preparations
nol†; Otirilin; Otodon†; Otofrin†.
of agranulocytosis were reported2 in 6 women using a cream USP 31: Phenazopyridine Hydrochloride Tablets.
containing phenazone; all recovered on withdrawal. Proprietary Preparations (details are given in Part 3)
1. Prankerd TAJ. Hemolytic effects of drugs and chemical agents. Arg.: Cistalgina; Belg.: Uropyrine; Braz.: Pyridium; Pyrisept; Urologin; Uro-
Clin Pharmacol Ther 1963; 4: 334–50. Phenazopyridine Hydrochloride tril†; Canad.: Phenazo; Pyridium†; Chile: Nazamit; Nordox; Pyridium†;
2. Delannoy A, Schmit J-C. Agranulocytosis after cutaneous con- (BANM, USAN, rINNM) Hong Kong: CP-Pyridine; Phenadine; Pyridium; India: Pyridium; Indon.:
tact with phenazone. Eur J Haematol 1993; 50: 124. Pyridium; Urogetix; Israel: Sedural; Mex.: Alvena; Azofur; Bioferina; Pirim-
Chloridrato de Fenazopiridina; Fenazopiridin Hidroklorür; Fena- ir; Urezol; Philipp.: Azomir; Pol.: Nefrecil; S.Afr.: Pyridium; Singapore:
Effects on the kidneys. Phenazone is considered nephrotoxic Urogesic; Thai.: Ammilazo; Anazo; Phendiridine; Sumedium; USA: Azo-
but only limited clinical information on phenazone is available zopirydyny chlorowodorek; Hidrocloruro de fenazopiridina;
Standard; Baridium; Prodium; Pyridiate†; Pyridium; Re-Azo; Urogesic; Ven-
because it has been mainly used with phenacetin.1 NC-150; NSC-1879; Phénazopyridine, Chlorhydrate de; Phena- ez.: Pyridium†.
1. Prescott LF. Analgesic nephropathy: a reassessment of the role zopyridini Hydrochloridum; W-1655. 3-Phenylazopyridine-2,6- Multi-ingredient: Arg.: Bacti-Uril; Nor 2; Priper Plus; Uro-Bactrim†; Uro-
of phenacetin and other analgesics. Drugs 1982; 23: 75–149. diyldiamine hydrochloride. tem Dol; Braz.: Minazol; Uro-Baxapril†; Urobiotic†; Uroctrin; Urofen†;
Феназопиридина Гидрохлорид Uropac; Uropielon; Chile: Uro-Micinovo; Ger.: Urospasmon†; India: Ne-
Effects on the skin. In a summary1 of 77 cases of fixed drug phrogesic; Mex.: Azo-Uronalin; Azo-Wintomylon; Azogen; Mictasol; Nalix-
eruption phenazone derivatives were considered to be the causa- C 11 H 11N 5 ,HCl = 249.7. one; Naxilan-Plus; Pirifur; Urovec; Vodelan; Spain: Micturol Sedante; Turk.:
tive agent in 9 of the 14 cases that were severe generalised reac- C AS — 94-78-0 (phenazopyridine); 136-40-3 (phenazo- Azo Gantrisin; Azosilin; Uriseptin; USA: Phenazopyridine Plus; Pyridium
tions. pyridine hydrochloride). Plus; Trellium Plus; Urelief Plus; Urobiotic-250; Venez.: Azo-Mandelamine;
Bacteval.
1. Stubb S, et al. Fixed drug eruptions: 77 cases from 1981 to 1985. ATC — G04BX06.
Br J Dermatol 1989; 120: 583. ATC Vet — QG04BX06.
 Phenazone/Piroxicam 117
Phenylbutazone (BAN, rINN) Rudesol†; Neth.: Butazolidin; Pol.: Butapirazol; Port.: Basireuma†; Rus.:
Butadion (Бутадион); S.Afr.: Inflazone; Spain: Butazolidina; Switz.: Buta- Piroxicam (BAN, USAN, rINN)
Butadione; Fenilbutazon; Fenilbutazona; Fenilbutazonas; Fenylb- dion; Thai.: Buta†; Neo-Pyrazol; Venez.: Promifen†; Ticinil. CP-16171; Piroksikaami; Piroksikam; Piroksikamas; Piroxicamum;
utazon; Fenylobutazon; Fenyylibutatsoni; Phénylbutazone; Phe- Piroxikám; Piroxikam. 4-Hydroxy-2-methyl-N-(2-pyridyl)-2H-
Multi-ingredient: Austria: Ambene; Ambene N; Braz.: Butazil†;
nylbutazonum. 4-Butyl-1,2-diphenylpyrazolidine-3,5-dione. Dorend†; Mioflex; Reumat†; Reumix†; Chile: Balsamo Analgesico con Fe- 1,2-benzothiazine-3-carboxamide 1,1-dioxide.
Фенилбутазон nilbutazona; Fr.: Dextrarine Phenylbutazone; Ger.: Ambene Comp†;
Hung.: Rheosolon; Indon.: Butamidon; Cetapyrin; Enkapyrin; New Skelan; Пироксикам
C 19 H 20N 2 O 2 = 308.4. Mex.: Butayonacol; Butisel; Dexadutil; Dibutasona; Vengesic†; Zolidime†; C 15 H 13 N 3 O 4 S = 331.3.
C AS — 50-33-9 (phenylbutazone); 129-18-0 (phenylbuta- Rus.: Ambene (Амбене); Spain: Artrodesmol Extra; Doctofril Antiinfla-
zone sodium); 4985-25-5 (phenylbutazone piperazine). mat; Switz.: Butaparin; Hepabuzone; Thai.: Alaxan; Asialax; Buta Pee
C AS — 36322-90-4.
ATC — M01AA01; M02AA01. Dee†; Butarion; Myophen; Trabit†. ATC — M01AC01; M02AA07; S01BC06.
ATC Vet — QM01AA01; QM02AA01. ATC Vet — QM01AC01; QM02AA07; QS01BC06.

Piketoprofen (rINN) O O

Pikétoprofène; Piketoprofeno; Piketoprofenum. m-Benzoyl-N- S CH3

N
(4-methyl-2-pyridyl)hydratropamide. H
N
O N Пикетопрофен
N
C 22 H 20 N 2 O 2 = 344.4. OH O N
H 3C C AS — 60576-13-8.
O Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, US, and Viet.
Ph. Eur. 6.2 (Piroxicam). A white or slightly yellow, crystalline
Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. powder. It shows polymorphism. Practically insoluble in water;
Ph. Eur. 6.2 (Phenylbutazone). A white or almost white, crystal- O CH3
slightly soluble in dehydrated alcohol; soluble in dichlorometh-
line powder. Practically insoluble in water; sparingly soluble in ane. Store in airtight containers. Protect from light.
alcohol; it dissolves in alkaline solutions. Protect from light. USP 31 (Piroxicam). An off-white to light tan or light yellow,
USP 31 (Phenylbutazone). A white to off-white, odourless, crys- HN
odourless powder. It forms a monohydrate that is yellow. Very
talline powder. Very slightly soluble in water; soluble in alcohol; N slightly soluble in water, in dilute acids, and in most organic sol-
freely soluble in acetone and in ether. Store in airtight containers. vents; slightly soluble in alcohol and in aqueous alkaline solu-
H 3C O
Profile tions. Store in airtight containers. Protect from light.
Phenylbutazone, a pyrazolone derivative, is an NSAID (p.96).
However, because of its toxicity and in particular its adverse hae- Profile Piroxicam Betadex (USAN, rINNM)
matological reactions (see Effects on the Blood, below), it is not Piketoprofen is an NSAID (p.96) that has been used topically as CHF-1194; Piroxicam Beta Cyclodextrin; Piroxicam Beta Cyclo-
used as a general analgesic or antipyretic. Although phenylbuta- the hydrochloride in concentrations of about 2% in musculoskel- dextrin Complex; Piroxicam Bétadex; Piroxicamum Betadexum.
zone is effective in almost all musculoskeletal and joint disorders etal, joint, peri-articular, and soft-tissue disorders.
Пироксикам Бетадекс
including ankylosing spondylitis, acute gout, osteoarthritis, and
rheumatoid arthritis, it should only be used in acute conditions Preparations (C 15 H 13 N 3 O 4S) 2,(C 42 H 70O 35 ) 5 = 6337.6.
where less toxic drugs have failed. Initial oral doses of up to C AS — 96684-40-1.
Proprietary Preparations (details are given in Part 3)
600 mg daily in divided doses have been used in the treatment of
rheumatic disorders although up to 800 mg daily may be re- Port.: Picalm; Zemalex; Spain: Calmatel; Triparsean. Adverse Effects and Treatment
quired in acute gout. After 1 to 3 days, the dose should be re- As for NSAIDs in general, p.96.
duced to the minimum effective amount, which may be as little Local irritation and occasionally bleeding may occur
as 200 mg daily; treatment should be given for the shortest peri-
od possible, up to a usual maximum of 1 week. Reduced doses with piroxicam suppositories and there may be pain
Piritramide (BAN, rINN) and occasionally tissue damage at the injection site on
are recommended in elderly patients.
In some countries phenylbutazone has also been given as a rectal Pirinitramide; Piritramid; Piritramida; Piritramidi; Piritramidum; R- intramuscular use. Application site reactions have also
suppository and applied topically for musculoskeletal pain and in 3365. 1-(3-Cyano-3,3-diphenylpropyl)-4-piperidinopiperidine-4- occurred with topical preparations of piroxicam.
soft-tissue injury. It has also been given intramuscularly as the carboxamide. Piroxicam is considered to be associated with an inter-
sodium salt. Other salts of phenylbutazone that have been used
in musculoskeletal, joint, and soft-tissue disorders include the Пиритрамид mediate risk of gastrointestinal effects although there is
calcium, megallate, and piperazine salts. some suggestion that the risk may be higher than for
C 27 H 34 N 4 O = 430.6.
Breast feeding. No adverse effects have been seen in breast- other intermediate-risk NSAIDs (p.97).
C AS — 302-41-0.
fed infants whose mothers were given phenylbutazone, and the ◊ A report1 of the adverse reactions associated with piroxicam in
American Academy of Pediatrics considers1 that it is therefore ATC — N02AC03. South Africa during 1981-86 included two reactions, paraesthe-
usually compatible with breast feeding. However, when phe- ATC Vet — QN02AC03. sia and hair loss, not previously recorded in the literature.
nylbutazone had been available in the UK the BNF had advised 1. Gerber D. Adverse reactions of piroxicam. Drug Intell Clin
that phenylbutazone should be avoided during breast feeding as Pharm 1987; 21: 707–10.
small amounts are distributed into breast milk. Effects on the blood. Decreases in haemoglobin and haemat-
1. American Academy of Pediatrics. The transfer of drugs and oth- O
NH2 ocrit not associated with obvious gastrointestinal bleeding, have
er chemicals into human milk. Pediatrics 2001; 108: 776–89. occurred in patients taking piroxicam. Thrombocytopenia,
Correction. ibid.; 1029. Also available at:
h tt p : // a a p p o l ic y. a a p p u b li c a t i o n s. o rg / c g i /c on t e n t /f u l l / thrombocytopenic purpura,1 and aplastic anaemia2 have been de-
pediatrics%3b108/3/776 (accessed 08/11/07) N scribed in patients on piroxicam.
NC N 1. Bjørnstad H, Vik Ø. Thrombocytopenic purpura associated with
Effects on the blood. Both phenylbutazone 1-3 and piroxicam. Br J Clin Pract 1986; 40: 42.
oxyphenbutazone1,3 are well known for their adverse effects on 2. Lee SH, et al. Aplastic anaemia associated with piroxicam. Lan-
the blood and especially for fatal agranulocytosis and aplastic cet 1982; i: 1186.
anaemia. Leucopenia, pancytopenia, haemolytic anaemia, and Effects on electrolytes. Reversible hyperkalaemic hyperchlo-
thrombocytopenia may also occur. The UK CSM4 noted that be- raemic acidosis has been reported1,2 in patients receiving piroxi-
tween July 1963 and January 1993 it had received 74 reports of cam. Severe hyponatraemia and symptoms resembling the syn-
agranulocytosis (39 fatal) associated with phenylbutazone and drome of inappropriate antidiuretic hormone secretion have also
40 reports of neutropenia (4 fatal). Up-to-date figures were not Profile
Piritramide is an opioid analgesic (p.101). been associated with piroxicam.3
provided on oxyphenbutazone, but it is considered to be more
See also Effects on the Kidneys, below.
toxic to the bone marrow than phenylbutazone.1 It is used for the management of severe pain including postoper- 1. Grossman LA, Moss S. Piroxicam and hyperkalemic acidosis.
1. Anonymous. Phenylbutazone and oxyphenbutazone: time to call ative pain, for premedication, and to provide analgesia during Ann Intern Med 1983; 99: 282.
a halt. Drug Ther Bull 1984; 22: 5–6. anaesthesia. It is given by intramuscular, subcutaneous, or slow 2. Miller KP, et al. Severe hyperkalemia during piroxicam therapy.
2. Böttiger LE, Westerholm B. Drug-induced blood dyscrasias in intravenous injection as the tartrate in doses equivalent of up to Arch Intern Med 1984; 144: 2414–15.
Sweden. BMJ 1973; 3: 339–43. 3. Petersson I, et al. Water intoxication associated with non-steroi-
3. The International Agranulocytosis and Aplastic Anemia Study.
about 30 mg of the base.
dal anti-inflammatory drug therapy. Acta Med Scand 1987; 221:
Risks of agranulocytosis and aplastic anemia: a first report of 221–3.
their relation to drug use with special reference to analgesics. ◊ Reviews.
JAMA 1986; 256: 1749–57. Effects on the kidneys. Acute nephropathy with characteristic
1. Kumar N, Rowbotham DJ. Piritramide. Br J Anaesth 1999; 82:
4. CSM/MCA. Drug-induced neutropenia and agranulocytosis. 3–5.
features of Henoch-Schönlein purpura,1 acute renal failure,2
Current Problems 1993; 19: 10–11. Also available at: http:// uraemia with hyperkalaemia, and acute interstitial nephritis3
w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ have been associated with systemic use of piroxicam. Nephrotic
FILE&dDocName=CON2024456&RevisionSelectionMethod= Porphyria. Piritramide is considered to be unsafe in patients
LatestReleased (accessed 27/04/07) with porphyria because it has been shown to be porphyrinogenic syndrome and interstitial nephritis have followed topical use of
in animals or in-vitro systems. piroxicam gel.4
Porphyria. Phenylbutazone has been associated with acute at- 1. Goebel KM, Mueller-Brodmann W. Reversible overt nephropa-
tacks of porphyria and is considered unsafe in porphyric patients. Preparations thy with Henoch-Schönlein purpura due to piroxicam. BMJ
1982; 284: 311–12.
Preparations 2. Frais MA, et al. Piroxicam-induced renal failure and hyperkale-
Proprietary Preparations (details are given in Part 3)
Proprietary Preparations (details are given in Part 3) mia. Ann Intern Med 1983; 99: 129–30.
Belg.: Butazolidin; Braz.: Butazolidina; Butazolon†; Butazona; Butazonil†; Austria: Dipidolor; Belg.: Dipidolor; Cz.: Dipidolor; Ger.: Dipidolor; 3. Mitnick PD, Klein WJ. Piroxicam-induced renal disease. Arch
Neo Butazol; Peralgin†; Fr.: Butazolidine†; Ger.: Ambene; exrheudon OPT; Neth.: Dipidolor. Intern Med 1984; 144: 63–4.
Indon.: Akrofen; Berlizon; Irgapan; Ital.: Kadol; Mex.: Astrofen; Bloken; 4. O’Callaghan CA, et al. Renal disease and use of topical non-
Bresal; Butalen; Butazolidina; Delbulasa†; Fezona†; Lorfenil†; Meprosona-F; steroidal anti-inflammatory drugs. BMJ 1994; 308: 110–11.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
118 Analgesics Anti-inflammatory Drugs and Antipyretics
Effects on the liver. Necrosis of the liver, sometimes fatal, has state concentrations are not reached for 7 to 12 days. It ◊ Following a review1 of the benefit-risk balance for piroxicam
been associated with piroxicam.1,2 is metabolised in the liver by hydroxylation and conju- the EMEA placed restrictions on its systemic use and stated that:
1. Lee SM, et al. Subacute hepatic necrosis induced by piroxicam.
BMJ 1986; 293: 540–1.
gation with glucuronic acid and excreted mainly in the • its use in acute painful and inflammatory conditions should be
2. Paterson D, et al. Piroxicam induced submassive necrosis of the urine with smaller amounts in the faeces. Enterohepat- abandoned
liver. Gut 1992; 33; 1436–8. ic recycling occurs. Less than 5% of the dose is excret- • its use should be limited only to the symptomatic relief of osteo-
Effects on the skin. As with other NSAIDs, rash has occurred ed unchanged in the urine and faeces. arthritis, rheumatoid arthritis, and ankylosing spondylitis
in patients taking piroxicam. Phototoxic reactions have been de-
scribed.1 Serious skin reactions attributed to piroxicam therapy Piroxicam betadex dissociates in the gastrointestinal • it should not be used as a first-line treatment
include toxic epidermal necrolysis,2 pemphigus vulgaris,3 ery- tract to its components piroxicam and betadex • the dose should be limited to 20 mg daily
thema multiforme,4 and Stevens-Johnson syndrome.5 Fixed drug (p.2291). Piroxicam absorption from piroxicam beta-
eruptions have also been reported.6 dex is more rapid than that of unmodified piroxicam; • treatment should be reviewed within 14 days of starting
Concern by the EMEA over the serious nature of skin reactions peak plasma concentrations of piroxicam are reached • it should only be started by doctors experienced in treating
associated with piroxicam has led to restrictions on the systemic 30 to 60 minutes after an oral dose. Betadex is not ab- chronic painful and inflammatory conditions
use of piroxicam in the EU (see below).
1. Stern RS. Phototoxic reactions to piroxicam and other nonsteroi-
sorbed but is metabolised in the colon to various sug- • use with a gastroprotective drug should be considered
dal antiinflammatory agents. N Engl J Med 1983; 309: 186–7. ars.
2. Chosidow O, et al. Intestinal involvement in drug-induced toxic
• it should not be given to patients at risk of gastrointestinal dis-
epidermal necrolysis. Lancet 1991; 337: 928. ◊ References. orders associated with bleeding or to those who have had skin
3. Martin RL, et al. Fatal pemphigus vulgaris in a patient taking 1. Richardson CJ, et al. Piroxicam and 5′-hydroxypiroxicam kinet- reactions to other drugs
piroxicam. N Engl J Med 1983; 309: 795–6. ics following multiple dose administration of piroxicam. Eur J
4. Prieto A, et al. Piroxicam-induced erythema multiforme. Con- Clin Pharmacol 1987; 32: 89–91. • it should not be used with another NSAID or an anticoagulant
tact Dermatitis 2004; 50: 263. 2. Mäkelä A-L, et al. Steady state pharmacokinetics of piroxicam 1. EMEA. Questions and answers on the review of piroxicam (is-
5. Katoh N, et al. Piroxicam induced Stevens-Johnson syndrome. J in children with rheumatic diseases. Eur J Clin Pharmacol 1991; sued 21st June, 2007). Available at: http://www.emea.europa.eu/
Dermatol 1995; 22: 677–80. 41: 79–81 (higher clearance and shorter half-life in children). pdfs/human/press/pr/piroxicam_26457807en.pdf (accessed
6. Cuerda Galindo E, et al. Fixed drug eruption from piroxicam. J 3. Rudy AC, et al. The pharmacokinetics of piroxicam in elderly 08/11/07)
Eur Acad Dermatol Venereol 2004; 18: 586–7. persons with and without renal impairment. Br J Clin Pharmacol
1994; 37: 1–5. Administration in children. In the UK, piroxicam may be
Overdosage. Details of 16 patients who were considered to
4. Deroubaix X, et al. Oral bioavailability of CHF1194, an inclu- used in children aged 6 years or over with juvenile idiopathic
have taken an overdosage of piroxicam alone were reported1 to sion complex of piroxicam and β-cyclodextrin, in healthy sub-
the National Poisons Information Service of the UK. Thirteen arthritis (p.10). The usual oral dose is:
jects under single dose and steady-state conditions. Eur J Clin
patients (including 5 children) had no symptoms after doses esti- Pharmacol 1995; 47: 531–6. • less than 15 kg: 5 mg once daily
mated to be up to 300 to 400 mg; 2 patients complained of dizzi- 5. Karim A, et al. Oxaprozin and piroxicam, nonsteroidal antiin-
ness and blurred vision after 200 to 300 mg; the last patient, who flammatory drugs with long half-lives: effect of protein-binding • 16 to 25 kg: 10 mg once daily
claimed to have taken 600 mg presented in coma, regained con- differences on steady-state pharmacokinetics. J Clin Pharmacol
1997; 37: 267–78. • 26 to 45 kg: 15 mg once daily
sciousness within one hour, and had recovered fully within 24
6. Wang D, et al. Comparative population pharmacokinetic-phar-
hours. Severe multisystem toxicity has been reported in a 2-year- macodynamic analysis for piroxicam-β-cyclodextrin and piroxi- • 46 kg or over: 20 mg once daily
old child after ingestion of 100 mg of piroxicam.2 cam. J Clin Pharmacol 2000; 40: 1257–66. UK licensed product information states that only the dispersible
1. Court H, Volans GN. Poisoning after overdose with non-steroi-
dal anti-inflammatory drugs. Adverse Drug React Acute Poison- tablets are recommended for use in children.
ing Rev 1984; 3: 1–21. Uses and Administration
2. MacDougall LG, et al. Piroxicam poisoning in a 2-year-old child: Piroxicam, an oxicam derivative, and piroxicam beta- Preparations
a case report. S Afr Med J 1984; 66: 31–3. dex are NSAIDs (p.99). Piroxicam betadex may have BP 2008: Piroxicam Capsules; Piroxicam Gel;
Pancreatitis. Pancreatitis has been associated with piroxicam a more rapid onset of therapeutic effect due to its en- USP 31: Piroxicam Capsules; Piroxicam Cream.
use.1,2 hanced solubility (see Pharmacokinetics above). Both Proprietary Preparations (details are given in Part 3)
1. Haye OL. Piroxicam and pancreatitis. Ann Intern Med 1986;
104: 895. have been used in musculoskeletal and joint disorders Arg.: Axis†; Benisan; Brionot; Calmapir†; Fabopxicam; Feldene†; Flogosine;
2. Heluwaert F, et al. Pancréatite aiguë au piroxicam. Gastroenterol such as ankylosing spondylitis, osteoarthritis, rheuma- Homocalmefyba; Ketazon†; Maxtol; Micar; Nac; Nalgesic; Osteocalmine;
Clin Biol 2006; 30: 635–6. Piroalgin; Pirofix†; Roxicam†; Sindrolen†; Solocalm; Tirovel; Tricifa†; Trixi-
toid arthritis including juvenile idiopathic arthritis, in cam; Truxa R†; Truxa†; Vefren†; Velaned†; Austral.: Candyl†; Feldene; Mo-
soft-tissue disorders, in acute gout, and in postopera- bilis; Pirohexal-D; Rosig†; Austria: Brexidol; Brexin; Felden; Pirocal; Piro-
Precautions tive pain but systemic usage in the EU is now restricted
cam; Pirorheum; Pirox; Piroxistad; Tonimed; Belg.: Brexine; Docpiroxi;
Feldene; Piromed; Piroxitop; Piroxymed; Polydene; Solicam; Braz.: Anar-
As for NSAIDs in general, p.98. (see below) to chronic painful and inflammatory con- trit†; Anflene; Brexin; Cicladol; Farmoxicam†; Feldanax; Feldene; Feldox†;
Feldran†; Flamostat; Flogene; Flogoxen†; Floxicam; Inflamene; Inflanan; In-
Breast feeding. No adverse effects have been seen in breast- ditions. flanox†; Inflax; Lisedema†; Pirogreen; Piroxam†; Piroxene; Piroxifar;
fed infants whose mothers were given piroxicam, and the Amer- Piroxifen†; Piroxiflam†; Piroxil; Piroxin; Piroxinid; Piroxiplus†; Prodoxidil;
ican Academy of Pediatrics considers1 that it is therefore usually In rheumatic disorders a usual initial oral dose of pirox- Canad.: Brexidol†; Feldene†; Fexicam†; Novo-Pirocam; Nu-Pirox; Chile:
compatible with breast feeding. The BNF also considers the icam is 20 mg daily as a single dose. Daily mainte- Fabudol; Feldene; Foldox; Notagol†; Pemar; Pricam; Sinartrol†; Cz.: Ar-
thremin†; Feldene†; Flamexin; Hotemin; Piroflam†; Pirox†; Pro-Roxikam†;
amount excreted into breast milk to be too small to be harmful to nance doses may vary between 10 and 30 mg given in Reumador†; Denm.: Brexidol†; Felden; Pirom; Piroxigea†; Fin.: Brexidol†;
a breast-fed infant. single or divided doses; use of doses in excess of 20 mg Felden; Piroxal; Piroxin; Fr.: Brexin; Cycladol; Feldene; Geldene; Inflaced;
Piroxicam appears in breast milk in concentrations of about 1% Proxalyoc; Zofora†; Ger.: Brexidol; clinit; durapirox†; Felden; Flexase; Jena-
daily for more than a few days is associated with an pirox; Mobilat Akut Piroxicam; Piro; Piro KD; Piro-Phlogont†; Pirobeta; Piro-
of those in the maternal plasma.2 Similar data are also included
in the licensed product information although it does not recom-
increased risk of gastrointestinal adverse effects. Pirox- flam; Piroflex†; Pirorheum†; PirorheumA; Pirox; Pra-Brexidol†; ratioMobil†;
Rheumitin†; Gr.: Bleduran; Brexin; Conzila; Feldene; Flodeneu; Neo Axedil;
mend piroxicam use during breast feeding as clinical safety has icam has been given in similar doses as a rectal suppos- Painrelipt-D; Pedifan; Proponol; Rheumaplus†; Ruvamed; Sinartrol; Valo-
not been established. itory or on a short-term basis by intramuscular injec- pon†; Zerospasm; Zitumex; Hong Kong: CP-Pirox; Feldene; Felxicam†;
Flamatrol†; Hotemin†; Piroxica; Piroxy†; Sefdene; Sotilen†; Synoxicam; Vi-
1. American Academy of Pediatrics. The transfer of drugs and oth- tion. dapirocam; Hung.: Brexin; Erazon†; Feldene; Flamexin; Hotemin; Huma-
er chemicals into human milk. Pediatrics 2001; 108: 776–89. Pirocam; Pirorheum; India: Brexic-DT; Dolokam; Dolonex; Mobicam DT;
Correction. ibid.; 1029. Also available at: For dosage in children, see below. Movon; Pirox; Suganril; Indon.: Faxiden; Felcam; Feldene; Infeld; Kifadene;
http://aappolicy.aappublications .org/cgi/ content/full/ Lanareuma; Licofel; Maxicam; Pirocam; Pirodene; Pirofel; Rexicam; Rexil;
pediatrics%3b108/3/776 (accessed 08/11/07) Piroxicam is also used in the local treatment of a vari- Rosic; Roxidene; Scandene; Sofden; Tropidene; Irl.: Feldene; Pericam; Isra-
2. Østensen M. Piroxicam in human breast milk. Eur J Clin Phar- ety of painful or inflammatory conditions as a topical el: Exipan; Feldene; Ital.: Algoxam; Antiflog; Artroxicam; Brexin; Brexivel;
macol 1983; 25: 829–30. gel in a concentration of 0.5% applied three or four Bruxicam; Cicladol; Ciclafast†; Clevian; Dexicam; Errekam; Euroxi; Feldene;
Flodol; Ipsoflog; Lampoflex; Oxicam†; Piroftal; Polipirox; Reucam†; Re-
Porphyria. Piroxicam has been associated with acute attacks of times daily; treatment should be reviewed after 4 udene†; Reumagil; Riacen†; Roxene; Roxenil; Roxiden; Sinartrol; Spirox; Ze-
porphyria and is considered unsafe in porphyric patients. weeks. A 1% gel is also available. Piroxicam has been lis; Jpn: Baxo; Malaysia: Brexin; Feldene; Felxicam†; Focam†; Rhumagel;
Roxitan†; Uphaxicam; Mex.: Ainek†; Androxicam; Apopiran†; Arlexicam;
used in some countries as a 0.5 or 1% cream and as eye Artinor†; Artyflam; Asabon; Axtrim; Bapixied; Bioximil; Brexicam; Brexodin;
Interactions drops in a concentration of 0.5%. Brucam; Campirex; Citoken T†; Dixonal; Dolzycam; Edecam; Facicam; Far-
For interactions associated with NSAIDs, see p.99. micam†; Feldene; Flogosan†; Glandicin; Osteral; Oxi-Reul; Oxicanol; Piro-
Doses of piroxicam betadex are expressed in terms of dax; Pirox; Piroxan; R-Tyflam; Reucam; Reutricam; Ripox; Serpicam; Tripirol;
Use of aspirin with piroxicam results in decreased plas- the equivalent amount of piroxicam. Piroxicam beta-
Vatrem; Neth.: Brexine; Norw.: Brexidol; Felden; Pirox; NZ: Candyl; Pi-
ram-D; Pirohexal-D; Philipp.: Feldene; Flaxine; Macroxam; Neperlan; Par-
ma concentrations of piroxicam to about 80% of nor- dex 191.3 mg is equivalent to about 20 mg of piroxi- ixam; Pirostad; Proximax; Raxicam; Pol.: Feldene; Flamexin; Hotemin;
mal. The UK licensed product information for ritonavir cam. In rheumatic and acute musculoskeletal disorders
Port.: Brexin; Feldene; Flexar; Flogocan; Remisil; Reumoxican; Roxazin;
Rus.: Erazon (Эразон); Finalgel (Финалгель); S.Afr.: Brexecam; Feldene†;
suggests that use of piroxicam with ritonavir may re- piroxicam betadex is given in an oral dose equivalent Pixicam; Pyrocaps; Rheugesic; Xycam; Singapore: Brexin†; Capxidin†;
sult in increased plasma concentrations of piroxicam to 20 mg of piroxicam daily as a single dose. This dose
Feldene; Rosiden; Sefdene; Vitaxicam; Spain: Artragil†; Brexinil; Cycladol;
Doblexan; Feldegel; Feldene; Improntal; Salvacam; Sasulen; Vitaxicam;
and an increased risk of toxicity; it recommends that may be reduced to 10 mg daily in elderly patients. Swed.: Brexidol; Felden†; Switz.: Brexidol†; Felden; Pirocam; Pirosol;
use together should be avoided. pirox-basan†; Thai.: Ammidene; Bicam†; Brexin; Felcam; Feldene; Felrox;
Other salts or compounds that have also been used in- Flamic; Ifemed; Manoxicam; Maswin; Moxicam; Neogel; Neotica†; PC-20;
Piram; Pirax; Pirox; Piroxam†; Piroxcin; Piroxen; Piroxsil; Polyxicam; Posed-
Pharmacokinetics clude piroxicam cinnamate (cinnoxicam), piroxicam ene; Pyroxy†; Roccaxin†; Roxifen; Roxium; Roxycam; Rumadene; Rumaxi-
Piroxicam is well absorbed from the gastrointestinal choline, and piroxicam pivalate. cam; Sotilen; Xicam; Turk.: Cycladol; Felden; Inflamex; Oksikam; UK: Brex-
idol; Feldene; USA: Feldene; Venez.: Biopirox†; Ciclofast†; Feldene;
tract; peak plasma concentrations are reached 3 to 5 ◊ Reviews. Feldenedi; Flamalit; Lepexal†; Maxipiro; Pirocam†; Piromax†; Piroval†; Pix-
orid.
hours after an oral dose. Piroxicam is more rapidly ab- 1. Lee CR, Balfour JA. Piroxicam-β-cyclodextrin: a review of its
sorbed after intramuscular use; it is also absorbed to pharmacodynamic and pharmacokinetic properties, and thera- Multi-ingredient: Arg.: Algio-Truxa†; Buta Rut B12; Calmapir-P†; Flexi-
peutic potential in rheumatic diseases and pain states. Drugs camin; Flexicamin A; Flexicamin B12; Flexicamin Crema†; Flogiatrin;
some degree after topical application. Piroxicam is 1994; 48: 907–29. Flogiatrin B12; Ketazon Flex†; Peganix; Rumisedan; Rumisedan Fuerte†; Sin-
99% bound to plasma proteins. It has been detected in 2. Moore A, et al. Single dose piroxicam for acute postoperative drolen Vitaminado†; Sindrolen†; Solocalm Plus; Solocalm-B; Solocalm-Flex;
pain. Available in The Cochrane Database of Systematic Re- Indon.: Counterpain-PXM; Thai.: Counterpain Plus.
breast milk. Piroxicam has a long plasma elimination views; Issue 2. Chichester: John Wiley; 2000 (accessed
half-life of about 50 hours. Because of this, steady- 29/08/08).
 Piroxicam/Proquazone 119
Pranoprofen (rINN) Propacetamol Hydrochloride (BANM, rINNM) Propyphenazone (BAN, rINN)
Pranoprofène; Pranoprofeno; Pranoprofenum. α-Methyl-5H-[1]- Hidrocloruro de propacetamol; Propacétamol, chlorhydrate de; Isopropylantipyrine; Isopropylantipyrinum; Isopropylphenazone;
benzopyrano[2,3-b]pyridine-7-acetic acid. Propacetamol-hidroklorid; Propacetamol-hydrochlorid; Propa- Propifenazon; Propifenazona; Propifenazonas; Propyfenatsoni;
Пранопрофен cetamolhydroklorid; Propacetamoli hydrochloridum; Propaceta- Propyfenazon; Propyphénazone; Propyphenazonum. 4-Isopro-
C 15 H 13NO 3 = 255.3. molio hidrochloridas; Propasetamolihydrokloridi. The hydrochlo- pyl-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one.
C AS — 52549-17-4. ride of N,N-diethylglycine ester with paracetamol; 4-Acetamido- Пропифеназон
ATC — S01BC09. phenyl diethylaminoacetate hydrochloride. C 14 H 18 N 2 O = 230.3.
ATC Vet — QS01BC09. Пропацетамола Гидрохлорид C AS — 479-92-5.
C 14 H 20 N 2 O 3 ,HCl = 300.8. ATC — N02BB04.
C AS — 66532-85-2 (propacetamol). ATC Vet — QN02BB04.
N O ATC — N02BE05.
O ATC Vet — QN02BE05.

OH
O
CH3
N CH3
Pharmacopoeias. In Jpn. HN O N O
N
Profile O H 3C CH3
Pranoprofen, a propionic acid derivative, is an NSAID (p.96). It CH3 H 3C CH3
is used as eye drops in a concentration of 0.1% for ocular inflam-
mation. Pranoprofen has also been given orally for the treatment (propacetamol) CH3
of pain, inflammation, and fever.
◊ References. Pharmacopoeias. In Eur. (see p.vii). Pharmacopoeias. In Eur. (see p.vii) and Jpn.
1. Notivol R, et al. Treatment of chronic nonbacterial conjunctivitis Ph. Eur. 6.2 (Propacetamol Hydrochloride). A white or almost Ph. Eur. 6.2 (Propyphenazone). A white or slightly yellowish
with a cyclo-oxygenase inhibitor or a corticosteroid. Am J Oph- white crystalline powder. Freely soluble in water; slightly solu- crystalline powder. Slightly soluble in water; freely soluble in al-
thalmol 1994; 117: 651–6. ble in dehydrated alcohol; practically insoluble in acetone. Pro- cohol and in dichloromethane. Protect from light.
Preparations tect from moisture. Profile
Proprietary Preparations (details are given in Part 3) Profile Propyphenazone, a pyrazolone derivative related to phenazone
Belg.: Pranox; Braz.: Difen; Gr.: Pranofen; Ital.: Oftalar; Pranoflog; Jpn: Propacetamol hydrochloride, a para-aminophenol derivative, is (p.116), has analgesic and antipyretic properties. It has been giv-
Niflan; Port.: Oftalar; Spain: Oftalar; Turk.: Oftalar. hydrolysed to paracetamol (p.108) in the plasma. It has been giv- en orally and as a rectal suppository in the treatment of pain and
en intramuscularly or intravenously in usual doses of 1 to 2 g fever. The usual oral adult dose is 0.5 to 1 g up to four times daily.
every 4 hours up to 4 times daily if necessary, to a maximum There have been some reports of severe hypersensitivity reac-
Proglumetacin Maleate (BANM, rINNM) dose of 8 g daily, for the treatment of pain (see Choice of Anal- tions in patients receiving propyphenazone.
gesic, p.2) and fever (p.10). For doses in children, see below. Porphyria. Propyphenazone has been associated with acute at-
CR-604; Maleato de proglumetacina; Proglumétacine, Maléate
de; Proglumetacinum Maleas; Protacine Maleate. 3-{4-[2-(1-p- Administration in children. In some countries propacetamol tacks of porphyria and is considered unsafe in porphyric patients.
Chlorobenzoyl-5-methoxy-2-methylindol-3-ylacetoxy)ethyl]pip- is used intravenously in the treatment of pain and fever in neo- Preparations
erazin-1-yl}propyl 4-benzamido-N,N-dipropylglutaramate di- nates and children.1,2 Doses range from 20 to 30 mg/kg given Proprietary Preparations (details are given in Part 3)
maleate. over 15 minutes up to 4 times daily, not exceeding a maximum Austria: Dim-Antos; Ger.: Demex; Eufibron†; Hewedolor propy†; Iso-
daily dose of 120 mg/kg propacetamol (equivalent to a daily prochin P†.
Проглуметацина Малеат dose of 60 mg/kg of paracetamol). Multi-ingredient: Arg.: Algio-Bladuril; Espasmo Cibalena; Saridon; Aus-
C 46 H 58ClN 5 O 8 ,2C 4 H 4 O 4 = 1076.6. 1. Allegaert K, et al. Pharmacokinetics of single dose intravenous tria: Adolorin; APA; Avamigran; Coldagrippin; Contraforte†; Eu-Med; Ge-
C AS — 57132-53-3 (proglumetacin); 59209-40-4 (pro- propacetamol in neonates: effect of gestational age. Arch Dis wadal; Melabon; Migradon; Montamed; Nervan; Rapidol; Saridon; Spasmo-
glumetacin maleate). Child Fetal Neonatal Ed 2004; 89: F25–F28. plus; Tonopan; Toximer ; Vivimed; Waldheim Influvidon; Waldheim
2. Walson PD, et al. Antipyretic efficacy and tolerability of a single Schmerztabletten; Belg.: Kranit Nova†; Optalidon†; Saridon†; Spasmo-
ATC — M01AB14. plus†; Braz.: Saridon; Tonopan; Chile: Abalgin; Droxel; Espasmo Cibalgina;
ATC Vet — QM01AB14. intravenous dose of the acetaminophen prodrug propacetamol in
children: a randomized, double-blind, placebo-controlled trial. Espasmo Cibalgina Compuesta; Feminosan†; Gripasan Compuesto; Imme-
diat†; SAE; Cz.: Saridon; Spasmoveralgin Neo†; Valetol; Denm.: Kodamid;
Clin Ther 2006; 28: 762–9. Ger.: Avamigran N†; Cibalgin Compositum N†; Copyrkal N†; Ergo-Kran-
Adverse effects. Occupational contact dermatitis has been re- it†; Eudorlin†; Fomagrippin N†; Ichtho-Bellol compositum S†; Migrane-
Cl Kranit Duo†; Migrane-Kranit N†; Migratan S†; Norgesic N†; Optalidon N;
ported in healthcare professionals after preparing injections of Optalidon special NOC†; RubieNex spezial†; Saridon; Schworalgan; Spas-
propacetamol.1-3 mo-Cibalgin S†; Titretta S; Hong Kong: Epizon†; Saridon; Tonterin†;
O Propacetamol is the hydrochloride of N,N-diethylglycine ester Hung.: Saridon; Trinell Pro; Indon.: Butamidon; Cetapyrin; Enkapyrin; Mi-
with paracetamol and the results of a study4 have suggested that gran; Paramex; Saridon; Ital.: Cistalgan; Influrem†; Influvit; Micranet†; Min-
dol-Merck†; Neo-Optalidon; Odontalgico Dr. Knapp con Vit. B1; Optal-
N CH3 allergic reactions to propacetamol are related to sensitisation to idon; Saridon; Sedol; Spasmo-Cibalgina†; Spasmoplus; Uniplus; Veramon;
O the activated ester rather than to paracetamol itself. Mex.: Espasmo Cibalgina; Tonopan; Neth.: Daro Hoofdpijnpoeders; Kru-
1. Barbaud A, et al. Occupational allergy to propacetamol. Lancet idvat; Para-don; Sanalgin; Saridon; Pol.: Analget; Cefalgin; Gardan P; Krople
H 3C 1995; 346: 902. Zoladkowe; Pabialgin P; Saridon; Port.: Avamigran†; Optalidon; Saridon N;
O O 2. Szczurko C, et al. Occupational contact dermatitis from propa- Rus.: Caffetin (Каффетин); Coffedon (Коффедон); Gewadal (Гевадал);
cetamol. Contact Dermatitis 1996; 35: 299–301. Kofan (Кофан); Saridon (Саридон); S.Afr.: Ilvico; Spain: Abdominol; Cal-
N 3. Gielen K, et al. Occupational allergic contact dermatitis from moplex; Dolodens; Flexagil†; Hubergrip†; Melabon; Meloka; Optalidon;
Quimpedor; Saridon; Sedalmerck†; Sulmetin Papaver; Sulmetin Papaveri-
drugs in healthcare workers Contact Dermatitis 2001; 45: na†; Tabletas Quimpe; Tonopan; Switz.: Barbamin†; Caposan†; Cerebrol†;
273–9. Comprimes analgesiques "S"†; Dialgine forte†; Dolopyrine†; Dolostop†; Es-
O 4. Berl V, et al. Mechanism of allergic contact dermatitis from
O N calgin sans codeine†; Escogripp sans codeine; Gewodine†; Nicaphlogyl†;
propacetamol: sensitization to activated N,N-diethylglycine. Saridon†; Seranex sans codeine†; Sinedal†; Spasmo-Barbamin†; Spasmo-
Contact Dermatitis 1998; 38: 185–8. Barbamine compositum†; Spasmo-Cibalgin comp†; Spasmo-Cibalgin†; Spe-
HN dralgin sans codeine†; Tonopan†; Turk.: Aljil; Bioptan; Minoset Plus; Panal-
O Preparations gine.
Proprietary Preparations (details are given in Part 3)
H3C Belg.: Pro-Dafalgan†; Denm.: Pro-Dafalgan†; Fin.: Pro-Dafalgan†; Gr.:
N O Pro-Dafalgan; Pro-depon†; Israel: Pro-Dafalgan†; Ital.: Pro-Efferalgan†;
Mex.: Tempra†; Norw.: Pro-Dafalgan; Port.: Pro-Dafalgan†; Spain: Pro- Proquazone (BAN, USAN, rINN)
H 3C Efferalgan†; Swed.: Pro-Dafalgan†; Switz.: Pro-Dafalgan†.
43-715; Procuazona; Prokuazon; Prokvatsoni; Prokvazon; Pro-
quazonum; RU-43-715-n. 1-Isopropyl-7-methyl-4-phenylquina-
(proglumetacin)
zolin-2(1H)-one.
Propyl Nicotinate
Проквазон
Profile Nicotinato de propilo.
Proglumetacin maleate, an indoleacetic acid derivative related to C 18 H 18 N 2 O = 278.3.
C 9 H 11 NO 2 = 165.2. C AS — 22760-18-5.
indometacin (p.66), is an NSAID (p.96). It has been used in mus- C AS — 7681-15-4. ATC — M01AX13.
culoskeletal and joint disorders in oral doses of up to 600 mg dai- ATC Vet — QM01AX13.
ly, in divided doses. Proglumetacin maleate has also been given
as rectal suppositories and topically as a 5% cream. N
◊ References.
1. Appelboom T, Franchimont P. Proglumetacin versus indomet- O
acin in rheumatoid arthritis: a double-blind multicenter study. CH3
Adv Therapy 1994; 11: 228–34.
2. Martens M. Double-blind randomized comparison of proglumet- O
acin and naproxen sodium in the treatment of patients with ankle
sprains. Curr Ther Res 1995; 56: 639–48. N
Profile
Preparations Propyl nicotinate is used in topical preparations as a rubefacient.
Proprietary Preparations (details are given in Part 3) Preparations O N CH3
Arg.: Alaidol†; Bruxel; Belg.: Tolindol; Chile: Afloxan†; Ger.: Protaxon;
Hong Kong: Afloxan; Ital.: Afloxan; Proxil; Jpn: Miridacin; Philipp.: Proprietary Preparations (details are given in Part 3)
Afloxan; Port.: Protaxil; Spain: Prodamox; Thai.: Afloxan. Ger.: Elacur; Nicodan†. H 3C CH3

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
120 Analgesics Anti-inflammatory Drugs and Antipyretics
Profile Precautions over 30 to 60 seconds particularly if the patient is to be
Proquazone is an NSAID (p.96) that has been used orally and As for Opioid Analgesics in general, p.103. intubated less than 8 minutes after the start of the infu-
rectally in musculoskeletal and joint disorders.
Administration. Remifentanil hydrochloride injections con-
sion.
Preparations
taining glycine should not be given by the epidural or intrathecal For provision of analgesia during maintenance of
Proprietary Preparations (details are given in Part 3) routes. anaesthesia in ventilated patients, usual infusion doses
Hung.: Biarison†; Turk.: Biarison.
Hepatic impairment. Although the pharmacokinetics of range from 0.05 to 2 micrograms/kg per minute de-
remifentanil are not changed in patients with severe hepatic im- pending on the anaesthetic drug employed and adjust-
pairment, such patients may be more sensitive to the respiratory ed according to response. Supplemental intravenous
Ramifenazone (rINN) depressant effects and should be monitored with doses titrated to
boluses of 0.5 to 1 micrograms/kg may be given every
individual requirements.
Isopropylaminophenazone; Isopyrin; Ramifenazona; Ramiféna- 2 to 5 minutes in response to light anaesthesia or
zone; Ramifenazonum. 4-Isopropylamino-2,3-dimethyl-1-phenyl- Renal impairment. The pharmacokinetics of remifentanil are intense surgical stress. The infusion dosage in sponta-
3-pyrazolin-5-one. not changed in patients with severe renal impairment (a creati-
nine clearance of less than 10 mL/minute) and licensed product
neous respiration is initially 0.04 micrograms/kg per
Рамифеназон minute adjusted according to response within a usual
information states that the carboxylic acid metabolite is unlikely
C 14 H 19 N 3 O = 245.3. to accumulate to clinically active concentrations in such patients range of 0.025 to 0.1 micrograms/kg per minute. Bolus
C AS — 3615-24-5. after remifentanil infusions given for up to 3 days. Dosage ad- doses are not recommended during spontaneous venti-
justment is considered to be unnecessary. This is supported by lation.
pharmacokinetic studies1,2 in intensive care patients with renal
impairment given remifentanil infusions at a rate of 100 to For continuation of analgesia into the immediate post-
150 nanograms/kg per minute for up to 3 days. operative period typical doses by intravenous infusion
1. Breen D, et al. Offset of pharmacodynamic effects and safety of have ranged from 100 to 200 nanograms/kg per
remifentanil in intensive care unit patients with various degrees
of renal impairment. Crit Care 2004; 8: R21–R30. minute; supplemental intravenous bolus doses are not
O N CH3 2. Pitsiu M, et al. Pharmacokinetics of remifentanil and its major recommended during the postoperative period.
N metabolite, remifentanil acid, in ICU patients with renal impair-
ment. Br J Anaesth 2004; 92: 493–503. To provide analgesia and sedation in ventilated pa-
H 3C tients under intensive care, remifentanil is given as an
N CH3 Interactions intravenous infusion at an initial rate of 100 to
H 3C H 150 nanograms/kg per minute. Doses should then be
For interactions associated with opioid analgesics, see
p.103. titrated to provide adequate analgesia and sedation; a
NOTE. The name Isopyrin has also been applied to isoniazid. period of 5 minutes should be allowed between dose
Profile Pharmacokinetics adjustments. Additional sedative drugs should be giv-
Ramifenazone is an NSAID (p.96) that has been used in prepa- en to those patients inadequately sedated with remifen-
rations for painful and inflammatory conditions; it has also been After parenteral doses remifentanil hydrochloride has a
used in veterinary medicine. Ramifenazone has been given as the rapid onset and short duration of action. Its effective tanil infusions of 200 nanograms/kg per minute. An in-
hydrochloride and the salicylate. biological half-life is about 3 to 10 minutes and is inde- crease in the rate of remifentanil infusion may be
pendent of dose. Remifentanil is about 70% bound to necessary if additional analgesia is required to cover
plasma proteins, mainly to α1-acid glycoprotein. It is stimulating or painful procedures such as wound dress-
hydrolysed by non-specific esterases in blood and tis- ing. Doses of up to 750 nanograms/kg per minute have
Remifentanil Hydrochloride sues to an essentially inactive carboxylic acid metabo- been given to some patients. Bolus doses of remifen-
⊗
(BANM, USAN, rINNM) lite. About 95% of a dose of remifentanil is excreted in tanil are not recommended in intensive care.
GI-87084B; Hidrocloruro de remifentanilo; Rémifentanil, Chlo- the urine as the metabolite. Studies in animals suggest Remifentanil is also used as an analgesic in patients
rhydrate de; Remifentanili Hydrochloridum. 4-Carboxyl-4-(N- that remifentanil may cross the placenta and is distrib- receiving monitored anaesthesia care. In the USA, it
phenylpropionamido)-1-piperidine propionic acid dimethyl ester uted into breast milk. may be given intravenously in a single dose of
monohydrate.
◊ Licensed product information for remifentanil gives values for
1 microgram/kg 90 seconds before the local anaesthet-
Ремифентанила Гидрохлорид a three-compartment pharmacokinetic model with a rapid distri- ic; alternatively, a dose of 100 nanograms/kg per
C 20 H 28 N 2 O 5 ,HCl = 412.9. bution half-life of 1 minute, a slower distribution half-life of 6 minute may be given as an intravenous infusion, start-
C AS — 132539-07-2. minutes, and a terminal elimination half-life of 10 to 20 minutes. ing 5 minutes before the local anaesthetic, which
ATC — N01AH06. References. should be reduced to 50 nanograms/kg per minute after
ATC Vet — QN01AH06. 1. Egan TD. Remifentanil pharmacokinetics and pharmacodynam- the local anaesthetic. Subsequent adjustments of
ics: a preliminary appraisal. Clin Pharmacokinet 1995; 29: 25 nanograms/kg per minute at 5-minute intervals may
80–94.
2. Egan TD. Pharmacokinetics and pharmacodynamics of remifen-
be made to maintain a balanced analgesia.
O OCH3 tanil: an update in the year 2000. Curr Opin Anaesthesiol 2000; Remifentanil has a very rapid offset of action and no
13: 449–55.
3. Ross AK, et al. Pharmacokinetics of remifentanil in anesthetized
residual opioid action remains 5 to 10 minutes after
pediatric patients undergoing elective surgery or diagnostic pro- stopping an infusion. When appropriate, alternative
N cedures. Anesth Analg 2001; 93: 1393–1401.
N OCH3 analgesics should be given before stopping remifen-
H 3C tanil, in sufficient time to provide continuous and more
O Uses and Administration prolonged pain relief.
O Remifentanil, an anilidopiperidine derivative, is an
opioid analgesic (p.104) related to fentanyl (p.58). It is ◊ References and reviews.
(remifentanil)
a short-acting μ-receptor opioid agonist used for anal- 1. Patel SS, Spencer CM. Remifentanil. Drugs 1996; 52: 417–27.
2. Duthie DJR. Remifentanil and tramadol. Br J Anaesth 1998; 81:
gesia during induction and/or maintenance of general 51–7.
Incompatibility. Remifentanil hydrochloride should not be
mixed in the same intravenous solution as blood products. UK
anaesthesia. It is also used to provide analgesia into the 3. Davis PJ, Cladis FP. The use of ultra-short-acting opioids in pae-
licensed product information states that it should not be mixed immediate postoperative period, and may be used as diatric anaesthesia: the role of remifentanil. Clin Pharmacokinet
2005; 44: 787–96.
with lactated Ringer’s injection with or without 5% glucose; the analgesic component of local or regional anaesthe-
4. Scott LJ, Perry CM. Remifentanil: a review of its use during the
however, in the USA the product literature states that remifen- sia with or without benzodiazepine sedation. Remifen- induction and maintenance of general anaesthesia. Drugs 2005;
tanil hydrochloride is stable for 4 hours at room temperature after tanil is also used to provide analgesia and sedation in 65: 1793–1823. Correction. ibid.; 2286.
reconstitution and dilution to 20 to 250 micrograms/mL with lac- 5. Battershill AJ, Keating GM. Remifentanil: a review of its anal-
tated Ringer’s injection and for 24 hours if lactated Ringer’s with mechanically ventilated patients under intensive care. gesic and sedative use in the intensive care unit. Drugs 2006; 66:
5% glucose is used. Incompatibilities have been reported be- Remifentanil is given intravenously as the hydrochlo- 365–85.
tween chlorpromazine hydrochloride 2 mg/mL and remifentanil ride, usually by infusion. Its onset of action is within 1 6. Welzing L, Roth B. Experience with remifentanil in neonates and
25 micrograms/mL (as the hydrochloride) in 5% glucose and ce- infants. Drugs 2006; 66: 1339–50.
foperazone sodium 40 mg/mL or amphotericin B 0.6 mg/mL minute and the duration of action is 5 to 10 minutes.
Doses are expressed in terms of the base; remifentanil Administration in children. Remifentanil hydrochloride,
and remifentanil 250 micrograms/mL (as the hydrochloride) in given by continuous intravenous infusion, is used for analgesia
5% glucose.1 hydrochloride 1.1 mg is equivalent to about 1 mg of during maintenance of general anaesthesia in children. Usual in-
1. Trissel LA, et al. Compatibility of remifentanil hydrochloride remifentanil. Initial doses for anaesthesia in elderly pa- fusion doses (expressed as the base) for those aged from 1 to 12
with selected drugs during simulated Y-site administration. Am J tients should be half the recommended adult doses and years range from 0.05 to 1.3 micrograms/kg per minute depend-
Health-Syst Pharm 1997; 54: 2192–6.
then titrated to individual requirements. Obese patients ing on the anaesthetic drug employed and adjusted according to
response; supplemental intravenous boluses of 1 microgram/kg
Dependence and Withdrawal may require doses based on their ideal (lean) body- may be given over at least 30 seconds. US licensed product in-
As for Opioid Analgesics, p.101. weight. For details of doses in children, see below. formation also states that neonates and children aged up to 2
When used to provide analgesia during induction of months may be given infusion doses of 0.4 to 1 micrograms/kg
per minute with supplemental boluses of 1 microgram/kg. Simi-
Adverse Effects and Treatment anaesthesia an intravenous infusion is given in doses of lar doses are suggested in the BNFC for use in neonates although
As for Opioid Analgesics in general, p.102 and for 0.5 to 1 micrograms/kg per minute. An additional ini- in the UK remifentanil is not licensed for use in children under 1
Fentanyl, p.56. tial intravenous bolus of 1 microgram/kg may be given year of age.
 Ramifenazone/Salix 121
Preparations blood pressure is greater in those patients receiving rofecoxib Pharmacopoeias. In Pol. and US.
Proprietary Preparations (details are given in Part 3) than in those receiving celecoxib.9 However, the manufacturers USP 31 (Salicylamide). A white practically odourless crystalline
Arg.: Remicit; Ultiva; Austral.: Ultiva; Austria: Ultiva; Belg.: Ultiva; Braz.: of rofecoxib have pointed out that the trial used doses of rofecox- powder. Slightly soluble in water and in chloroform; soluble in
Ultiva; Canad.: Ultiva; Chile: Ultiva; Cz.: Ultiva; Denm.: Ultiva; Fin.: Ultiva; ib greater than those recommended for elderly or hypertensive alcohol and in propylene glycol; freely soluble in ether and in so-
Fr.: Ultiva; Ger.: Ultiva; Gr.: Ultiva; Hong Kong: Ultiva; Hung.: Ultiva†; Irl.: patients. lutions of alkalis.
Ultiva†; Israel: Ultiva; Ital.: Ultiva; Mex.: Ultiva; Neth.: Ultiva; Norw.: Ul- 1. CSM/MCA. COX-2 selective NSAIDs lack antiplatelet activity.
tiva; NZ: Ultiva; Pol.: Ultiva; Port.: Ultiva; S.Afr.: Ultiva; Singapore: Ultiva;
Spain: Ultiva; Swed.: Ultiva; Switz.: Ultiva; Turk.: Ultiva; UK: Ultiva; USA: Current Problems 2001; 27: 7. Also available at: http:// Profile
Ultiva; Venez.: Ultiva. w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ Salicylamide is a salicylic acid derivative (see Aspirin, p.20) but
FILE&dDocName=CON007458&RevisionSelectionMethod= is not hydrolysed to salicylate; it is almost completely metabo-
LatestReleased (accessed 08/11/07)
2. Bombardier C, et al. Comparison of upper gastrointestinal toxic-
lised to inactive metabolites during absorption and on first pass
ity of rofecoxib and naproxen in patients with rheumatoid arthri- through the liver. It is given in usual oral doses of 325 to 650 mg
Rofecoxib (BAN, USAN, rINN) tis. N Engl J Med 2000; 343: 1520–8. or more, usually with other analgesics, three or four times daily
MK-966; MK-0966; Rofécoxib; Rofecoxibum; Rofekoksibi; Rofe- 3. Bresalier RS, et al. Cardiovascular events associated with ro- for pain and fever. Salicylamide has also been applied topically
koxib. 4-[p-(Methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone. fecoxib in a colorectal adenoma chemoprevention trial. N Engl J in rubefacient preparations in concentrations of up to about 5%
Med 2005; 352: 1092–1102. Correction. ibid. 2006; 355: 221. for the relief of muscular and rheumatic pain.
Рофекоксиб 4. Merck, USA. Merck announces preliminary analyses of off-drug
C 17 H 14O 4 S = 314.4. extension of APPROVe study (issued 11th May, 2006). Available Preparations
C AS — 162011-90-7. at: http://www.merck.com/newsroom/press_releases/corporate/
ATC — M01AH02. 2006_0511.html (accessed 08/11/07) Proprietary Preparations (details are given in Part 3)
ATC Vet — QM01AH02. 5. Afilalo J, et al. Long-term risk of ischemic stroke associated
with rofecoxib. Cardiovasc Drugs Ther 2007; 21: 117–20. Austria: Waldheim Rheuma-Creme.
6. Kerr DJ, et al. Rofecoxib and cardiovascular adverse events in Multi-ingredient: Arg.: Finagrip†; Funciogrip; Venter; Austria: Rilfit; Ru-
adjuvant treatment of colorectal cancer. N Engl J Med 2007; 357:
O 360–9.
briment; Sigmalin B ; Sigmalin B forte; Sigmalin B ohne Coffein; Spalt†;
Waldheim Influvidon; Waldheim Sport- und Rheuma-Fluid; Belg.: Percutal-
7. Jüni P, et al. Risk of cardiovascular events and rofecoxib: cumu- gine; Braz.: Coristina R; Nogripe; Resprax; Termogripe C†; Vita Grip;
lative meta-analysis. Lancet 2004; 364: 2021–9. Denm.: Kodamid; Koffisal; Fr.: Percutalgine; Ger.: Glutisal†; Salistoperm†;
O 8. Johnson DL, et al. Effect of cyclooxygenase-2 inhibitors on Gr.: Myalgesic†; Hong Kong: Antiflu Forte; Antiflu-N-Forte; DF Multi-
blood pressure. Ann Pharmacother 2003; 37: 442–6. Symptom; Flu-Zep; Neozep; Qualizep; Indon.: Cold Cap; Corexin; Ne-
9. Whelton A, et al. Cyclooxygenase-2-specific inhibitors and car- ozep; Refagan; Ital.: Anticorizza†; Mex.: Artrilan; Butayonacol; NZ: Calm-
diorenal function: a randomized, controlled trial of celecoxib and U; Pol.: Reumosol; Scorbolamid; Rus.: Cefecon N (Цефекон Н); Percutal-
rofecoxib in older hypertensive osteoarthritis patients. Am J Ther gine (Перкуталжин)†; S.Afr.: Colcaps; Flutex Cold and Flu; Histamed
2001; 8: 85–95. Compound; Ilvico; Specific Nerve Pain Remedy; Spain: Coricidin†; Huber-
grip†; Pridio; Rinomicine; Rinomicine Activada; Yendol; Switz.: Escalgin sans
Preparations codeine†; Escogripp sans codeine; Grippalgine N†; Osa Gel de dentition;
H 3C S Proprietary Preparations (details are given in Part 3) Thai.: Apracur; Fecol; Percutalgine†; UAE: Adol Compound; Flukit; UK:
Intralgin†; USA: Anabar; BC; Be-Flex Plus; By-Ache; Combiflex; Duraxin;
Arg.: Antidol†; Blokium Cox†; Coxiro†; Foldoxx†; Toloxane†; Vioxx†; Aus-
O tral.: Vioxx†; Austria: Ceoxx†; Coxxil†; Vioxx†; Belg.: Vioxx†; Braz.: Vi-
Levacet; Lobac; Painaid; Saleto; Stanback Headache; Trim-Elim†; Venez.:
O Cotar†; Praxona.
oxx†; Canad.: Vioxx†; Chile: Ceoxx†; Cz.: Vioxx†; Denm.: Vioxx†; Vi-
oxxalt†; Fin.: Vioxx†; Fr.: Vioxx†; Ger.: Vioxx†; Gr.: Peroxx†; Vioxx†;
Profile Hong Kong: Vioxx†; Hung.: Vioxx†; India: Alrof†; Dolib†; Rofetab†;
Rofecoxib is an NSAID (p.96) reported to be a selective inhibitor Rofib; Rofixx†; Rofiz; Versatil†; Irl.: Ceoxx†; Vioxx†; Israel: Vioxx†; Ital.:
of cyclo-oxygenase-2 (COX-2). It was given orally for sympto- Arofexx†; Coxxil†; Dolcoxx†; Dolostop†; Miraxx†; Vioxx†; Malaysia: Vi-
oxx†; Mex.: Vioxx†; Neth.: Vioxx†; Norw.: Vioxx†; NZ: Vioxx†; Port.: Salix
matic relief in the treatment of osteoarthritis and rheumatoid ar- Ceoxx†; Coxxil†; Vioxx†; S.Afr.: Vioxx†; Singapore: Vioxx†; Spain:
thritis, and in the management of acute pain, dysmenorrhoea, and Ceoxx†; Vioxx†; Swed.: Vioxx†; Vioxxakut†; Switz.: Vioxx†; Thai.: Vi- Corteza de sauce; Écorce de Saule; Fűzfakéreg; Gluosniu˛ žievė;
migraine but was generally withdrawn worldwide after reports oxx†; UK: Vioxx†; USA: Vioxx†; Venez.: Vioxx†. Kora wierzby; Pajunkuori; Sälgbark; Salicis cortex; Saule, écorce
of cardiovascular adverse effects (see below). Multi-ingredient: India: Rofecip Plus†. de; Vrbová kůra; Weidenbaumrinde; White Willow Bark; Willow
Rofecoxib has been applied topically in some countries. Bark.
Effects on the cardiovascular system. As of February 2001,
the UK CSM had received a small number of reports of myocar- Salamidacetic Acid
dial infarction or ischaemia associated with the selective cyclo- Carbamoylphenoxyacetic acid; Salamidacético, ácido; Salicyla-
oxygenase-2 (COX-2) inhibitors.1 At that time it noted that mide O-acetic acid. (2-Carbamoylphenoxy)acetic acid.
COX-2 inhibitors such as rofecoxib did not possess the intrinsic
antiplatelet activity associated with aspirin, and consequently did Натрия Салициламидацетат (sodium salamidacetate) HO
not provide protection against ischaemic cardiac events. Data C 9 H 9 NO 4 = 195.2.
from a large, randomised study also showed the incidence of my- C AS — 25395-22-6 (salamidacetic acid); 3785-32-8 (so- O O
ocardial infarction to be greater in patients taking rofecoxib than dium salamidacetate). HO
in those taking naproxen.2 Postmarketing surveillance of ro-
fecoxib continued to provide further case reports of adverse car-
diovascular effects. In addition, results of the then unpublished O HO OH
APPROVe study of rofecoxib for prevention of adenomatous OH OH
polyposis indicated that the risk of myocardial infarction and
stroke was markedly increased in patients receiving the drug
compared to those on placebo; however, this difference was only (salicin)
O
apparent after 18 months of treatment. As a result, the study was
stopped early and, in September 2004, the manufacturer general- NH2 Pharmacopoeias. In Eur. (see p.vii).
ly withdrew rofecoxib worldwide. The cardiovascular findings Ph. Eur. 6.2 (Willow Bark). The whole or fragmented dried bark
from the APPROVe study were published in 2005;3 the results of young branches or whole dried pieces of current year twigs of
showed a twofold increase in the risk of adverse cardiovascular O various species of the genus Salix, including Salix purpurea, S.
events in patients receiving rofecoxib 25 mg daily when com- daphnoides, and S. fragilis. It contains not less than 1.5% of total
pared with those on placebo. More recently, 1-year follow-up Profile salicylic derivatives, expressed as salicin (C13H18O7 = 286.3),
data for patients in the APPROVe study has been released. In a Salamidacetic acid is a salicylic acid derivative (see Aspirin, calculated with reference to the dried drug. Protect from light.
statement from the manufacturer,4 it is noted that in the year after p.20) that has also been used as the sodium and diethylamine
rofecoxib was stopped there was no statistically significant dif- salts for the treatment of musculoskeletal and joint disorders. Profile
ference in the risk of confirmed thrombotic cardiovascular Salix contains variable amounts of tannin and also of salicin,
events in those patients who had previously taken rofecoxib
Preparations
which has antipyretic and analgesic actions similar to those of
compared with those who had been given placebo; however, Proprietary Preparations (details are given in Part 3) aspirin. Salix has been used in a variety of herbal remedies for
when data from both the on- and off-treatment periods were con- Austria: Akistin; Ger.: Clinit N†.
painful and inflammatory conditions and for fever. It was once
sidered together, the difference in the risk of cardiovascular Multi-ingredient: Austria: Ambene; Rheumesser; Ger.: Caye Rheuma- used as a bitter.
events between the rofecoxib and the placebo groups remained Balsam; Rus.: Ambene (Амбене); Thai.: Trabit†.
significant. Combined data from the on- and off-treatment peri- Adverse effects. An anaphylactic reaction developed in a 25-
ods also showed that there was an increased risk of confirmed year-old woman with asthma and a known allergy to aspirin,
heart attacks and ischaemic strokes in the rofecoxib group when Salicylamide (BAN, rINN) within 75 minutes of ingesting a dietary supplement containing
compared to the placebo group. (The data for ischaemic stroke willow bark extract.1 The link between salicylate and willow
Salicilamida; Salicylamid; Salicylamidum; Salisyyliamidi. 2-Hydroxy-
were later published.5) Similar data, suggesting a 1.5-fold in- bark allergy was also reported in a carpenter who experienced a
crease in risk of thrombotic events with rofecoxib, were reported benzamide. widespread rash, similar to that he developed with aspirin, when
from a study of adjuvant use for colorectal cancer.6 A cumulative Салициламид working with willow wood.2
meta-analysis also indicated an increased risk of myocardial inf- C 7 H 7 NO 2 = 137.1. 1. Boullata JI, et al. Anaphylactic reaction to a dietary supplement
arction in patients receiving rofecoxib.7 C AS — 65-45-2. containing willow bark. Ann Pharmacother 2003; 37: 832–5.
Subsequent investigation by US and European regulatory au- ATC — N02BA05.
2. Jennings A. Link between salicylate and willow bark. Pharm J
thorities has confirmed that other COX-2 inhibitors are also as- ATC Vet — QN02BA05. 2006; 276: 417.
sociated with some increased cardiovascular risk (see under
Celecoxib, p.34), as are some non-selective NSAIDs (see Pain. Preparations containing willow bark extract have been
Thrombotic Events, p.97). O NH2 tried with some success in the treatment of musculoskeletal dis-
A review8 of prospective studies evaluating the effect of selective orders such as low back pain1-3 and osteoarthritis.4 However, the
COX-2 inhibitors on blood pressure was unable to determine if OH quality of reporting in trials is generally poor and further studies
there was any association between the use of these drugs and are needed to establish their place in therapy.
blood pressure elevations. Of the studies considered, a ran- 1. Chrubasik S, et al. Treatment of low back pain exacerbations
domised study in elderly, hypertensive patients with osteoarthri- with willow bark extract: a randomized double-blind study. Am
tis has suggested that the risk of developing increased systolic J Med 2000; 109: 9–14.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
122 Analgesics Anti-inflammatory Drugs and Antipyretics
2. Chrubasik S, et al. Treatment of low back pain with a herbal or cause fewer gastric lesions than piroxicam.1 However, small- cally insoluble in alcohol and in dichloromethane. A 10% solu-
synthetic anti-rheumatic: a randomized controlled study. Willow bowel ulcerations were reported in a patient when salsalate was tion in water has a pH of 6.0 to 7.0. Store in airtight containers.
bark extract for low back pain. Rheumatology (Oxford) 2001; 40: added to a regimen of ranitidine and metoclopramide which had
1388–93.
USP 31 (Gold Sodium Thiomalate). A mixture of the mono-
3. Gagnier JJ, et al. Herbal medicine for low back pain. Available been prescribed for duodenal ulcer.2 sodium and disodium salts of gold thiomalic acid [(auro-
in The Cochrane Database of Systematic Reviews; Issue 2. 1. Porro GB, et al. Salsalate in the treatment of rheumatoid arthri- thio)succinic acid] (C4H4AuNaO4S = 368.1 and
Chichester: John Wiley; 2006 (accessed 05/10/06). tis: a double-blind clinical and gastroscopic trial versus piroxi- C4H3AuNa2O4S = 390.1) that has a gold content of 44.8 to
4. Biegert C, et al. Efficacy and safety of willow bark extract in the cam: II—endoscopic evaluation. J Int Med Res 1989; 17: 320–3. 49.6%, and 49.0 to 52.5% calculated on the dried alcohol-free
treatment of osteoarthritis and rheumatoid arthritis: results of 2 2. Souza Lima MA. Ulcers of the small bowel associated with
randomized double-blind controlled trials. J Rheumatol 2004; stomach-bypassing salicylates. Arch Intern Med 1985; 145: and glycerol-free material. pH of a 10% solution in water is be-
31: 2121–30. 1139. tween 5.8 and 6.5. Store in airtight containers at a temperature of
25°, excursions permitted between 15° and 30°. Protect from
Preparations Effects on the kidneys. A case of minimal-change nephrotic
light.
Proprietary Preparations (details are given in Part 3) syndrome associated with salsalate use.1
Braz.: Zortrix; Ger.: Assalix; Assplant; Lintia†; Rheumakaps; Rheumatab 1. Vallès M, Tovar JL. Salsalate and minimal-change nephrotic
Salicis†; Pol.: Salicortex; Switz.: Assalix. syndrome. Ann Intern Med 1987; 107: 116. Adverse Effects
Multi-ingredient: Austral.: Arthritic Pain Herbal Formula 1; Bioglan Ar- Effects on the mouth. Ulcerated lesions on the tongue of a Reports show a wide range for the incidence of adverse
thri Plus; Extralife Migrai-Care; Extralife PMS-Care; Guaiacum Complex†; effects of sodium aurothiomalate. However, some con-
Lifesystem Herbal Formula 1 Arthritic Aid†; Prost-1†; Austria: Digestodor- 77-year-old man were caused by taking salsalate tablets incor-
on; Braz.: Calman; Calmiplan; Floriny; Pasalix; Pasic; Passi Catha†; Passiflor- rectly.1 The patient had placed the tablets under his tongue rather sider that with careful treatment about one-third of pa-
ine; Cz.: Antirevmaticky Caj; Erkaltungstee†; Valofyt Neo; Fr.: Arkophy- than swallowing them whole, resulting in prolonged, direct con- tients will experience adverse effects. It is also consid-
tum†; Mediflor Tisane Circulation du Sang No 12; Phytheol; Ger.: tact with the tongue.
Digestodoron; Dr Wiemanns Rheumatonikum; Ital.: Biothymus DS; Body- 1. Ruscin JM, Astroth JD. Lingual lesions secondary to prolonged
ered that about 5% of patients will experience severe
guard; Donalg; Influ-Zinc; Nepiros; Nevril; Passiflorine; Reumafort; Malay- adverse effects and that some of the effects will be
sia: Celery Plus†; Mex.: Ifupasil; Pol.: Enterosol; Pyrosal; Reumacor; Reu- contact with salsalate tablets. Ann Pharmacother 1998; 32:
mosol; Termasil; Port.: Neurocardol†; S.Afr.: Digestodoron; Spain: 1248. fatal. The most common effects involve the skin and
Dolosul†; Jaquesor†; Mesatil†; Natusor Harpagosinol†; Natusor Jaquesan†; Interactions mucous membranes with pruritus (an early sign of
Switz.: Dragees antirhumatismales; Strath Gouttes Rhumatisme; Tisane For interactions associated with salicylates, see Aspirin, p.23.
antirhumatismale; UK: Bio-Strath Willow Formula; Gerard House Reu- intolerance) and stomatitis (often with a metallic taste)
malex; Herbal Pain Relief; St Johnswort Compound; Venez.: Passiflorum. Pharmacokinetics being the most prominent. Rashes with pruritus often
Salsalate is insoluble in acidic gastric fluids but is soluble in the occur after 2 to 6 months of intramuscular treatment
small intestine. One molecule of salsalate is hydrolysed to 2 mol-
ecules of salicylic acid; hydrolysis occurs both in the small intes- and may require stopping therapy. Other reactions af-
Salol
tine and after absorption of the parent compound. Additional de- fecting the skin and mucous membranes include ery-
Benzofenolsalicylaat; Benzophénol Salicylate; Fenylsalicylat; Feny-
lu salicylan; Fenyylisalisylaatti; Phenyli Salicylas; Phenylis Salicylas;
tails on the pharmacokinetics of salicylic acid are provided in thema, maculopapular eruptions, erythema multi-
aspirin (see p.23). Not all of the absorbed salsalate is hydrolysed forme, urticaria, eczema, seborrhoeic dermatitis,
Salicilato de fenilo. Phenyl salicylate. and about 13% of salsalate is excreted as glucuronide conjugates
C 13 H 10 O 3 = 214.2. in the urine; thus, the amount of salicylic acid available from sal- lichenoid eruptions, alopecia, exfoliative dermatitis,
C AS — 118-55-8. salate is less than that from aspirin when the two drugs are given glossitis, pharyngitis, vaginitis, photosensitivity reac-
ATC — G04BX12. in equimolar equivalents of salicylic acid. tions, and irreversible pigmentation (chrysiasis).
ATC Vet — QG04BX12.
Uses and Administration Toxic effects on the blood include eosinophilia, throm-
Salsalate is a salicylic acid derivative that has analgesic, anti-in- bocytopenia, leucopenia, agranulocytosis, and aplastic
flammatory, and antipyretic actions similar to those of aspirin anaemia.
OH O (see p.23). It is used for pain and fever and also in inflammatory
disorders such as osteoarthritis and rheumatoid arthritis. A usual Effects on the kidneys include mild transient proteinu-
O oral dose is up to 3 g daily given in divided doses with food. ria which may lead to heavy proteinuria, haematuria,
Preparations and nephrosis.
USP 31: Salsalate Capsules; Salsalate Tablets. Other effects reported include pulmonary fibrosis, dys-
Pharmacopoeias. In Pol.
Proprietary Preparations (details are given in Part 3) pnoea, toxic hepatitis, cholestatic jaundice, peripheral
USA: Amigesic; Argesic-SA; Artha-G; Disalcid; Marthritic; Mono-Gesic†;
Salflex; Salsitab. neuritis, encephalitis, psychoses, fever, and gastroin-
Profile testinal disorders including enterocolitis. Gold deposits
Salol is a salicylic acid derivative (see Aspirin, p.20). It was for-
merly used as an intestinal antiseptic, but effective doses were may occur in the eyes. Vasomotor or nitritoid reactions,
toxic owing to the liberation of phenol. It is used in oral prepara- Sarracenia Purpurea with weakness, flushing, palpitations, and syncope,
tions containing methenamine for the treatment of lower urinary- Pitcher Plant. may occur after injection of sodium aurothiomalate.
tract infections. Local irritation may also follow injection.
Salol has been used topically as a sunscreen. Profile
The roots and leaves of Sarracenia purpurea (Sarraceniaceae) Sometimes there is an initial exacerbation of the ar-
Preparations have been used in the form of an aqueous distillate, given by lo- thritic condition.
Proprietary Preparations (details are given in Part 3) cal injection, for neuromuscular or neuralgic pain.
Austral.: Aussie Tan Sunstick. Some adverse effects of gold have an immunogenic
Preparations component.
Multi-ingredient: Arg.: Dermithan; Austria: Carl Baders Divinal; Belg.:
Borostyrol; Braz.: Talco Alivio†; Canad.: Franzbranns†; Chile: Galutec†; Proprietary Preparations (details are given in Part 3)
Polisep†; Cz.: Parodontal F5†; Fr.: Borostyrol; Dermophil Indien†; Nisa- USA: Sarapin. ◊ Reviews.
calm; Pol.: Salotannal; Urosal; Switz.: Borostyrol N†; Dermophil Indien; 1. Tozman ECS, Gottlieb NL. Adverse reactions with oral and
GU Eau†; Penta; Turk.: Sandolin; USA: Atrosept; Dolsed†; MHP-A; MSP- parenteral gold preparations. Med Toxicol 1987; 2: 177–89.
Blu; Prosed/DS; Trac Tabs 2X†; UAA; Urelle; Uretron; Uridon Modified†; 2. van Roon EN, et al. Parenteral gold preparations. Efficacy and
Urimar-T; Urimax; Urised; Uriseptic; UriSym†; Uritact; Uro Blue; Urogesic
Blue; Utira. Sodium Aurothiomalate (rINN) safety of therapy after switching from aurothioglucose to au-
rothiomalate. J Rheumatol 2005; 32: 1026–30.
Aurothiomalate de Sodium; Aurotiomalato de sodio; Gold Sodi- Effects on the blood. Blood disorders such as eosinophilia,
um Thiomalate; Natrii aurothiomalas; Natrium-aurothiomalát; leucopenia, granulocytopenia, and thrombocytopenia have oc-
Salsalate (BAN, USAN, rINN) Natriumaurotiomalaatti; Natriumaurotiomalat; Sodium, aurothi- curred in patients receiving gold therapy. Eosinophilia has been
NSC-49171; Salicyl Salicylate; Salicylosalicylic Acid; Salicylsalicylic omalate de; Sodium Aurothiosuccinate; Sodu aurotiojabłczan; reported to be the most frequent haematological abnormality.1 It
Acid; Salsalato; Salsalatum; Salysal; Sasapyrine. O-(2-Hydroxyben- Sodyum Orotiyomalat. has been estimated that thrombocytopenia develops in 1 to 3% of
zoyl)salicylic acid. Натрия Ауротиомалат patients receiving gold salts.2
Сальсалат C AS — 12244-57-4 (anhydrous xNa); 39377-38-3 (diso- Fatal consumption coagulopathy occurred in 4 children after the
dium monohydrate). second injection of sodium aurothioglucose or sodium aurothi-
C 14 H 10 O 5 = 258.2.
C AS — 552-94-3. ATC — M01CB01. omalate.3
ATC — N02BA06. 1. Foster RT. Eosinophilia—a marker of gold toxicity. Can J Hosp
ATC Vet — QM01CB01. Pharm 1985; 85: 150–1.
ATC Vet — QN02BA06. 2. Coblyn JS, et al. Gold-induced thrombocytopenia: a clinical and
immunogenetic study of twenty-three patients. Ann Intern Med
1981; 95: 178–81.
Na+ -O O
3. Jacobs JC, et al. Consumption coagulopathy after gold therapy
OH O O
for JRA. J Pediatr 1984; 105: 674–5.
Au Effects on the cardiovascular system. Vasomotor or nitri-
O S O- Na+ toid reactions associated with gold compounds are usually tran-
sient and self-limiting and although they may be mild there have
COOH been isolated reports of associated complications such as myo-
HO O cardial infarction, stroke, transient ischaemic attack, and tran-
Pharmacopoeias. In Chin. and US. O sient monocular visual loss.1 Most reactions have been associat-
USP 31 (Salsalate). Store in airtight containers. ed with sodium aurothiomalate (a reported incidence of 4.7%)
Au but they have also occurred with auranofin and sodium aurothi-
Adverse Effects, Treatment, and Precautions S O- Na+
As for Aspirin, p.20. oglucose. Tachyphylaxis usually occurs to the reactions and most
patients are able to continue treatment but paradoxically in some
The use of aspirin and other acetylated salicylates is generally Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. the severity increases with repeated doses; 2.8% of patients re-
not recommended for children because of the risk of Reye’s syn- Ph. Eur. 6.2 (Sodium Aurothiomalate). A mixture of monoso- ceiving sodium aurothiomalate may require a change of treat-
drome, unless specifically indicated. Some licensed product in- dium and disodium salts of (2RS)-2-(aurosulphanyl)butanedioic ment due to recurrent reactions. It is important to distinguish
formation extends this precaution to salsalate. acid. It contains 44.5 to 46.0% of gold and 10.8 to 11.8% of so- such reactions from true anaphylactic reactions to gold.1 Patients
Effects on the gastrointestinal tract. Salsalate is associated dium, calculated with reference to the dried substance. A fine, taking ACE inhibitors may be at increased risk of nitritoid reac-
with less faecal blood loss than aspirin and has been reported to pale yellow, hygroscopic powder. Very soluble in water; practi- tions.2,3 Transfer of the patient to sodium aurothioglucose or re-
 Salol/Sodium Aurothiomalate 123
duction of the dose by 50%, injection in the recumbent position, tion is permanent but benign, although the cosmetic effects may because of the relatively high exposure it was recommended that
and observation for 20 minutes have been recommended for the cause some patients distress. Prevention of chrysiasis is difficult breast-fed infants should be closely monitored.
next few injections after a reaction.2 but avoidance of exposure to sunlight may be helpful. 1. American Academy of Pediatrics. The transfer of drugs and oth-
1. Ho M, Pullar T. Vasomotor reactions with gold. Br J Rheumatol 1. Smith RW, et al. Chrysiasis revisited: a clinical and pathological er chemicals into human milk. Pediatrics 2001; 108: 776–89.
1997; 36: 154–6. study. Br J Dermatol 1995; 133: 671–8. Correction. ibid; 1029. Also available at:
2. Arthur AB, et al. Nitritoid reactions: case reports, review, and h t tp : / /a a p po l i c y. a a pp u b l ica ti o n s .o rg/ c g i / c o nt e n t / f u ll /
recommendations for management. J Rheumatol 2001; 28: Hypersensitivity. Many adverse effects associated with gold pediatrics%3b108/3/776 (accessed 13/11/06)
2209–12. treatment have an immunological basis. Patients with contact al- 2. Bennett PN, et al. Use of sodium aurothiomalate during lacta-
3. Nixon J, Pande I. Gold, nitritoid reactions and angiotensin-con- lergy to gold may exhibit a flare-up, associated with cytokine re- tion. Br J Clin Pharmacol 1990; 29: 777–9.
verting enzyme inhibitors. Rheumatology (Oxford) 2006; 45: lease, when given sodium aurothiomalate intramuscularly.1 3. Needs CJ, Brooks PM. Antirheumatic medication during lacta-
118–19. tion. Br J Rheumatol 1985; 24: 291–7.
Small amounts of nickel have been detected in sodium aurothi- 4. Blau SP. Metabolism of gold during lactation. Arthritis Rheum
Effects on the gastrointestinal tract. A case report of ente- omalate injection2 and in sodium aurothioglucose injection3 and 1973; 16: 777–8.
rocolitis due to sodium aurothiomalate has been published1 and it has been suggested that gold therapy may also exacerbate or
27 other cases associated with gold therapy reviewed. For colitis induce hypersensitivity to nickel.2-4 Porphyria. Sodium aurothiomalate has been associated with
associated with oral gold see also under Auranofin, p.25. acute attacks of porphyria and is considered unsafe in porphyric
Anaphylaxis may occur occasionally5 but vasomotor or ‘nitri-
1. Jackson CW, et al. Gold induced enterocolitis. Gut 1986; 27: patients.
toid’ reactions (see Effects on the Cardiovascular System, above)
452–56. may produce similar symptoms. Pregnancy. Although healthy neonates have been born after in-
Effects on the immune system. Details of a patient who de- 1. Möller H, et al. The flare-up reactions after systemic provocation utero exposure to gold compounds,1,2 animal studies and a
veloped an immune deficiency syndrome that was attributed to in contact allergy to nickel and gold. Contact Dermatitis 1999; report1 of malformation in a child born to a woman treated with
gold therapy with sodium aurothiomalate.1 40: 200–4. sodium aurothiomalate led to a suggestion that gold might possi-
1. Haskard DO, Macfarlane D. Adult acquired combined immune 2. Choy EHS, et al. Nickel contamination of gold salts: link with bly have teratogenic effects. Licensed product information ad-
deficiency in a patient with rheumatoid arthritis on gold. J R Soc gold-induced skin rash. Br J Rheumatol 1997; 36: 1054–8. vises that sodium aurothiomalate should be avoided during preg-
Med 1988; 81: 548–9. 3. Wijnands MJH, et al. Chrysotherapy provoking exacerbation of
contact hypersensitivity to nickel. Lancet 1990; 335: 867–8. nancy.
Effects on the kidneys. Proteinuria developed in 21 patients 4. Fulton RA, et al. Another hazard of gold therapy? Ann Rheum 1. Rogers JG, et al. Possible teratogenic effects of gold. Aust Pae-
while receiving a standard regimen of sodium aurothiomalate.1 Dis 1982; 41: 100–1. diatr J 1980; 16: 194–5.
The severity of the proteinuria varied greatly and in 11 it in- 5. Neustadt DH. Another anaphylactic reaction after gold (aurothi- 2. Bennett PN, et al. Use of sodium aurothiomalate during lacta-
omalate) injection. J Rheumatol 1995; 22: 190. tion. Br J Clin Pharmacol 1990; 29: 777–9.
creased for 4 months after treatment was stopped. Eight patients
were considered to have developed the nephrotic syndrome. The Pancreatitis. It was suggested that pancreatitis reported in a
median duration of proteinuria was 11 months, resolving in all 21 woman receiving gold injections and in a woman on oral gold
Interactions
patients when treatment was withdrawn; at 24 months 3 patients therapy may have been due to a hypersensitivity reaction.1 There is an increased risk of toxicity when gold com-
were still experiencing proteinuria and it was not until 39 months 1. Eisemann AD, et al. Pancreatitis and gold treatment of rheuma- pounds are given with other nephrotoxic, hepatotoxic,
that all were free of the condition. Renal biopsy indicated several toid arthritis. Ann Intern Med 1989; 111: 860–1. or myelosuppressive drugs. Use of gold compounds
types of kidney damage.
See under Auranofin (p.25) for a comparative incidence of pro-
with penicillamine may increase the risk of haemato-
Treatment of Adverse Effects logic or renal adverse reactions.
teinuria in patients receiving sodium aurothiomalate or au- The treatment of the adverse effects of gold is usually
ranofin. ACE inhibitors. For a possible increased risk of nitritoid reac-
1. Hall CL, et al. The natural course of gold nephropathy: long term symptomatic and most effects resolve when gold ther-
tions when gold compounds are given to patients taking ACE
study of 21 patients. BMJ 1987; 295: 745–8. apy is withdrawn. In severe cases a chelator such as inhibitors, see Effects on the Cardiovascular System, above.
Effects on the lungs. ‘Gold lung’ is the term used to describe dimercaprol (p.1444) may be used.
Penicillamine. For a discussion on the effects of previous ther-
symptoms of dyspnoea on exertion, weakness, dry cough, and apy with gold salts affecting penicillamine toxicity, see p.1458.
malaise that are seen rarely in patients on gold treatment.1 Such Precautions
symptoms usually develop some weeks or months after starting Gold therapy is contra-indicated in exfoliative derma-
gold treatment and are associated with cumulative doses of sev- Pharmacokinetics
eral hundred milligrams although, very rarely, they have been titis, SLE, necrotising enterocolitis, and pulmonary fi- Sodium aurothiomalate is absorbed readily after intra-
seen with cumulative doses of less than 100 mg.2 Pulmonary brosis. It should be used with caution in the elderly and muscular injection and 85 to 95% becomes bound to
insufficiency may eventually develop and there have been occa- in renal or hepatic impairment; use is contra-indicated plasma proteins. With doses of 50 mg weekly a steady-
sional fatalities.3 The pulmonary lesions usually subside on with- if renal or hepatic disorders are severe. Patients with a
drawal of gold therapy, although persistent symptoms have been state serum concentration of gold of about 3 to
reported. history of haematological disorders or who have previ- 5 micrograms/mL is reached in 5 to 8 weeks. It is wide-
Nonbacterial thrombotic endocarditis associated with gold-in- ously shown toxicity to heavy metals should not be ly distributed to body tissues and fluids, including syn-
duced pulmonary disease has also been reported.4 This was con- given gold salts, nor should any severely debilitated ovial fluid, and accumulates in the body.
sidered to be a manifestation of gold-induced immune complex patient. The serum half-life of gold is about 5 to 6 days but this
deposition.
1. Sinha A, et al. Gold-induced pneumonitis: computed tomogra-
It is recommended that diabetes mellitus and heart fail- increases after successive doses and after a course of
phy findings in a patient with rheumatoid arthritis. Rheumatolo- ure should be adequately controlled in any patient be- treatment, gold may be found in the urine for up to 1
gy (Oxford) 2001; 40: 712–14. fore gold is given. Patients with a history of urticaria,
2. Hafejee A, Burke MJ. Acute pneumonitis starting 2 hours after
year or more owing to its presence in deep body com-
intramuscular gold administration in a patient with rheumatoid eczema, or colitis should be treated with caution. Pa- partments. Sodium aurothiomalate is mainly excreted
arthritis. Ann Rheum Dis 2004; 63: 1525–6. tients with a poor sulfoxidation status may be more in the urine, with smaller amounts in the faeces.
3. Soler MJ, et al. Fatal, gold-induced pneumonitis. Rheumatol Int
2003; 23: 207–10. susceptible to adverse effects of sodium aurothioma- Gold has been detected in the fetus when sodium au-
4. Kollef MH, et al. Nonbacterial thrombotic endocarditis associat- late. rothiomalate was given to the mother. Gold is distrib-
ed with gold induced pulmonary disease. Ann Intern Med 1988;
108: 903–4. Use of gold compounds with other therapy capable of uted into breast milk.
Effects on the nails. A 34-year-old woman with severe rheu- inducing blood disorders should be undertaken with ◊ Reviews.
matoid arthritis receiving intramuscular gold developed yellow caution, if at all. 1. Blocka KLN, et al. Clinical pharmacokinetics of oral and inject-
thickened toenails and fingernails after 2 years of treatment.1 Al- Because of the risk of vasomotor reactions, patients able gold compounds. Clin Pharmacokinet 1986; 11: 133–43.
though there was some improvement in nail growth on stopping 2. Tett SE. Clinical pharmacokinetics of slow-acting antirheumatic
treatment, some light yellow discoloration in all 20 nails persist-
should remain recumbent for about 10 minutes after drugs. Clin Pharmacokinet 1993; 25: 392–407.
ed. each injection.
1. Roest MAB, Ratnavel R. Yellow nails associated with gold ther- Urine should be tested for albumin before each injec- Uses and Administration
apy for rheumatoid arthritis. Br J Dermatol 2001; 145: 855–6. Sodium aurothiomalate and other gold compounds are
tion and a full blood count carried out. Patients receiv-
Effects on the nervous system. Neurological complications ing gold compounds either orally or parenterally used mainly for their anti-inflammatory effect in active
with gold salts are infrequent but may include peripheral neurop- progressive rheumatoid arthritis and progressive juve-
athy, Guillain-Barré syndrome, myokymia (repeated involuntary should be warned to report the appearance of sore
contractions of muscle fibre), and encephalopathy. Some throat or tongue, metallic taste, pruritus, rash, buccal nile idiopathic arthritis; they may also be beneficial in
reports1-6 are given below. ulceration, easy bruising, purpura, epistaxis, bleeding psoriatic arthritis. They are generally used as disease-
1. Dick DJ, Raman D. The Guillain-Barre syndrome following gold gums, unexplained bleeding, menorrhagia, pyrexia, modifying antirheumatic drugs in patients whose
therapy. Scand J Rheumatol 1982; 11: 119–20. symptoms are unresponsive to or inadequately control-
2. Schlumpf U, et al. Neurologic complications induced by gold indigestion, diarrhoea, or unexplained malaise. The de-
treatment. Arthritis Rheum 1983; 26: 825–31. velopment of breathlessness or cough should also be led by NSAIDs alone.
3. Cerinic MM, et al. Gold polyneuropathy in juvenile rheumatoid
arthritis. BMJ 1985; 290: 1042.
reported. Effects such as eosinophilia, proteinuria, pru- Sodium aurothiomalate therapy should only be under-
4. Cohen M, et al. Acute disseminated encephalomyelitis as a com- ritus, and rash arising during gold treatment should be taken where facilities are available to carry out the tests
plication of treatment with gold. BMJ 1985; 290: 1179–80. allowed to resolve before therapy is continued. specified under Precautions, above.
5. Dubowitz MN, et al. Gold-induced neuroencephalopathy re-
sponding to dimercaprol. Lancet 1991; 337: 850–1. Licensed product information recommends that annual Sodium aurothiomalate is given by deep intramuscular
6. Garrido JA, et al. Mioquimias inducidas por sales de oro. Neur-
ologia 1995; 10: 235–7.
chest X-rays should be carried out. injection; the area should be gently massaged and, due
Breast feeding. The American Academy of Pediatrics consid- to the possibility of vasomotor reactions, the patient
Effects on the skin. Chrysiasis is a distinctive pigmentation
that develops in light-exposed skin of patients receiving ers that gold compounds are usually compatible with breast feed- should remain recumbent for 10 minutes and kept un-
parenteral gold salts. In a study1 of 31 patients with chrysiasis ing.1 der close observation for 30 minutes after each injec-
who were receiving intramuscular sodium aurothiomalate for Gold has been detected in breast milk2-4 and found bound to the tion. In the UK, 10 mg is given in the first week to test
rheumatoid arthritis, it was noted that visible changes developed red blood cells of breast-fed babies.3,4 In a report2 of a breast-fed the patient’s tolerance. If satisfactory, this may be fol-
above a threshold equivalent to 20 mg/kg gold content. The se- infant it was calculated that the weight-adjusted dose of gold re-
verity of the pigmentation depended upon cumulative dose. ceived by the infant exceeded that received by the mother al-
lowed by doses of 50 mg at weekly intervals until signs
Focal aggregates of gold are deposited in the reticular and papil- though the infant exhibited no ill-effects during 100 days of of remission occur; the dosage interval is then in-
lary dermis with no obvious increase in melanin. The pigmenta- breast feeding and developed normally thereafter. Nonetheless, creased to 2 weeks until full remission occurs and then
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
124 Analgesics Anti-inflammatory Drugs and Antipyretics
increased gradually to every 4 to 6 weeks. Treatment Preparations Although sodium salicylate has been used in the treatment of
may be continued for up to 5 years after remission. BP 2008: Sodium Aurothiomalate Injection; rheumatic fever, its high sodium content may cause problems in
USP 31: Gold Sodium Thiomalate Injection. patients with cardiac complications.
Improvement may not be seen until a total dose of 300 Proprietary Preparations (details are given in Part 3) The use of aspirin and other acetylated salicylates is generally
to 500 mg has been given. If no major improvement Austral.: Myocrisin; Austria: Tauredon; Canad.: Myochrysine; Cz.: Taure- not recommended for children because of the risk of Reye’s syn-
don; Denm.: Myocrisin; Fin.: Myocrisin; Ger.: Tauredon; Gr.: Miocrin; My- drome, unless specifically indicated. Some licensed drug infor-
has occurred after a total of 1 g has been given (exclud- ocrysine†; Tauredon; Tuaredon†; Hung.: Tauredon†; Irl.: Myocrisin; Neth.: mation extends this precaution to sodium salicylate.
ing the test dose) therapy should be stopped; alterna- Tauredon; Norw.: Myocrisin; NZ: Myocrisin; Port.: Tauredon; S.Afr.: My-
ocrisin†; Singapore: Miocrin; Spain: Miocrin; Swed.: Myocrisin; Switz.: Effects on the eyes. Retinal haemorrhages were reported in a
tively in the absence of toxicity, 100 mg may be given Tauredon; Thai.: Myocrisin; UK: Myocrisin; USA: Aurolate; Myochrysine. 60-year-old woman taking sodium salicylate 6 g daily by mouth
weekly for a further 6 weeks; should there be no re- for 2 months and in a 10-year-old girl taking sodium salicylate,
sponse at this dose other forms of therapy should be 4 g daily by mouth, for 40 days.1 In both cases the haemorrhages
tried. In patients who relapse while receiving mainte- Sodium Aurotiosulfate (rINN) gradually resolved after the treatment was stopped.
nance therapy, the interval between doses should be re- Aurotiosulfate de Sodium; Aurotiosulfato de sodio; Gold Sodium 1. Mortada A, Abboud I. Retinal haemorrhages after prolonged use
of salicylates. Br J Ophthalmol 1973; 57: 199–200.
duced to one week and should not be increased again Thiosulphate; Natrii Aurotiosulfas; Natrii Aurotiosulphas; Natriu-
until control has been obtained; however, if no re- maurotiosulfaatti; Natriumaurotiosulfat; Sodium Aurothiosul- Interactions
phate; Sodium Dithiosulfatoaurate. For interactions associated with salicylates, see Aspirin, p.23.
sponse is obtained within 2 months, alternative treat-
ment should be used. It is important to avoid complete Натрия Ауротиосульфат Uses and Administration
Na 3 Au(S 2 O 3 ) 2 ,2H 2 O = 526.2. Sodium salicylate is a salicylic acid derivative that has analgesic,
relapse since a second course of gold therapy is not C AS — 10233-88-2 (anhydrous sodium aurotiosulfate); anti-inflammatory, and antipyretic actions similar to those of
usually effective. 10210-36-3 (sodium aurotiosulfate dihydrate). aspirin (p.23). Sodium salicylate 1 g is equivalent to about 1.1 g
ATC — M01CB02. of aspirin. It is used in the treatment of pain, fever, and in rheu-
For doses in juvenile idiopathic arthritis, see Adminis- ATC Vet — QM01CB02. matic disorders such as osteoarthritis and rheumatoid arthritis.
tration in Children, below. Profile The usual oral dose of sodium salicylate for pain or fever is 325
Sodium aurotiosulfate has a gold content of about 37%. It has to 650 mg every four hours as required. The oral dose for rheu-
NSAIDs may be continued when sodium aurothioma- matic disorders is 3.6 to 5.4 g daily in divided doses. Sodium sal-
similar actions and uses to those of sodium aurothiomalate
late therapy is begun. (p.122). It is given by intramuscular injection in a usual dose of icylate has also been used in the symptomatic treatment of rheu-
56.1 mg every 5 to 7 days. matic fever but its high sodium content may cause problems in
Other gold compounds that have been used include au- patients with cardiac complications.
ranofin (p.25), aurothioglucose (p.26), aurotioprol Preparations Sodium salicylate has also been given by intravenous infusion
(p.26), gold keratinate (p.62), and sodium aurotiosul- Proprietary Preparations (details are given in Part 3) and topically.
Arg.: Crytion; Chile: Crytioro; Ital.: Fosfocrisolo.
fate (below). Preparations
USP 31: Sodium Salicylate Tablets.
Administration in children. For children with progressive ju-
Sodium Gentisate (rINN) Proprietary Preparations (details are given in Part 3)
venile idiopathic arthritis the suggested initial weekly dose of so- Canad.: Dodds†; Saliject; NZ: Hairscience Shampoo†; Turk.: Enter-Sal;
dium aurothiomalate is 1 mg/kg by deep intramuscular injection Gentisate de Sodium; Gentisato de sodio; Gentisato Sodico; UK: Jackson’s Pain & Fever.
to a maximum of 50 mg weekly (one-tenth to one-fifth of the Natrii Gentisas. Sodium 2,5-dihydroxybenzoate dihydrate. Multi-ingredient: Braz.: A Saude da Mulher; Abacateirol†; Pilulas De
calculated initial weekly dose may be given for 2 to 3 weeks to Witt’s†; Canad.: Plax; Thunas Tab for Menstrual Pain†; Chile: Eucerin
Натрия Гентизат Shampoo Anticaspa; Fr.: Brulex; Ger.: Gelonida NA†; Hong Kong: Gly
test the patient’s tolerance). Weekly doses should continue until
signs of remission occur, at which point the dosage interval may C 7 H 5 NaO 4 ,2H 2 O = 212.1. Thymol; S.Afr.: Colphen; Doans Backache Pills; Ilvico; TCP; UK: Antiseptic
be increased to fortnightly. With full remission, the dosage inter- C AS — 490-79-9 (gentisic acid); 4955-90-2 (anhydrous Mouthwash; Doans Backache Pills; TCP; USA: Cystex; Scot-Tussin Original
sodium gentisate). 5-Action; Tussirex; Venez.: Boncilin†; Inquilim†.
val may again be increased gradually to every 4 weeks. If no im-
provement has occurred after 20 weeks, the dose could be raised
slightly or another antirheumatic drug tried. For the view that use
of gold compounds is no longer appropriate to treat juvenile idi- HO Sodium Thiosalicylate
opathic arthritis see Rheumatic Disorders, below. O Tiosalicilato sódico. Sodium 2-sulfanylbenzoate.
Тиосалицилат Натрия
Asthma. For comment on the use of parenteral gold com-
pounds in the treatment of asthma, see under Auranofin, p.26. C 7 H 5 O 2 NaS = 176.2.
OH C AS — 134-23-6.
Pemphigus and pemphigoid. Corticosteroids are the main OH
treatment for blistering in pemphigus and pemphigoid (p.1582).
Intramuscular gold therapy has been used concomitantly to per- (gentisic acid) O O-
mit a reduction in corticosteroid dosage although evidence for
the steroid-sparing effect is lacking;1,2 it has been suggested that Pharmacopoeias. In Fr.
SH Na+
gold therapy should be reserved for patients who cannot tolerate Profile
corticosteroids or in whom they are contra-indicated.1 Sodium gentisate has been used as an analgesic in the treatment
1. Bystryn J-C, Steinman NM. The adjuvant therapy of pemphigus: of musculoskeletal and joint disorders. It is also used as a pre-
an update. Arch Dermatol 1996; 132: 203–12. servative.
2. Pandya AG, Dyke C. Treatment of pemphigus with gold. Arch Profile
Dermatol 1998; 134: 1104–7. Sodium thiosalicylate is a salicylic acid derivative (see Aspirin,
Sodium Salicylate p.20) that has been used parenterally in the treatment of muscu-
Rheumatic disorders. Gold compounds are among the dis-
loskeletal disorders, osteoarthritis, rheumatic fever, and acute
ease-modifying antirheumatic drugs (DMARDs) that may be Natrii salicylas; Natrio salicilatas; Natriumsalicylat; Natriumsalisy-
gout.
used in the treatment of rheumatoid arthritis (p.11). Although laatti; Nátrium-szalicilát; Salicilato sódico; Salicylan sodný; Sodium,
toxicity has now reduced its popularity, intramuscular gold has salicylate de; Sodu salicylan; Sodyum Salisilat. Sodium 2-hydroxy- Preparations
long been used for the treatment of rheumatoid arthritis1-4 and is benzoate. Proprietary Preparations (details are given in Part 3)
often the standard against which the efficacy of other treatments Салицилат Натрия
USA: Rexolate†.
is measured. Oral gold is less toxic but is also much less effec-
C 7 H 5 NaO 3 = 160.1.
tive. It is unclear if there are differences between available intra-
C AS — 54-21-7.
muscular forms, but a study5 in 120 patients converted from
aurothioglucose to aurothiomalate found that 29 withdrew from
ATC — N02BA04.
ATC Vet — QN02BA04. Sufentanil (BAN, rINN) ⊗
the latter drug within 12 months, mostly because of lack of effi-
R-30730; Sufentaniili; Sufentanilis; Sufentanilo; Sufentanilum;
cacy or the development of adverse effects not seen with the pre-
vious drug. Szufentanil. N-{4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-pip-
HO eridyl}propionanilide.
Gold compounds have also been used in the treatment of juvenile O Суфентанил
idiopathic arthritis (p.10); however, the BNFC states that gold is C 22 H 30N 2 O 2 S = 386.6.
no longer used for this indication.
C AS — 56030-54-7.
Gold compounds may also be of benefit in psoriatic arthritis (see NaO
ATC — N01AH03.
under Spondyloarthropathies, p.13). ATC Vet — QN01AH03.
Pharmacopoeias. In Eur. (see p.vii), Int., Jpn, US, and Viet.
1. Epstein WV, et al. Effect of parenterally administered gold ther- Ph. Eur. 6.2 (Sodium Salicylate). Colourless small crystals or
apy on the course of adult rheumatoid arthritis. Ann Intern Med shiny flakes, or white or almost white, crystalline powder. Freely
1991; 114: 437–44. CH3
soluble in water; sparingly soluble in alcohol. Store in airtight
2. Anonymous. Gold therapy in rheumatoid arthritis. Lancet 1991; containers. Protect from light. O
338: 19–20. USP 31 (Sodium Salicylate). Amorphous or microcrystalline
S O
3. Klinkhoff AV, Teufel A. How low can you go? Use of very low powder or scales. It is colourless or has not more than a faint pink
dosage of gold in patients with mucocutaneous reactions. J tinge. It is odourless or has a faint characteristic odour. A freshly
Rheumatol 1995; 22: 1657–9.
made 10% solution in water is neutral or acid to litmus. Freely N N
4. Clark P, et al. Injectable gold for rheumatoid arthritis. Available (and slowly) soluble in water and in glycerol; very soluble in
in The Cochrane Database of Systematic Reviews; Issue 4. boiling water and in boiling alcohol; slowly soluble in alcohol. CH3
Chichester: John Wiley; 1997 (accessed 13/11/06).
Protect from light.
5. van Roon, EN, et al. Parenteral gold preparations: efficacy and
safety of therapy after switching from aurothioglucose to au- Adverse Effects, Treatment, and Precautions
rothiomalate. J Rheumatol 2005; 32: 1026–30. As for Aspirin, p.20.
 Sodium Aurotiosulfate/Sufentanil 125
Pharmacopoeias. In Eur. (see p.vii). Handling. Avoid contact with skin and the inhalation of parti- Hepatic impairment. Because of the efficient hepatic extrac-
Ph. Eur. 6.2 (Sufentanil). A white or almost white powder. Prac- cles of sufentanil citrate. tion and clearance of sufentanil1 liver dysfunction might be ex-
tically insoluble in water; freely soluble in alcohol and in methyl pected to affect its pharmacokinetics. However, elimination ki-
alcohol. Protect from light. Obesity. The elimination half-life and volume of distribution of netics and plasma protein binding were found to be similar in
sufentanil were increased in obese subjects.1,2 Licensed product cirrhotic and non-cirrhotic patients after a single dose of sufen-
information recommends that for obese patients more than 20% tanil.2
Sufentanil Citrate (BANM, USAN, rINNM) ⊗ above ideal body-weight the dosage of sufentanil should be de-
termined on the basis of the patients’ lean body-weight. 1. Schedewie H, et al. Sufentanil and fentanyl hepatic extraction
Citrato de sufentanilo; R-33800; Sufentaniilisitraatti; Sufentanil cit- rate and clearance in obese patients undergoing gastroplasty.
rát; Sufentanil, citrate de; Sufentanil Sitrat; Sufentanilcitrat; Sufen- 1. Schwartz AE, et al. Pharmacokinetics of sufentanil in the obese. Clin Pharmacol Ther 1988; 43: 132.
tanili citras; Sufentanilio citratas; Szufentanil-citrát. N-{4-(Meth- Anesthesiology 1986; 65 (suppl 3A): A562. 2. Chauvin M, et al. Sufentanil pharmacokinetics in patients with
oxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide cit- 2. Schwartz AE, et al. Pharmacokinetics of sufentanil in obese pa- cirrhosis. Anesth Analg 1989; 68: 1–4.
rate. tients. Anesth Analg 1991; 73: 790–3.
Renal impairment. The pharmacokinetics of sufentanil were
Суфентанила Цитрат reported1 to be unaffected in patients with chronic renal failure,
C 22 H 30N 2 O 2 S,C 6 H 8 O 7 = 578.7.
Interactions although elevated plasma concentrations of sufentanil have been
C AS — 60561-17-3. For interactions associated with opioid analgesics, see noted2 in one such patient.
ATC — N01AH03. p.103. 1. Sear JW. Sufentanil disposition in patients undergoing renal
ATC Vet — QN01AH03. transplantation: influence of choice of kinetic model. Br J
Benzodiazepines. For the effects of using opioids such as suf- Anaesth 1989; 63: 60–7.
Pharmacopoeias. In Eur. (see p.vii) and US. entanil with benzodiazepines, see Analgesics under Interactions 2. Wiggum DC, et al. Postoperative respiratory depression and el-
Ph. Eur. 6.2 (Sufentanil Citrate). A white or almost white pow- of Diazepam, p.989. evated sufentanil levels in a patient with chronic renal failure.
der. Soluble in water and in alcohol; freely soluble in methyl al- Anesthesiology 1985; 63: 708–10.
cohol. Protect from light.
USP 31 (Sufentanil Citrate). A white powder. Soluble in water;
Pharmacokinetics
sparingly soluble in alcohol, in acetone, and in chloroform; free- After parenteral doses sufentanil citrate has a rapid on- Uses and Administration
ly soluble in methyl alcohol. Store at a temperature of 25°, excur- set and short duration of action. The terminal elimina- Sufentanil, a phenylpiperidine derivative, is an opioid
sions permitted between 15° and 30°. tion half-life of sufentanil is about 2.5 hours. It is exten- analgesic (p.104) related to fentanyl (p.58). It is highly
sively bound to plasma proteins (about 90%). It is lipid-soluble and more potent than fentanyl. Sufentanil
S t a b i l i t y. S u f e n t a n i l ( a s t h e c i t r a t e ) d i l u t e d t o
50 micrograms/mL with sodium chloride 0.9% remained stable metabolised in the liver and small intestine by N- is used as an analgesic adjunct in anaesthesia and as a
for at least 14 days when stored at room temperature in PVC res- dealkylation and O-demethylation and the inactive primary anaesthetic in procedures requiring assisted
ervoirs for portable patient-controlled systems.1 metabolites are excreted in the urine and faeces. About ventilation. It has a rapid onset and recovery is consid-
1. Chapalain-Pargarde S, et al. Microbiological and physicochem- 80% of a dose is excreted within 24 hours and 2% is ered to be more rapid than with fentanyl. It is also used
ical stability of fentanyl and sufentanil solutions for patient-con-
trolled delivery systems. J Pain Symptom Manage 2006; 32: eliminated as unchanged drug. Sufentanil crosses the as an analgesic in the management of postoperative
90–7. placenta and is distributed into breast milk. pain and labour pain.
◊ The pharmacokinetics of sufentanil have been reviewed.1,2 Sufentanil is given as the citrate either intravenously
Dependence and Withdrawal
Sufentanil is very lipid-soluble. Like alfentanil it is highly bound by slow injection or as an infusion, or epidurally.
As for Opioid Analgesics, p.101.
to plasma proteins, mainly to α1-acid glycoprotein. The elimina- Doses are expressed as the base; sufentanil citrate
tion half-life lies between that of alfentanil and fentanyl. The 15 micrograms is equivalent to about 10 micrograms
Adverse Effects, Treatment, and Precau- manufacturers of sufentanil have given values for a three-com- of sufentanil. Lower initial doses are advised in the eld-
tions partment pharmacokinetic model with a distribution half-life of
erly and debilitated patients. For obese patients more
As for Opioid Analgesics in general, p.102 and Fenta- 1.4 minutes, a redistribution half-life of 17.1 minutes, and an
elimination half-life of 164 minutes. Accumulation may be rela- than 20% above ideal body-weight the dosage of suf-
nyl, p.56. tively limited when compared with fentanyl. In practice the phar- entanil should be determined on the basis of the pa-
Breast feeding. Concentrations of sufentanil were similar in macokinetics of sufentanil may vary according to the age and tient’s lean body-weight. For details of doses in chil-
colostrum and serum in 7 women given sufentanil by continuous condition of the patient and the procedures undertaken. For ex-
ample, the elimination half-life of sufentanil has been reported to dren, see below. In all patients supplementary
epidural infusion during the first postoperative day after caesar-
ean section. In the light of its poor oral availability such an be longer in patients undergoing cardiac surgery (595 minutes),3 maintenance doses should be based on individual re-
amount was not considered to be a hazard to the breast-fed infant, in hyperventilated patients (232 minutes),4 in those undergoing sponse and length of procedure. Doses of up to the
and a maternal dose of 5 micrograms/hour epidurally was con- abdominal aortic surgery (more than 12 hours),5 and in ventilated equivalent of 8 micrograms/kg of sufentanil produce
sidered to be safe for such infants.1 intensive care patients under sedation (25.5 hours).6 profound analgesia. Higher doses produce a deep level
1. Ausseur A, et al. Continuous epidural infusion of sufentanil after 1. Monk JP, et al. Sufentanil: a review of its pharmacological prop- of anaesthesia but are associated with prolonged respi-
caesarean section: concentration in breast milk. Br J Anaesth erties and therapeutic use. Drugs 1988; 36: 286–313.
1994; 72 (suppl 1): 106. 2. Scholz J, et al. Clinical pharmacokinetics of alfentanil, fentanyl
ratory depression and assisted ventilation may be re-
and sufentanil: an update. Clin Pharmacokinet 1996; 31: quired in the postoperative period.
Effects on the cardiovascular system. For a reference to the 275–92.
effects of sufentanil on histamine release compared with some
3. Howie MB, et al. Serum concentrations of sufentanil and fenta-
When used as an analgesic adjunct to anaesthesia
other opioids, see under Pethidine, p.114. nyl in the post-operative course in cardiac surgery patients. An- with nitrous oxide and oxygen for surgical procedures
Effects on the nervous system. There have been reports of esthesiology 1984; 61: A131. lasting up to 8 hours, the total intravenous dosage
tonic-clonic movements or seizures in a few patients receiving 4. Schwartz AE, et al. Pharmacokinetics of sufentanil in neurosur- should not exceed 1 microgram/kg per hour. It is cus-
sufentanil.1 There was no evidence of cortical seizure activity in gical patients undergoing hyperventilation. Br J Anaesth 1989;
63: 385–8. tomary to give up to 75% of the dose before intubation
a patient whose EEG was recorded,2 suggesting that the ob-
served myoclonus was not a convulsion or seizure. 5. Hudson RJ, et al. Pharmacokinetics of sufentanil in patients un- followed as necessary during surgery by additional in-
dergoing abdominal aortic surgery. Anesthesiology 1989; 70: jections of 10 to 50 micrograms or by a suitable contin-
1. Zaccara G, et al. Clinical features, pathogenesis and management 426–31.
of drug-induced seizures. Drug Safety 1990; 5: 109–51.
6. Ethuin F, et al. Pharmacokinetics of long-term sufentanil infu-
uous or intermittent infusion given so that the total
2. Bowdle TA. Myoclonus following sufentanil without EEG sei- sion for sedation in ICU patients. Intensive Care Med 2003; 29: hourly dose is not exceeded. Thus, for an operation
zure activity. Anesthesiology 1987; 67: 593–5. 1916–20. lasting 1 to 2 hours the total dose would be 1 to
Effects on the respiratory system. Sufentanil, like other Administration. References to the pharmacokinetics of sufen- 2 micrograms/kg with 0.75 to 1.5 micrograms/kg be-
opioid agonists, causes dose-related respiratory depression. tanil given epidurally,1,2 intrathecally,1 or transdermally.3 ing given before intubation.
There have been reports of significant respiratory depression as-
sociated with chest wall rigidity in the early postoperative period 1. Ionescu TI, et al. Pharmacokinetic study of extradural and in- When used as a primary anaesthetic in major surgery
after anaesthesia with intravenous sufentanil.1,2 Respiratory de- trathecal sufentanil anaesthesia for major surgery. Br J Anaesth
1991; 66: 458–64. intravenous doses of 8 to 30 micrograms/kg are given
pression has also been reported after intrathecal sufentanil for
postoperative analgesia3 and labour pain.4. A retrospective chart 2. Hansdottir V, et al. The cerebrospinal fluid and plasma pharma- with 100% oxygen; doses of 25 to 30 micrograms/kg
cokinetics of sufentanil after thoracic or lumbar epidural admin- block sympathetic response including catecholamine
review3 of a 6-year period, during which 4870 patients received istration. Anesth Analg 1995; 80: 724–9.
intrathecal sufentanil for the management of labour pain, found
3. Sebel PS, et al. Transdermal absorption of fentanyl and sufen-
release and are indicated in procedures such as cardio-
that the case above was the only one of respiratory arrest reported tanil in man. Eur J Clin Pharmacol 1987; 32: 529–31. vascular surgery or neurosurgery. Anaesthesia may be
in the group. maintained by additional injections of 0.5 to
1. Goldberg M, et al. Postoperative rigidity following sufentanil Children. Neonates (up to 1 month old) had a significantly low-
administration. Anesthesiology 1985; 63: 199–201. er plasma clearance rate and greater elimination half-life than in- 10 micrograms/kg or by a suitable continuous or inter-
2. Chang J, Fish KJ. Acute respiratory arrest and rigidity after an- fants (1 month to 2 years), children, and adolescents.1 Others2 mittent infusion given so that the total dosage for the
esthesia with sufentanil: a case report. Anesthesiology 1985; 63: have found that infants and small children (1 month to 3 years) procedure does not exceed 30 micrograms/kg.
710–11. with cardiac disease had higher clearance rates and shorter elim-
3. Fournier R, et al. Respiratory depression after 5 μgrams of in- ination half-lives than reported for adults. Older children (aged 2 In postoperative pain, sufentanil is given epidurally in
trathecal sufentanil. Anesth Analg 1998; 87: 1377–8. to 8 years) with no history of cardiac, renal, or hepatic disease an initial dose of 30 to 60 micrograms, which should
4. Ferouz F, et al. Risk of respiratory arrest after intrathecal sufen- have also been noted to have shorter elimination half-lives and
tanil. Anesth Analg 1997; 85: 1088–90. provide analgesia for 4 to 6 hours. Additional boluses
higher clearance rates than adults.3 of up to 25 micrograms may be given at intervals of not
The elderly. The pharmacokinetics of sufentanil in elderly pa- 1. Greeley WJ, et al. Sufentanil pharmacokinetics in pediatric car-
tients have been variable in different studies, but a review1 con- less than 1 hour if necessary.
diovascular patients. Anesth Analg 1987; 66: 1067–72.
sidered that there had been no evidence overall for differences 2. Davis PJ, et al. Pharmacodynamics and pharmacokinetics of Sufentanil is also given epidurally for the relief of pain
between the elderly and younger adults. Nevertheless, as with high-dose sufentanil in infants and children undergoing cardiac
fentanyl, reduced initial doses have been advised in the elderly. surgery. Anesth Analg 1987; 66: 203–8.
during labour and delivery. Recommended doses are
1. Monk JP, et al. Sufentanil: a review of its pharmacological prop- 3. Guay J, et al. Pharmacokinetics of sufentanil in normal children.
10 to 15 micrograms given with 10 mL of bupivacaine
erties and therapeutic use. Drugs 1988; 36: 286–313. Can J Anaesth 1992; 39: 14–20. 0.125% (or its equivalent) with or without adrenaline;
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
126 Analgesics Anti-inflammatory Drugs and Antipyretics
the dose may be repeated twice at not less than one- 3. Nielsen PE, et al. Fetal heart rate changes after intrathecal sufen- Pharmacopoeias. In Chin., Eur. (see p.vii), and US.
tanil or epidural bupivacaine for labor analgesia: incidence and Ph. Eur. 6.2 (Sulindac). A yellow, polymorphic, crystalline pow-
hour intervals until delivery. The total dose of sufen- clinical significance. Anesth Analg 1996; 83: 742–6.
der. Very slightly soluble in water and in ether; sparingly soluble
tanil should not exceed 30 micrograms. 4. Van de Velde M, et al. Intrathecal sufentanil and fetal heart rate
in alcohol; soluble in dichloromethane; dissolves in dilute solu-
abnormalities: a double-blind, double placebo-controlled trial
◊ General reviews of sufentanil. comparing two forms of combined spinal epidural analgesia with tions of alkali hydroxides. Protect from light.
1. Monk JP, et al. Sufentanil: a review of its pharmacological prop- epidural analgesia in labor. Anesth Analg 2004; 98: 1153–9. USP 31 (Sulindac). A yellow, odourless or practically odourless,
erties and therapeutic use. Drugs 1988; 36: 286–313. 5. Fournier R, et al. Intrathecal sufentanil is more potent than intra- crystalline powder. Practically insoluble in water and in hexane;
2. Clotz MA, Nahata MC. Clinical uses of fentanyl, sufentanil, and venous for postoperative analgesia after total-hip replacement. slightly soluble in alcohol, in acetone, in chloroform, and in
alfentanil. Clin Pharm 1991; 10: 581–93. Reg Anesth Pain Med 2005; 30: 249–54.
6. Waara-Wolleat KL, et al. A review of intrathecal fentanyl and
methyl alcohol; very slightly soluble in ethyl acetate and in iso-
Administration. Sufentanil is usually given intravenously, but sufentanil for the treatment of chronic pain. Pain Med 2006; 7: propyl alcohol.
the epidural route is also used (see below). Intranasal (see Anaes- 251–9.
thesia, Pain, and Sedation, below), intrathecal (see below), and Administration in children. Although experience of paediat- Adverse Effects, Treatment, and Precau-
sublingual use (see Pain, below) have also been tried. ric use is limited, sufentanil citrate is licensed for the induction tions
EPIDURAL. In a laboratory assessment of epidural sufentanil in and maintenance of anaesthesia in children under 12 years of age As for NSAIDs in general, p.96. Urine discoloration
healthy subjects,1 a dose of 50 micrograms produced analge- undergoing cardiovascular surgery. Intravenous doses of 10 to has occasionally been reported with sulindac.
sia for 2 to 3 hours; analgesia was intensified and prolonged, 25 micrograms/kg are given with 100% oxygen with mainte-
and respiratory and other adverse effects, especially drowsi- nance doses of up to 25 to 50 micrograms. Sulindac metabolites have been reported as major or
ness, were reduced by the addition of adrenaline. Epidural Anaesthesia. Sufentanil, like fentanyl (p.59), appears to pro- minor components in renal stones. It should therefore
sufentanil or fentanyl provided effective postoperative duce fewer circulatory changes than morphine, which may offer be used with caution in patients with a history of renal
analgesia following caesarean section with comparable ad- some advantages in cardiovascular surgery. stones and such patients should be kept well hydrated
verse effect profiles. 2 Sufentanil doses of 20 and
30 micrograms showed equivalent efficacy and provided Premedication with sufentanil given intranasally has been tried while receiving sulindac.
greater analgesia for a longer duration than a dose of in children1-3 and in adults.4 UK licensed product information recommends that pa-
10 micrograms. Addition of sufentanil to local anaesthetics Sufentanil is one of the opioids that have been used with a neu-
roleptic to produce neuroleptanalgesia.
tients with hepatic impairment should not be given
such as bupivacaine during labour has considerably reduced
the local anaesthetic requirements3 and improved the quality 1. Henderson JM, et al. Pre-induction of sufentanil. Anesthesiology sulindac; in the USA, however, licensed information
of epidural analgesia.4 Combination of sufentanil with a local 1988; 68: 671–5. states that patients with poor hepatic function may be
anaesthetic (ropivacaine or bupivacaine) has been used for 2. Zedie N, et al. Comparison of intranasal midazolam and sufen- given a reduced dose of sulindac with close monitor-
tanil premedication in pediatric outpatients. Clin Pharmacol
patient-controlled epidural analgesia (PCEA),5-9 although an Ther 1996; 59: 341–8. ing. The dose of sulindac may also need to be reduced
early study suggested that PCEA with sufentanil alone had 3. Bayrak F, et al. A comparison of oral midazolam, oral tramadol, in those with renal impairment. Licensed information
little advantage over patient-controlled analgesia with intra- and intranasal sufentanil premedication in pediatric patients. J
venous morphine.10 Opioid Manag 2007; 3: 74–8. recommends that sulindac is not used in patients with
Effective analgesia has been achieved in children with epidural 4. Helmers JHJH, et al. Comparison of intravenous and intranasal advanced renal disease, but this appears to be based on
sufentanil absorption and sedation. Can J Anaesth 1989; 36: a lack of data in such patients.
sufentanil.11 494–7.
1. Klepper ID, et al. Analgesic and respiratory effects of extradural Effects on the blood. Agranulocytosis,1 thrombocytopenia,2
sufentanil in volunteers and the influence of adrenaline as an Pain. For the epidural or intrathecal use of sufentanil in the man-
adjuvant. Br J Anaesth 1987; 59: 1147–56. agement of pain, see above. Intranasal sufentanil has been tried haemolytic anaemia,3 and aplastic anaemia4 have been reported
2. Grass JA, et al. A randomized, double-blind, dose-response for breakthrough cancer pain1 and postoperative analgesia.2 It in patients taking sulindac.
comparison of epidural fentanyl versus sufentanil analgesia af- has also been tried sublingually in the management of break- 1. Romeril KR, et al. Sulindac induced agranulocytosis and bone
ter cesarean section. Anesth Analg 1997; 85: 365–71. marrow culture. Lancet 1981; ii: 523.
3. Buyse I, et al. Effect of sufentanil on minimum local analgesic through cancer pain.3
2. Karachalios GN, Parigorakis JG. Thrombocytopenia and sulin-
concentrations of epidural bupivacaine, ropivacaine and lev- 1. Jackson K, et al. Pilot dose finding study of intranasal sufentanil dac. Ann Intern Med 1986; 104: 128.
obupivacaine in nullipara in early labour. Int J Obstet Anesth for breakthrough and incident cancer-associated pain. J Pain 3. Johnson FP, et al. Immune hemolytic anemia associated with
2007; 16: 22–8. Symptom Manage 2002; 23: 450–2. sulindac. Arch Intern Med 1985; 145: 1515–16.
4. Reynolds F. Extradural opioids in labour. Br J Anaesth 1989; 2. Mathieu N, et al. Intranasal sufentanil is effective for postopera- 4. Andrews R, Russell N. Aplastic anaemia associated with a non-
63: 251–3. tive analgesia in adults. Can J Anesth 2006; 53: 60–6. steroidal anti-inflammatory drug: relapse after exposure to an-
5. Gogarten W, et al. A multicentre trial comparing different con- 3. Gardner-Nix J. Oral transmucosal fentanyl and sufentanil for in- other such drug. BMJ 1990; 301: 38.
centrations of ropivacaine plus sufentanil with bupivacaine plus cident pain. J Pain Symptom Manage 2001; 22: 627–30.
sufentanil for patient-controlled epidural analgesia in labour. Effects on the CNS. Acute deterioration of parkinsonism oc-
Eur J Anaesthesiol 2004; 21: 38–45. Sedation. Some references to the use of sufentanil for sedation curred in a patient after starting sulindac.1
6. Boselli E, et al. Background infusion is not beneficial during are given below. See also Anaesthesia, above.
labor patient-controlled analgesia with 0.1% ropivacaine plus See also Hypersensitivity, below.
1. Bates BA, et al. A comparison of intranasal sufentanil and mida-
0.5 microg/ml sufentanil. Anesthesiology 2004; 100: 968–72. 1. Sandyk R, Gillman MA. Acute exacerbation of Parkinson’s dis-
zolam to intramuscular meperidine, promethazine, and chlorpro-
7. Bremerich DH, et al. Comparison of continuous background in- mazine for conscious sedation in children. Ann Emerg Med 1994; ease with sulindac. Ann Neurol 1985; 17: 104–5.
fusion plus demand dose and demand-only parturient-controlled 24: 646–51.
epidural analgesia (PCEA) using ropivacaine combined with Effects on the endocrine system. A case of reversible gy-
sufentanil for labor and delivery. Int J Obstet Anesth 2005; 14: 2. Lefrant JY, et al. Sufentanil short duration infusion for postoper- naecomastia associated with sulindac therapy has been reported.1
114–20. ative sedation in critically ill patients. Br J Anaesth 1995; 74
(suppl 1): 114. There has also been a report2 of reversible hypothyroidism in an
8. Missant C, et al. Patient-controlled epidural analgesia following
combined spinal-epidural analgesia in labour: the effects of add- 3. Kinirons BP, et al. Sedation with sufentanil and midazolam de- elderly patient taking sulindac.
ing a continuous epidural infusion. Anaesth Intensive Care creases pain in patients undergoing upper limb surgery under 1. Kapoor A. Reversible gynecomastia associated with sulindac
2005; 33: 452–6. multiple nerve block. Anesth Analg 2000; 90: 1118–21. therapy. JAMA 1983; 250: 2284–5.
9. Schenk MR, et al. Postoperative analgesia after major spine sur- Preparations 2. Iyer RP, Duckett GK. Reversible secondary hypothyroidism in-
gery: patient-controlled epidural analgesia versus patient-con- duced by sulindac. BMJ 1985; 290: 1788.
trolled intravenous analgesia. Anesth Analg 2006; 103: USP 31: Sufentanil Citrate Injection.
1311–17. Effects on the gallbladder. A "sludge" composed of crystal-
Proprietary Preparations (details are given in Part 3)
10. Grass JA, et al. Patient-controlled analgesia after cesarean de- Arg.: Sufenta; Austria: Sufenta; Belg.: Sufenta; Braz.: Fastfen; Sufenta; Ca-
line metabolites of sulindac has been found in the common bile
livery: epidural sufentanil versus intravenous morphine. Reg nad.: Sufenta; Chile: Sufenta; Cz.: Sufenta; Denm.: Sufenta; Fin.: Sufenta; duct during surgery for biliary obstruction in patients who had
Anesth 1994; 19: 90–7. Fr.: Sufenta; Ger.: Sufenta; Indon.: Sufenta; Ital.: Disufen; Fentatienil; Ma- been taking sulindac.1
11. Benlabed M, et al. Analgesia and ventilatory response to CO laysia: Sufenta†; Neth.: Sufenta; Norw.: Sufenta; Port.: Sufenta; S.Afr.:
following epidural sufentanil in children. Anesthesiology 1987; 1. Anonymous. Rare complication with sulindac. FDA Drug Bull
Sufenta; Swed.: Sufenta; Switz.: Sufenta; Turk.: Sufenta; USA: Sufenta†. 1989; 19: 4.
67: 948–51.
INTRATHECAL. Sufentanil, alone or in combination, has been Effects on the kidneys. Sulindac-induced renal impairment,
given intrathecally for labour pain: a combination of sufen- interstitial nephritis, and nephrotic syndrome have been report-
tanil, bupivacaine, and adrenaline given intrathecally provid- Sulindac (BAN, USAN, rINN) ed.1 It has been suggested that sulindac, as a prodrug, may not
ed excellent analgesia during labour and had a more rapid on- inhibit renal prostaglandin synthesis in therapeutic doses. How-
set, a longer duration of action, and reduced local anaesthetic MK-231; Sulindaakki; Sulindaco; Sulindacum; Sulindak; Szulindak. ever, this potentially important therapeutic advantage has not
requirements compared with epidural administration.1 In- (Z)-[5-Fluoro-2-methyl-1-(4-methylsulphinylbenzylidene)inden- been uniformly seen in short-term studies in patients with renal
trathecal sufentanil and bupivacaine provided shorter dura- 3-yl]acetic acid. dysfunction.2-4
tion of analgesia when given during the advanced stages of Сулиндак There have been reports of renal stones consisting of between 10
labour compared with early labour.2 There has been some C 20 H 17FO 3 S = 356.4. and 90% of sulindac metabolites developing in patients given
concern about the effect of intrathecal use on fetal heart rate. sulindac.5
An early study3 found no significant difference in the heart C AS — 38194-50-2.
1. Whelton A, et al. Sulindac and renal impairment. JAMA 1983;
rate when intrathecal sufentanil was compared with epidural ATC — M01AB02. 249: 2892.
bupivacaine; however, a more recent study4 reported that ATC Vet — QM01AB02. 2. Klassen DK, et al. Sulindac kinetics and effects on renal function
high-dose intrathecal sufentanil (7.5 micrograms) when given and prostaglandin excretion in renal insufficiency. J Clin Phar-
macol 1989; 29: 1037–42.
on its own increased the risk of fetal heart rate abnormalities 3. Eriksson L-O, et al. Effects of sulindac and naproxen on prostag-
when compared with low-dose intrathecal sufentanil O landin excretion in patients with impaired renal function and
(2.5 micrograms) given with bupivacaine and adrenaline. rheumatoid arthritis. Am J Med 1990; 89: 313–21.
Nonetheless, there was no evidence of a difference in adverse S 4. Whelton A, et al. Renal effects of ibuprofen, piroxicam, and
neonatal outcomes between the groups. sulindac in patients with asymptomatic renal failure. Ann Intern
H3C Med 1990; 112: 568–76.
A small study in patients undergoing hip replacement found that 5. Anonymous. Rare complication with sulindac. FDA Drug Bull
intrathecal sufentanil 7.5 micrograms produced better and longer 1989; 19: 4.
lasting analgesia than the same dose given intravenously.5
Effects on the liver. Hepatotoxicity reported in patients receiv-
Intrathecal sufentanil has also been tried in the treatment of
ing sulindac includes hepatocellular injury and cholestatic jaun-
chronic pain.6 CH3 dice.1,2 Symptoms of hypersensitivity including rash, fever, or
1. Kartawiadi SL, et al. Spinal analgesia during labor with low-
eosinophilia have been reported in 35 to 55% of patients with
dose bupivacaine, sufentanil, and epinephrine: a comparison F
with epidural analgesia. Reg Anesth 1996; 21: 191–6. sulindac-induced liver damage;2 in these patients the liver dam-
2. Viscomi CM, et al. Duration of intrathecal labor analgesia: early COOH age occurred usually within 4 to 8 weeks of beginning sulindac
versus advanced labor. Anesth Analg 1997; 84: 1108–12. therapy. For reference to a report citing the strongest evidence for
 Sulindac/Superoxide Dismutase 127
an association of sulindac with liver disease compared with other Uses and Administration cant fetal or maternal adverse effects but also found the drug to
NSAIDs, see under NSAIDs, p.98. Sulindac is an NSAID (p.99) structurally related to in- be ineffective in extending gestation or improving outcome.
See also Effects on the Skin, below. 1. Carlan SJ, et al. Randomized comparative trial of indomethacin
dometacin (p.68); its activity appears to be due to its and sulindac for the treatment of refractory preterm labor. Obstet
1. Gallanosa AG, Spyker DA. Sulindac hepatotoxicity: a case re- sulfide metabolite. Sulindac is used in musculoskeletal Gynecol 1992; 79: 223–8.
port and review. Clin Toxicol 1985; 23: 205–38. 2. Carlan SJ, et al. Outpatient oral sulindac to prevent recurrence of
2. Tarazi EM, et al. Sulindac-associated hepatic injury: analysis of and joint disorders such as ankylosing spondylitis, os- preterm labor. Obstet Gynecol 1995; 85: 769–74.
91 cases reported to the Food and Drug Administration. Gastro- teoarthritis, and rheumatoid arthritis, and also in the 3. Kramer WB, et al. A randomized double-blind study comparing
enterology 1993; 104: 569–74.
short-term management of acute gout and peri-articu- the fetal effects of sulindac to terbutaline during the management
of preterm labor. Am J Obstet Gynecol 1999; 180: 396–401.
Effects on the lungs. For reference to pneumonitis associated lar conditions such as bursitis and tendinitis. It has also 4. Humphrey RG, et al. Sulindac to prevent recurrent preterm labor:
with sulindac therapy, see Hypersensitivity, below. been used to reduce fever. a randomized controlled trial. Obstet Gynecol 2001; 98: 555–62.
Effects on the skin. Toxic epidermal necrolysis has occurred A usual initial oral dose of sulindac is 150 or 200 mg Preparations
in patients taking sulindac.1 In a patient toxic hepatitis and the twice daily, reduced according to response; the maxi- BP 2008: Sulindac Tablets;
Stevens-Johnson/toxic epidermal necrolysis syndrome resulted USP 31: Sulindac Tablets.
in death.2 mum recommended daily dose is 400 mg. Licensed
product information recommends that the treatment of Proprietary Preparations (details are given in Part 3)
An unusual pernio-like reaction affecting the toes, which was Austral.: Aclin; Clinoril†; Austria: Clinoril; Belg.: Clinoril; Canad.: Apo-
also confirmed by rechallenge, has been reported.3 peri-articular disorders should be limited to 7 to 14 Sulin; Novo-Sundac; Cz.: Clinoril†; Denm.: Clinoril†; Fr.: Arthrocine;
days; for acute gout, 7 days of therapy is usually ade- Hong Kong: Aclin; Clinoril; Irl.: Clinoril; Ital.: Algocetil; Clinoril; Sulen†;
Sulindac has also been reported to cause photosensitivity reac- Malaysia: Aclin†; Apo-Sulin†; Clinoril†; Mex.: Atriser; Bio-Dac; Clinoril;
tions.4 quate. Clison; Copal; Kenalin; Renidac; Sulifur; Vindacin; Norw.: Clinoril; NZ:
Clinoril; Daclin; Port.: Artribid; Singapore: Apo-Sulin; Spain: Sulindal;
1. Small RE, Garnett WR. Sulindac-induced toxic epidermal Sulindac sodium has been given by rectal suppository. Swed.: Clinoril; Switz.: Clinoril†; Thai.: Cenlidac; Clinoril; UK: Clinoril;
necrolysis. Clin Pharm 1988; 7: 766–71.
Administration in hepatic or renal impairment. The dose USA: Clinoril; Venez.: Clinoril†.
2. Klein SM, Khan MA. Hepatitis, toxic epidermal necrolysis and
pancreatitis in association with sulindac therapy. J Rheumatol of sulindac may need to be reduced in patients with hepatic or
1983; 10: 512–13. renal impairment but see Adverse Effects and Precautions,
3. Reinertsen JL. Unusual pernio-like reaction to sulindac. Arthritis above.. Superoxide Dismutase
Rheum 1981; 24: 1215.
4. Anonymous. Drugs that cause photosensitivity. Med Lett Drugs Gastrointestinal disorders. In placebo-controlled studies1,2 SOD; Superóxido dismutasa.
Ther 1986; 28: 51–2. sulindac 150 to 200 mg twice daily for 6 to 9 months has reduced
the number and size of polyps in patients with familial adenom- Description. Superoxide dismutase represents a group of wa-
Hypersensitivity. Hypersensitivity reactions to sulindac in- ter-soluble protein congeners widely distributed in nature which
atous polyposis but the effect may be incomplete and in a study2 catalyse the conversion of superoxide radicals to peroxide. Sev-
clude pneumonitis,1,2 generalised lymphadenopathy,3 aseptic only polyps less than 2 mm in size regressed. In addition, the size
meningitis,4 and anaphylactoid reaction.5 eral different forms exist, which vary in their metal content;
and number of polyps has been reported1 to increase on stopping forms containing copper or copper and zinc are common.
See also Effects on the Liver and Effects on the Skin, above. treatment. The benefit of long-term therapy has therefore been
1. Smith FE, Lindberg PJ. Life-threatening hypersensitivity to studied. Reduced effectiveness has been seen3 with long-term
sulindac. JAMA 1980; 244: 269–70. use but others4 have reported management of recurrences by ad-
Orgotein (BAN, USAN, rINN)
2. Fein M. Sulindac and pneumonitis. Ann Intern Med 1981; 95: justment of maintenance dosage; there seemed to be individual Bovine Superoxide Dismutase; Orgoteiini; Orgoteína; Orgot-
245. variations in sensitivity to sulindac with respect to prevention of éine; Orgoteinum; Ormetein.
3. Sprung DJ. Sulindac causing a hypersensitivity reaction with pe- polyp recurrence although an average maintenance dose of Орготеин
ripheral and mediastinal lymphadenopathy. Ann Intern Med 200 mg daily appeared to be needed.4
1982; 97: 564. C AS — 9016-01-7.
4. Fordham von Reyn C. Recurrent aseptic meningitis due to sulin- There is evidence5 that sulindac alters the ratio of apoptosis of ATC — M01AX14.
dac. Ann Intern Med 1983; 99: 343–4. surface cells relative to those lying deeper in the crypt of rectal ATC Vet — QM01AX14.
5. Hyson CP, Kazakoff MA. A severe multisystem reaction to mucosa, thus altering epithelial homoeostasis. Whether sulindac
Description. Orgotein is a superoxide dismutase produced
sulindac. Arch Intern Med 1991; 151: 387–8. prevents malignant degeneration is unknown but there have been from beef liver as Cu-Zn mixed chelate. Mol. wt about 33 000
reports6-8 of patients who developed rectal cancer during or after with a compact conformation maintained by about 4 gram-atoms
Pancreatitis. Reports1-4 of pancreatitis associated with sulindac long-term therapy for adenomatous polyposis. A more recent,
therapy. of chelated divalent metal.
placebo-controlled trial9 has also reported that sulindac did not
1. Goldstein J, et al. Sulindac associated with pancreatitis. Ann In- reduce the development of adenomas in patients with familial
tern Med 1980; 93: 151. adenomatous polyposis. Some1,9 consider that sulindac is unlike-
Pegorgotein (USAN, rINN)
2. Siefkin AD. Sulindac and pancreatitis. Ann Intern Med 1980; 93: ly to replace surgery as primary therapy for familial adenoma- Pegorgoteína; Pégorgotéine; Pegorgoteinum; PEG-SOD; Win-
932–3.
tous polyposis. 22118.
3. Lilly EL. Pancreatitis after administration of sulindac. JAMA
1981; 246: 2680. A sulfone metabolite of sulindac, exisulind (p.720) has also been Пэгорготеин
4. Memon AN. Pancreatitis and sulindac. Ann Intern Med 1982; 97: investigated for the treatment of familial adenomatous polyposis. C AS — 155773-57-2.
139. Sulindac has also been reported to have produced beneficial ef- Description. Pegorgotein is a superoxide dismutase conjugated
fects in a patient with duodenal polyps associated with Gardner’s with polyethylene glycol to prolong its duration of action.
Interactions syndrome10 but a placebo-controlled study has suggested that it
For interactions associated with NSAIDs, see p.99. may not be effective against sporadic type colonic polyps.11
Sudismase (rINN)
For a discussion of evidence suggesting that regular use of
Dimethyl sulfoxide reduces plasma concentrations of NSAIDs may protect against various types of malignant neo- Sudismasa; Sudismasum.
the active metabolite of sulindac and use of the two plasms of the gastrointestinal tract, see Malignant Neoplasms in Судизмаза
drugs together has also resulted in peripheral neuropa- NSAIDs, p.100. C AS — 110294-55-8.
thy. Diflunisal and aspirin are reported to reduce the 1. Giardiello FM, et al. Treatment of colonic and rectal adenomas Description. Sudismase is a human N-acetylsuperoxide dis-
with sulindac in familial adenomatous polyposis. N Engl J Med
plasma concentration of the active metabolite of sulin- 1993; 328: 1313–16. mutase produced by recombinant DNA technology and contain-
dac. Unlike other NSAIDs, sulindac is reported not to 2. Debinski HS, et al. Effect of sulindac on small polyps in familial ing a copper and zinc prosthetic group.
adenomatous polyposis. Lancet 1995; 345: 855–6.
reduce the antihypertensive effects of drugs such as thi- 3. Tonelli F, Valanzano R. Sulindac in familial adenomatous poly-
Adverse Effects
posis. Lancet 1993; 342: 1120. Anaphylaxis and other hypersensitivity reactions, sometimes
azide diuretics, but nevertheless licensed product infor- 4. Labayle D, et al. Sulindac in familial adenomatous polyposis. fatal, have been reported with orgotein. Local reactions and pain
mation recommends that blood pressure be closely Lancet 1994; 343: 417–18. may occur at the site of injection of orgotein.
monitored in patients taking antihypertensives with 5. Keller JJ, et al. Rectal epithelial apoptosis in familial adenoma-
tous polyposis patients treated with sulindac. Gut 1999; 45: Pharmacokinetics
sulindac. 822–8.
6. Thorson AG, et al. Rectal cancer in FAP patient after sulindac. ◊ References.
Lancet 1994; 343: 180. 1. Tsao C, et al. Pharmacokinetics of recombinant human superox-
Pharmacokinetics 7. Matsuhashi N, et al. Rectal cancer after sulindac therapy for a ide dismutase in healthy volunteers. Clin Pharmacol Ther 1991;
Sulindac is absorbed from the gastrointestinal tract. It sporadic adenomatous colonic polyp. Am J Gastroenterol 1998; 50: 713–20.
93: 2261–6. 2. Uematsu T, et al. Pharmacokinetics and safety of intravenous re-
is metabolised by reversible reduction to the sulfide 8. Cruz-Correa M, et al. Long-term treatment with sulindac in fa- combinant human superoxide dismutase (NK341) in healthy
metabolite, which appears to be the active form, and by milial adenomatous polyposis: a prospective cohort study. Gas- subjects. Int J Clin Pharmacol Ther 1994; 32: 638–41.
troenterology 2002; 122: 641–5. 3. Jadot G, et al. Clinical pharmacokinetics and delivery of bovine
irreversible oxidation to the sulfone metabolite. Peak 9. Giardiello FM, et al. Primary chemoprevention of familial ade- superoxide dismutase. Clin Pharmacokinet 1995; 28: 17–25.
plasma concentrations of the sulfide metabolite are nomatous polyposis with sulindac. N Engl J Med 2002; 346: 4. Rosenfeld WN, et al. Safety and pharmacokinetics of recom-
1054–9. binant human superoxide dismutase administered intrathecally
achieved in about 2 hours. The mean elimination half- 10. Parker AL, et al. Disappearance of duodenal polyps in Gardn- to premature neonates with respiratory distress syndrome. Pedi-
life of sulindac is about 7.8 hours and of the sulfide er’s syndrome with sulindac therapy. Am J Gastroenterol 1993; atrics 1996; 97: 811–17.
88: 93–4.
metabolite about 16.4 hours. Sulindac and its metabo- 11. Ladenheim J, et al. Effect of sulindac on sporadic colonic pol- 5. Davis JM, et al. Safety and pharmacokinetics of multiple doses
of recombinant human CuZn superoxide dismutase administered
lites are over 90% bound to plasma proteins. About yps. Gastroenterology 1995; 108: 1083–7.
intrathecally to premature neonates with respiratory distress syn-
50% is excreted in the urine mainly as the sulfone Premature labour. The most common approach to postpon- drome. Pediatrics 1997; 100: 24–30.
metabolite and its glucuronide conjugate, with smaller ing premature labour (p.2003) with drugs has historically been 6. Schwedhelm E, et al. Clinical pharmacokinetics of antioxidants
with a selective beta2 agonist. However, as prostaglandins have a and their impact on systemic oxidative stress. Clin Pharmacoki-
amounts of sulindac and its glucuronide conjugate; role in uterine contraction and cervical ripening and dilatation, net 2003; 42: 437–59.
about 25% appears in the faeces, primarily as sulfone prostaglandin synthetase inhibitors such as indometacin have Uses and Administration
and sulfide metabolites. Sulindac and its metabolites also been used. Sulindac has also been tried1,2 as an alternative to Superoxide dismutases have anti-inflammatory properties.
are also excreted in bile and undergo extensive entero- indometacin as it appears to have little placental transfer and may Orgotein, a bovine derived superoxide dismutase, has been given
hepatic circulation. therefore have fewer fetal adverse effects.1 However, the authors by local injection, into the joints for degenerative joint disorders,
of a subsequent study suggested that sulindac had many of the but hypersensitivity reactions have limited its use. It has also
◊ References. same adverse fetal effects as indometacin and its use could only been tried for the amelioration of adverse effects from radiother-
1. Davies NM, Watson MS. Clinical pharmacokinetics of sulindac: be described as investigational.3 A study4 using relatively low apy. Forms of human superoxide dismutase derived by recom-
a dynamic old drug. Clin Pharmacokinet 1997; 32: 437–59. doses of sulindac (100 mg twice daily) did not note any signifi- binant DNA technology have been developed.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
128 Analgesics Anti-inflammatory Drugs and Antipyretics
Superoxide dismutases are also under investigation for their free- Suxibuzone (BAN, rINN) difference in the incidence of dyspepsia between the 2 groups
radical scavenging properties in a variety of conditions including was not significant.
the prevention of bronchopulmonary dysplasia in neonates. Suksibutsoni; Suksibuzonas; Suxibuzon; Suxibuzona; Suxibuzon-
1. Todd PA, Clissold SP. Tenoxicam: an update of its pharmacology
um; Szuxibuzon. 4-Butyl-4-hydroxymethyl-1,2-diphenylpyrazolid- and therapeutic efficacy in rheumatic diseases. Drugs 1991; 41:
Bronchopulmonary dysplasia. Use of sudismase in prema- ine-3,5-dione hydrogen succinate (ester). 625–46.
ture infants treated for respiratory distress syndrome did not pre- 2. Merry AF, et al. Clinical tolerability of perioperative tenoxicam
vent development of bronchopulmonary dysplasia (p.1500) in Суксибузон
in 1001 patients – a prospective, controlled, double-blind, multi-
the first month.1 However, treated infants subsequently showed C 24 H 26N 2 O 6 = 438.5. centre study. Pain 2004; 111: 313–22.
a lower incidence of severe respiratory disease and hospitalisa- C AS — 27470-51-5.
tions in the first year, suggesting a reduction in chronic lung in- Effects on the kidneys. A review1 of the effects of tenoxicam
ATC — M02AA22. on renal function concluded that tenoxicam could be given at
jury. The antoxidant was given intratracheally in a dose of ATC Vet — QM01AA90; QM02AA22.
5 mg/kg every 48 hours as long as intubation and ventilation normal recommended doses to elderly patients or those with
were necessary. A systematic review2 was unable to reach a firm mild to moderate renal impairment who were not at high risk of
conclusion about the efficacy of superoxide dismutases in pre- renal failure or receiving potentially nephrotoxic therapy. Data
venting chronic lung disease. from the manufacturer’s database1 on 67 063 patients, including
17 005 over 65 years of age, who had received tenoxicam indi-
1. Davis JM, et al. Pulmonary outcome at 1 year corrected age in cated that there had been 45 adverse events relating to urinary
premature infants treated at birth with recombinant human CuZn
superoxide dismutase. Pediatrics 2003; 111: 469–76. system function, described as severe in 7. The prevalence of ad-
2. Suresh GK, et al. Superoxide dismutase for preventing chronic O HO verse events was similar in elderly and non-elderly patients, the
N O most common effects being dysuria and renal pain.
lung disease in mechanically ventilated preterm infants. Availa-
ble in The Cochrane Database of Systematic Reviews; Issue 1. N O O
1. Heintz RCA. Tenoxicam and renal function. Drug Safety 1995;
Chichester: John Wiley; 2001 (accessed 09/05/05). 12: 110–19.
Head injury. Pegorgotein was found1 to be little more effective Effects on the liver. A report1 of acute hepatitis associated with
than placebo in improving neurological outcome or reducing O CH3 the use of tenoxicam.
mortality in patients with severe head injury.
1. Sungur C, et al. Acute hepatitis caused by tenoxicam. Ann Phar-
1. Young B, et al. Effects of pegorgotein on neurologic outcome of Pharmacopoeias. In Eur. (see p.vii). macother 1994; 28: 1309.
patients with severe head injury: a multicenter, randomized con- Ph. Eur. 6.2 (Suxibuzone). A white or almost white, crystalline
trolled trial. JAMA 1996; 276: 538–43. powder. Practically insoluble in water; soluble in alcohol; freely Effects on the skin. A report of 3 cases of toxic epidermal
soluble in acetone; practically insoluble in cyclohexane. necrolysis (Lyell’s syndrome) associated with tenoxicam.1
Motor neurone disease. A small percentage of patients with
familial amyotrophic lateral sclerosis (see Motor Neurone Dis- For the general incidence of dermatological effects see above.
ease, p.2380) have been shown to have a mutation in the gene
Profile
1. Chosidow O, et al. Toxidermies sévères au ténoxicam (Til-
Suxibuzone, a derivative of phenylbutazone (p.117), is an cotil ). Ann Dermatol Venereol 1991; 118: 903–4.
encoding for the enzyme copper-zinc superoxide dismutase but
NSAID (p.96) that has been applied topically at a concentration
there has been no consensus as to whether patients with this mu- Interactions
of about 7% in musculoskeletal and joint disorders. Concern
tation should be given superoxide dismutase supplements.1 For interactions associated with NSAIDs, see p.99.
over safety and toxicity after oral use has led to its withdrawal
1. Orrell RW, deBelleroche JS. Superoxide dismutase and ALS. from the market in many countries.
Lancet 1994; 344: 1651–2. Pharmacokinetics
Preparations Tenoxicam is well absorbed after oral doses; peak plasma con-
Radiotherapy. Although some studies1,2 indicate that orgotein centrations occur within about 2 hours in fasting subjects; this
can ameliorate the adverse effects of radiotherapy for bladder tu- Proprietary Preparations (details are given in Part 3)
may be delayed to about 6 hours when tenoxicam is given with
mours, another study3 was terminated prematurely because of Spain: Danilon.
food but the extent of absorption is not affected. It is also rapidly
unacceptable hypersensitivity reactions and apparent inefficacy. absorbed when given by intramuscular injection. Tenoxicam is
1. Sanchiz F, et al. Prevention of radioinduced cystitis by orgotein: about 99% protein bound and penetrates synovial fluid. The plas-
a randomized study. Anticancer Res 1996; 16: 2025–8. ma elimination half-life ranges from 42 to 81 hours; with daily
2. Valencia J, et al. The efficacy of orgotein in the treatment of
Tenoxicam (BAN, USAN, rINN)
dosage, steady-state concentrations are reached within 10 to 15
acute toxicity due to radiotherapy on head and neck tumors. Tu- Ro-12-0068; Ro-12-0068/000; Tenoksikaami; Tenoksikam; Ten- days. Tenoxicam is completely metabolised to inactive metabo-
mori 2002; 88: 385–9.
oksikamas; Ténoxicam; Tenoxicamum; Tenoxikám; Tenoxikam. 4- lites which are excreted mainly in the urine; there is some biliary
3. Nielsen OS, et al. Orgotein in radiation treatment of bladder can-
cer: a report on allergic reactions and lack of radioprotective ef-
Hydroxy-2-methyl-N-(2-pyridyl)-2H-thieno[2,3-e][1,2]thiazine- excretion of glucuronide conjugates of the metabolites.
3-carboxamide 1,1-dioxide.
fect. Acta Oncol 1987; 26: 101–4. ◊ References.
Preparations Теноксикам 1. Nilsen OG. Clinical pharmacokinetics of tenoxicam. Clin Phar-
Proprietary Preparations (details are given in Part 3) C 13 H 11N 3 O 4 S 2 = 337.4. macokinet 1994; 26: 16–43.
C AS — 59804-37-4. 2. Guentert TW, et al. Relative bioavailability of oral dosage forms
Spain: Ontosein†. of tenoxicam. Arzneimittelforschung 1994; 44: 1051–4.
Multi-ingredient: Arg.: Vitix; Indon.: Glisodin.
ATC — M01AC02.
3. Nilsen OG, et al. Single- and multiple-dose pharmacokinetics,
ATC Vet — QM01AC02. kidney tolerability and plasma protein binding of tenoxicam in
renally impaired patients and healthy volunteers. Pharmacol
Toxicol 2001; 89: 265–72.
Suprofen (BAN, USAN, rINN) O O Uses and Administration
R-25061; Suprofeeni; Suprofène; Suprofeno; Suprofenum; Suto- CH3 Tenoxicam, a piroxicam (p.117) analogue, is an NSAID (p.99).
S It is used in the symptomatic management of musculoskeletal
profen. 2-[4-(2-Thenoyl)phenyl]propionic acid. N
H and joint disorders such as osteoarthritis and rheumatoid arthritis,
Супрофен and also in the short-term management of soft-tissue injury. Ten-
N
C 14 H 12 O 3 S = 260.3. S oxicam is given as a single oral daily dose usually of 20 mg. In
C AS — 40828-46-4. acute musculoskeletal disorders treatment for up to 7 days is usu-
OH O N ally sufficient but in severe cases it may be given for up to a max-
ATC — M01AE07.
imum of 14 days. Doses similar to those given orally have been
ATC Vet — QM01AE07.
Pharmacopoeias. In Eur. (see p.vii). given by intramuscular or intravenous injection for initial treat-
Ph. Eur. 6.2 (Tenoxicam). A yellow, polymorphic, crystalline ment for 1 or 2 days. Tenoxicam has also been given by rectal
powder. Practically insoluble in water; very slightly soluble in suppository.
O
dehydrated alcohol; sparingly soluble in dichloromethane; it dis- ◊ References.
S solves in solutions of acids and alkalis. Protect from light.
1. Todd PA, Clissold SP. Tenoxicam: an update of its pharmacology
Stability. An admixture of tenoxicam 0.02% and ceftazidime and therapeutic efficacy in rheumatic diseases. Drugs 1991; 41:
COOH 625–46.
0.5% (as the sodium salt) in glucose injection 5% appeared stable
when stored for up to 120 hours at 25° in glass bottles;1 when Preparations
CH3 stored in PVC bags, the admixture was stable for up to 72 hours BP 2008: Tenoxicam Injection; Tenoxicam Tablets.
at 25° and for up to 144 hours at 4°.
Proprietary Preparations (details are given in Part 3)
Pharmacopoeias. In US. 1. Wang D-P, et al. Compatibility and stability of ceftazidime sodi-
um and tenoxicam in 5% dextrose injection. Am J Health-Syst Arg.: Mefenix†; Austria: Tilcotil; Belg.: Tilcotil; Braz.: Inflagel; Prodoxican;
USP 31 (Suprofen). A white to off-white powder, odourless or Pharm 2004; 61: 1924–7. Teflan; Tenobio†; Tenocam†; Tenotec; Tenoxen†; Tilatil; Tilonax; Tiloxican†;
having a slight odour. Sparingly soluble in water. Titenil†; Chile: Avancel†; Bioflam; Mitrotil; Recaflex; Texicam†; Tilcotil;
Adverse Effects, Treatment, and Precautions Denm.: Tilcotil; Fin.: Tilcotil; Fr.: Tilcotil; Gr.: Admiral; Algin-Vek; Amcinafal;
Profile As for NSAIDs in general, p.96. Ampirovix; Artroxicam; Artruic†; Aspagin; Biodruff; Docticam†; Dranat;
Suprofen is an NSAID (p.96). Suprofen has been used as 1% eye Hobaticam; Indo-bros; Istotosal; Liaderyl; Neo-adlibamin; Neo-antiperstam;
Incidence of adverse effects. Adverse effects associated with Neo-endusix; Octiveran; Oxytel; Ponsolit; Redac; Soral; Tenox†; Tentepanil;
drops to inhibit the miosis that may occur during ocular surgery. Tilcitin; Toscacalm; Velasor; Voir; Zibelant; Hong Kong: Nadamen†; Seftil†;
It was formerly given orally in mild to moderate pain and in os- tenoxicam have been reviewed.1 The majority of adverse effects Tilcotil; Hung.: Tilcotil; India: Tobitil; Indon.: Artricom; Meditil; Notritis;
teoarthritis and rheumatoid arthritis but, after reports of adverse relate to the gastrointestinal tract (11.4%), nervous system Oxaflam; Pilopil; Thenil; Tilcotil; Tilflam; Xotilon; Irl.: Mobiflex†; Ital.: Dol-
(2.8%), or skin (2.5%). men; Rexalgan; Tilcotil; Jpn: Tilcotil; Malaysia: Nadamen†; Seftil; Sinoral†;
renal reactions, marketing of the oral dose form was suspended Tilcotil; Mex.: Tilcotil; Neth.: Tilcotil; NZ: Tilcotil; Philipp.: Tilcotil; Port.:
worldwide. Gastrointestinal disturbances including nausea and vomiting Bioreucam†; Calibral†; Doxican; Tenalgin; Tilcotil; S.Afr.: Tilcotil; Tobitil†;
(14.7%) and dyspepsia (2.3%), surgical site bleeding (4.3%), Singapore: Nadamen†; Spain: Artriunic; Reutenox; Tilcotil†; Swed.: Al-
Preparations wound infection (2.7%), dizziness (5.7%), and headache ganex; Switz.: Tilcotil; Thai.: Memzotil; Nadamen†; Seftil; Sinoral; Teco-
nam; Tenax; Tenocam; Tenox; Tenoxil; Tenxil; Tilcotil; Tonox; Turk.: No-
USP 31: Suprofen Ophthalmic Solution. (10.7%) were the most common adverse effects reported in a pla- bateks; Oksamen; Tenoksan; Tenoktil; Tenox; Tilcotil; Tilko; VienOks; Zikaral;
Proprietary Preparations (details are given in Part 3) cebo-controlled study involving 1001 patients following the UK: Mobiflex; Venez.: Rodix; Tecam†; Tenoxin; Tilcotil†.
perioperative use of oral and intravenous tenoxicam.2 It was
USA: Profenal†. Multi-ingredient: Arg.: Mefenix Relax†.
noted, however, that the incidence of dizziness, nausea and vom-
iting, and headache was greater in the placebo group and that the
 Suprofen/Tilidine Hydrochloride 129
Tepoxalin (USAN, rINN) osteoarthritis, and rheumatoid arthritis, in peri-articular disorders
such as fibrositis and capsulitis, and in soft-tissue disorders such
ORF-20485; RWJ-20485; Tepoksaliini; Tepoxalina; Tépoxaline; O CH3 as sprains and strains. The usual oral dose is 600 mg daily given
Tepoxalinum. 5-(p-Chlorophenyl)-1-(p-methoxyphenyl)-N- in 2 or 3 divided doses; in patients with cardiac, hepatic, or renal
methylpyrazole-3-propionohydroxamic acid. S
COOH impairment, licensed product information suggests that the dose
Тепоксалин is reduced to 200 mg twice daily. A modified-release preparation
C 20 H 20ClN 3 O 3 = 385.8. may be available for once-daily use. Tiaprofenic acid has also
C AS — 103475-41-8. been given rectally. It has been given intramuscularly as the
ATC Vet — QM01AE92. trometamol salt in acute conditions.
Pharmacopoeias. In Eur. (see p.vii).
Ph. Eur. 6.2 (Tiaprofenic Acid). A white or almost white, crys- ◊ References.
talline powder. Practically insoluble in water; freely soluble in al- 1. Plosker GL, Wagstaff AJ. Tiaprofenic acid: a reappraisal of its
H3CO cohol, in acetone, and in dichloromethane. Protect from light. pharmacological properties and use in the management of rheu-
matic diseases. Drugs 1995; 50: 1050–75.
Adverse Effects, Treatment, and Precautions
As for NSAIDs in general, p.96. Administration in hepatic or renal impairment. Tiapro-
fenic acid is contra-indicated in patients with severe hepatic or
Tiaprofenic acid may cause cystitis, bladder irritation, and other renal impairment; for dosage details in those with more moderate
urinary-tract symptoms (see below). It should not be given to pa- impairment, see Uses and Administration, above.
N N CH3 tients with active urinary-tract disorders or prostatic disease or a
history of recurrent urinary-tract disorders. It should be stopped Preparations
N immediately if urinary-tract symptoms occur and urinalysis and Proprietary Preparations (details are given in Part 3)
OH urine culture performed. Austral.: Surgam; Canad.: Albert Tiafen†; Surgam; Cz.: Surgam; Thialgin;
Denm.: Surgamyl; Fin.: Surgamyl; Fr.: Flanid; Surgam; Ger.: Surgam;
Tiaprofenic acid is contra-indicated in patients with severe hepat-
O Hung.: Surgam; Irl.: Surgam; Ital.: Suralgan†; Surgamyl; Tiaprofen†; Mex.:
Cl ic or renal impairment. Surgam; Neth.: Surgam; NZ: Surgam; Pol.: Surgam; Port.: Surgam; S.Afr.:
Surgam; Thai.: Fengam; Surgam†; Turk.: Surgam; UK: Surgam; Venez.:
Breast feeding. Although tiaprofenic acid is distributed into Torpas.
Profile breast milk, the amount is considered by the BNF to be too small
Tepoxalin, a propionic acid derivative, is an NSAID used in vet- to be harmful to a breast-fed infant. Licensed product informa-
erinary medicine for the treatment of inflammation and pain in tion also states that exposure to tiaprofenic acid via breast milk is
dogs. unlikely to be of pharmacological significance; however, it is Tiaramide Hydrochloride (BANM, USAN, rINNM)
recommended that either treatment or breast feeding is stopped Hidrocloruro de tiaramida; NTA-194; Tiaperamide Hydrochlo-
as necessary. ride; Tiaramide, Chlorhydrate de; Tiaramidi Hydrochloridum. 5-
Effects on the urinary tract. Cystitis and bladder irritation Chloro-3-{2-[4-(2-hydroxyethyl)piperazin-1-yl]-2-oxoethyl}ben-
Tetridamine (rINN) have been associated with the use of tiaprofenic acid.1-6 In Au- zothiazolin-2-one hydrochloride.
POLI-67; Tetridamina; Tétridamine; Tetridaminum; Tetrydamine gust 1994 the UK CSM stated4 that since the introduction of ti- Тиарамида Гидрохлорид
(USAN). 4,5,6,7-Tetrahydro-2-methyl-3-(methylamino)-2H-inda- aprofenic acid in the UK in 1982 they had received 69 reports of C 15 H 18 ClN 3 O 3 S,HCl = 392.3.
zole. cystitis and 32 other reports of urinary-tract symptoms associated C AS — 32527-55-2 (tiaramide); 35941-71-0 (tiaramide
with tiaprofenic acid including frequency, dysuria, and haematu- hydrochloride).
Тетридамин ria whereas only 8 cases of cystitis had been reported for all other
C 9 H 15N 3 = 165.2. NSAIDs combined. Analysis of spontaneous reports received by
C AS — 17289-49-5. WHO7 confirmed that cystitis was more commonly associated Cl
with tiaprofenic acid than with other NSAIDs. The Australian
Adverse Drug Reactions Advisory Committee had received sim-
H3C NH ilar reports.3 Since the 1994 warning, the CSM8 had received re-
ports of a further 74 cases of cystitis, but the majority of these had
occurred before the warning was issued. The duration of treat-
H3 C N ment in patients affected had varied considerably. Most patients N
N recovered when tiaprofenic acid was withdrawn. S
The CSM recommended that tiaprofenic acid should not be giv- N N
Profile en to patients with urinary-tract disorders and that it should be O O OH
Tetridamine is an NSAID (p.96) that has been used as the stopped in patients who develop urinary-tract symptoms. Pa-
tients should be advised that if they develop symptoms such as (tiaramide)
maleate as a douche in the treatment of vaginitis.
urinary frequency, nocturia, urgency, or pain on urination, or
Preparations have blood in their urine they should stop taking tiaprofenic acid Pharmacopoeias. In Jpn.
Proprietary Preparations (details are given in Part 3) and consult their doctor. Older patients may be at increased risk.9
1. Ahmed M, Davison OW. Severe cystitis associated with tiapro-
Profile
Ital.: Deb; Spain: Fomene.
fenic acid. BMJ 1991; 303: 1376. Tiaramide hydrochloride is an NSAID (p.96) that has been given
2. O’Neill GFA. Tiaprofenic acid as a cause of non-bacterial cysti- orally for the relief of pain and inflammation.
tis. Med J Aust 1994; 160: 123–5. Preparations
Thurfyl Salicylate 3. Australian Adverse Drug Reactions Advisory Committee
(ADRAC). Update on tiaprofenic acid and urinary symptoms. Proprietary Preparations (details are given in Part 3)
Salicilato de turfilo. Tetrahydrofurfuryl salicylate. Aust Adverse Drug React Bull 1994; 13: 6. Jpn: Solantal†.
4. CSM/MCA. Severe cystitis with tiaprofenic acid (Surgam). Cur-
C 12 H 14O 4 = 222.2. rent Problems 1994; 20: 11. Also available at: http://
C AS — 2217-35-8. w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _
FILE&dDocName=CON2015615&RevisionSelectionMethod= Tilidine Hydrochloride (USAN, pINNM)
LatestReleased (accessed 08/11/07)
5. Harrison WJ, et al. Adverse reactions to tiaprofenic acid mim-
Gö 1261-C; Hidrocloruro de tilidina; Tilidate Hydrochloride
icking interstitial cystitis. BMJ 1994; 309: 574. (BANM); Tilidiinihydrokloridihemihydraatti; Tilidine, Chlorhydrate
6. Mayall FG, et al. Cystitis and ureteric obstruction in patients tak- de; Tilidine (chlorhydrate de) hémihydraté; Tilidin-hydrochlorid
O ing tiaprofenic acid. BMJ 1994: 309: 599. hemihydrát; Tilidinhydroklorid hemihydrat; Tilidini Hydrochlori-
O 7. The ADR Signals Analysis Project (ASAP) Team. How does
cystitis affect a comparative risk profile of tiaprofenic acid with dum; Tilidini hydrochloridum hemihydricum; Tilidino hidrochlori-
OH O other non-steroidal antiinflammatory drugs? An international das hemihidratas; W-5759A. (±)-Ethyl trans-2-dimethylamino-1-
study based on spontaneous reports and drug usage data. Phar- phenylcyclohex-3-ene-1-carboxylate hydrochloride hemihy-
macol Toxicol 1997; 80: 211–17. drate.
Profile 8. Crawford MLA, et al. Severe cystitis associated with tiaprofenic
Thurfyl salicylate is a salicylic acid derivative that has been used acid. Br J Urol 1997; 79: 578–84. Тилидина Гидрохлорид
similarly to methyl salicylate (p.85) in topical rubefacient prepa- 9. Buchbinder R, et al. Clinical features of tiaprofenic acid (sur- C 17 H 23 NO 2 ,HCl, ⁄ H 2 O = 318.8.
gam) associated cystitis and a study of risk factors for its devel- C AS — 20380-58-9 (tilidine); 27107-79-5 (anhydrous ti-
rations at concentrations of up to 14% for musculoskeletal, joint, opment. J Clin Epidemiol 2000; 53: 1013–19.
peri-articular, and soft-tissue disorders. lidine hydrochloride); 24357-97-9 (anhydrous +-trans-tili-
Interactions dine hydrochloride).
Preparations For interactions associated with NSAIDs, see p.99. ATC — N02AX01.
Proprietary Preparations (details are given in Part 3) ATC Vet — QN02AX01.
Pharmacokinetics
Multi-ingredient: Austral.: Biosal Arthritis; Belg.: Transvane; Irl.: Trans- Tiaprofenic acid is absorbed from the gastrointestinal tract with
vasin; UK: Transvasin Heat Rub. peak plasma concentrations being reached within about 1.5 H3C CH3
hours after oral doses. It has a short elimination half-life of about N O
2 hours and is highly bound to plasma proteins (about 98%). Ex-
Tiaprofenic Acid (BAN, rINN) cretion of tiaprofenic acid and its metabolites is mainly in the
urine in the form of acyl glucuronides; some is excreted in the O CH3
Acide tiaprofénique; Ácido tiaprofénico; Acidum tiaprofenicum; bile. Tiaprofenic acid crosses the placenta and is distributed into
FC-3001; Kyselina tiaprofenová;_ RU-15060; Tiaprofeenihappo; breast milk.
Tiaprofenik Asit; Tiaprofeno ru gštis; Tiaprofensyra. 2-(5-Ben-
◊ References.
zoyl-2-thienyl)propionic acid.
1. Davies NM. Clinical pharmacokinetics of tiaprofenic acid and its
Тиапрофеновая Кислота enantiomers. Clin Pharmacokinet 1996; 31: 331–47. (tilidine)
C 14 H 12O 3 S = 260.3. Uses and Administration
C AS — 33005-95-7. Tiaprofenic acid, a propionic acid derivative, is an NSAID Pharmacopoeias. In Eur. (see p.vii).
ATC — M01AE11. (p.99). It is used for the relief of pain and inflammation in musc- Ph. Eur. 6.2 (Tilidine Hydrochloride Hemihydrate). A white or
ATC Vet — QM01AE11. uloskeletal and joint disorders such as ankylosing spondylitis, almost white, crystalline powder. A suitable antoxidant may be
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
130 Analgesics Anti-inflammatory Drugs and Antipyretics
added. Freely soluble in water and in alcohol; very soluble in Interactions Hypersensitivity. Anaphylactic shock,1 urticaria and an-
dichloromethane. Protect from light. For interactions associated with NSAIDs, see p.99. gioedema,2 and aseptic meningitis3 are among the hypersensitiv-
Dependence and Withdrawal ity reactions reported in patients taking tolmetin.
Pharmacokinetics
As for Opioid Analgesics in general, p.101. 1. Rossi AC, Knapp DE. Tolmetin-induced anaphylactoid reac-
Tolfenamic acid is readily absorbed from the gastrointestinal tions. N Engl J Med 1982; 307: 499–500.
Adverse Effects, Treatment, and Precautions tract. Peak plasma concentrations are reached about 60 to 90 2. Ponte CD, Wisman R. Tolmetin-induced urticaria/angioedema.
As for Opioid Analgesics in general, p.102. minutes after an oral dose. Tolfenamic acid is about 99% bound Drug Intell Clin Pharm 1985; 19: 479–80.
to plasma proteins. The plasma half-life is about 2 hours. 3. Ruppert GB, Barth WF. Tolmetin-induced aseptic meningitis.
Overdosage. Cyanosis, respiratory depression, and seizures Tolfenamic acid is metabolised in the liver; the metabolites and JAMA 1981; 245: 67–8.
developed in a 28-year-old woman after an overdose of a combi- unchanged drug are conjugated with glucuronic acid. About Interactions
nation preparation of tilidine and naloxone.1 The authors com- 90% of an ingested dose is excreted in the urine and the remain- For interactions associated with NSAIDs, see p.99.
mented that the amount of naloxone included in the preparation, der in the faeces. Tolfenamic acid is distributed into breast milk.
in order to prevent abuse, was insufficient to prevent respiratory Pharmacokinetics
depression after severe overdose. Uses and Administration Tolmetin is almost completely absorbed from the gastrointestinal
1. Regenthal R, et al. Poisoning with tilidine and naloxone: toxi- Tolfenamic acid, an anthranilic acid derivative related to tract and peak plasma concentrations are attained about 30 to 60
cokinetic and clinical observations. Hum Exp Toxicol 1998; 17: mefenamic acid (p.80), is an NSAID (p.99). In the treatment of minutes after ingestion. It is extensively bound to plasma pro-
593–7. acute attacks of migraine tolfenamic acid is given in a usual oral teins (over 99%) and has a biphasic plasma half-life of about 1 to
Porphyria. Tilidine has been associated with acute attacks of dose of 200 mg when the first symptoms appear; if a satisfactory 2 hours and 5 hours, respectively. Tolmetin penetrates synovial
porphyria and is considered unsafe in porphyric patients. response is not obtained this dose may be repeated once after 1 fluid and very small amounts are distributed into breast milk. It
to 2 hours. Tolfenamic acid has also been given for the relief of is excreted in the urine as an inactive dicarboxylic acid metabo-
Interactions mild to moderate pain in disorders such as dysmenorrhoea, rheu- lite and its glucuronide and as tolmetin glucuronide with small
For interactions associated with opioid analgesics, see p.103. matoid arthritis, or osteoarthritis in doses of 100 to 200 mg three amounts of unchanged drug.
Pharmacokinetics times daily.
Uses and Administration
Tilidine is absorbed from the gastrointestinal tract. It is metabo- Preparations Tolmetin sodium is an NSAID (p.99). It is used in musculoskel-
lised and excreted in the urine mainly as metabolites nortilidine etal and joint disorders such as osteoarthritis and rheumatoid ar-
(nortilidate) and bisnortilidine (bisnortilidate). Nortilidine is re- Proprietary Preparations (details are given in Part 3)
Arg.: Flocur; Austria: Migea; Braz.: Fenamic†; Cz.: Migea; Denm.: thritis, including juvenile idiopathic arthritis. It is given orally as
sponsible for the analgesic activity of tilidine. Clotam†; Migea; Fin.: Clotam; Migea†; Gr.: Clotam; Gantil; Polmonin; Pri- the sodium salt although doses are expressed in terms of the base;
◊ References. mactam; Purfalox; Tolfamic; Turbaund; Mex.: Bifenac†; Flocur†; Neth.: tolmetin sodium dihydrate 122.5 mg is equivalent to about
Clotam; Rociclyn†; Norw.: Migea†; Pol.: Migea; Swed.: Migea†; Switz.: 100 mg of tolmetin.
1. Vollmer K-O, et al. Pharmacokinetics of tilidine and metabolites Clotam†; UK: Clotam; Venez.: Clotan†.
in man. Arzneimittelforschung 1989; 39: 1283–8. For the treatment of rheumatoid arthritis and osteoarthritis, the
2. Seiler K-U, et al. Pharmacokinetics of tilidine in terminal renal usual initial oral dose is the equivalent of 400 mg of tolmetin
failure. J Clin Pharmacol 2001; 41: 79–84.
3. Hajda JP, et al. Sequential first-pass metabolism of nortilidine:
three times daily. Doses should be adjusted after 1 to 2 weeks
the active metabolite of the synthetic opioid drug tilidine. J Clin Tolmetin Sodium (BANM, USAN, rINNM) according to response; maintenance doses of 600 mg to a maxi-
Pharmacol 2002; 42: 1257–61. McN-2559-21-98; McN-2559 (tolmetin); Natrii Tolmetinum; mum of 1800 mg daily in divided doses have been used.
4. Brennscheidt U, et al. Pharmacokinetics of tilidine and naloxone For dosage details in children, see below.
in patients with severe hepatic impairment. Arzneimittelforsc- Tolmetina sódica; Tolmétine Sodique. Sodium (1-methyl-5-p-
hung 2007; 57: 106–11. toluoylpyrrol-2-yl)acetate dihydrate. Tolmetin as the free acid has been applied as a topical gel.
Uses and Administration Натрий Тольметин Administration in children. For the treatment of juvenile
Tilidine hydrochloride is an opioid analgesic (p.104). It is used in C 15 H 14NNaO 3 ,2H 2 O = 315.3. idiopathic arthritis in children aged 2 years and over, tolmetin
the control of moderate to severe pain. sodium is given in initial oral doses equivalent to 20 mg/kg of
C AS — 26171-23-3 (tolmetin); 35711-34-3 (anhydrous
Tilidine hydrochloride may be given in usual oral doses of up to tolmetin sodium); 64490-92-2 (tolmetin sodium dihy- tolmetin daily in three or four divided doses; maintenance doses
50 mg four times daily. It has been given as a suppository, or by drate). of 15 mg/kg to a maximum of 30 mg/kg daily have been used.
intravenous, intramuscular, or subcutaneous injection. Tilidine ATC — M01AB03; M02AA21. Preparations
has also been given as the phosphate in modified release tablets. ATC Vet — QM01AB03; QM02AA21. USP 31: Tolmetin Sodium Capsules; Tolmetin Sodium Tablets.
As a deterrent to abuse combined oral preparations of tilidine hy- Proprietary Preparations (details are given in Part 3)
drochloride with naloxone hydrochloride are available in some Austria: Tolectin†; Canad.: Tolectin†; Mex.: Tolectin; S.Afr.: Tolectin;
countries. CH3 Spain: Artrocaptin; Switz.: Tolectin†; Turk.: Tolectin; USA: Tolectin.
O
Preparations
Proprietary Preparations (details are given in Part 3) N
Belg.: Tinalox; Valoron†; Valtran; Cz.: Valoron†; Ger.: Andolor; Celldolor; COOH
Findol N†; Gruntin Tropfen†; Nalidin; Tili Comp; Tili-Puren; Tili†; Tilicomp; Tramadol Hydrochloride
Tilidalor†; Tilidin comp; Tilidin N; Tilidin plus; Tilidin-saar; Tilidura; Tiligetic†; (BANM, USAN, rINNM)
Tilimerck†; Tilnalox; Valoron N; S.Afr.: Valoron; Switz.: Valoron. H3C
CG-315; CG-315E; Hidrocloruro de tramadol; Tramadol, chlo-
(tolmetin) rhydrate de; Tramadol Hidroklorür; Tramadol-hidroklorid; Tra-
Tolfenamic Acid (BAN, rINN) madol-hydrochlorid; Tramadolhydroklorid; Tramadoli hydro-
Acide Tolfénamique; Ácido tolfenámico; Acidum tolfenamicum; Pharmacopoeias. In US. chloridum; Tramadolihydrokloridi; Tramadolio hidrochloridas;
USP 31 (Tolmetin Sodium). A light yellow to light orange crys- U-26225A. (±)-trans-2-Dimethylaminomethyl-1-(3-methoxy-
Kyselina
_ tolfenamová; Tolfenaamihappo; Tolfenaminsav; Tolfena- talline powder. Freely soluble in water and in methyl alcohol; phenyl)cyclohexanol hydrochloride.
mo ru gštis; Tolfenamsyra. N-(3-Chloro-o-tolyl)anthranilic acid. slightly soluble in alcohol; very slightly soluble in chloroform.
Толфенамовая Кислота Трамадола Гидрохлорид
C 14 H 12 ClNO 2 = 261.7. Adverse Effects, Treatment, and Precautions C 16 H 25NO 2 ,HCl = 299.8.
C AS — 13710-19-5. As for NSAIDs in general, p.96. C AS — 27203-92-5 (tramadol); 22204-88-2 (tramadol
ATC — M01AG02. Breast feeding. No adverse effects have been seen in breast- hydrochloride); 36282-47-0 (tramadol hydrochloride).
ATC Vet — QM01AG02. fed infants whose mothers were given tolmetin, and the Ameri- ATC — N02AX02.
can Academy of Pediatrics considers1 that it is therefore usually ATC Vet — QN02AX02.
compatible with breast feeding. However, licensed product in-
COOH CH3 formation recommends that tolmetin should be avoided in nurs-
H H3C CH3
N Cl ing mothers.
1. American Academy of Pediatrics. The transfer of drugs and oth- N
er chemicals into human milk. Pediatrics 2001; 108: 776–89.
Correction. ibid.; 1029. Also available at:
h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l /
pediatrics%3b108/3/776 (accessed 08/11/07) H
Pharmacopoeias. In Eur. (see p.vii). H3CO
Effects on the blood. Case reports of agranulocytosis1 and
Ph. Eur. 6.2 (Tolfenamic Acid). A white or slightly yellow crys-
thrombocytopenia2 associated with tolmetin. OH
talline powder. Practically insoluble in water; sparingly soluble
in dehydrated alcohol and in dichloromethane; soluble in 1. Sakai J, Joseph MW. Tolmetin and agranulocytosis. N Engl J
Med 1978; 298: 1203.
dimethylformamide. It dissolves in dilute solutions of alkali hy- 2. Lockhart JM. Tolmetin-induced thrombocytopenia. Arthritis
droxides. Protect from light. (tramadol)
Rheum 1982; 25: 1144–5.
Adverse Effects, Treatment, and Precautions Effects on the CNS. See Hypersensitivity, below.
As for NSAIDs in general, p.96. Pharmacopoeias. In Chin. and Eur. (see p.vii).
Effects on the gastrointestinal tract. Erosive oesophagitis Ph. Eur. 6.2 (Tramadol Hydrochloride). A white or almost
Dysuria, most commonly in males and probably due to local ir-
ritation of the urethra by a metabolite, has been reported. Tremor, has been reported1 in an 11-year-old child after ingestion of a white, crystalline powder. Freely soluble in water and in methyl
euphoria, and fatigue have also occurred. Tolfenamic acid is con- dose of tolmetin while lying down and without drinking any wa- alcohol; very slightly soluble in acetone. Protect from light.
tra-indicated in patients with significant hepatic or renal impair- ter. Incompatibility. Some manufacturers state that tramadol hy-
ment. 1. Palop V, et al. Tolmetin-induced esophageal ulceration. Ann drochloride injection 50 mg/mL is incompatible with injections
Pharmacother 1997; 31: 929. of diazepam, diclofenac sodium, flunitrazepam, glyceryl trini-
Breast feeding. Although tolfenamic acid is distributed into
breast milk, the amount is considered by the BNF and licensed Effects on the kidneys. Interstitial nephritis1 and nephrotic trate, indometacin, midazolam, piroxicam, and phenylbutazone
product information to be too small to be harmful to a breast-fed syndrome2,3 have been reported in patients given tolmetin. if mixed in the same syringe. A study1 also found tramadol hy-
infant. 1. Katz SM, et al. Tolmetin: association with reversible renal fail- drochloride injection (diluted to 400 micrograms/mL) to be
ure and acute interstitial nephritis. JAMA 1981; 246: 243–5. incompatible with aciclovir and clindamycin when mixed to-
Effects on the lungs. Pulmonary infiltration has been associat- 2. Chatterjee GP. Nephrotic syndrome induced by tolmetin. JAMA gether.
ed with tolfenamic acid treatment in 6 patients.1 1981; 246: 1589. 1. Abanmy NO, et al. Compatibility of tramadol hydrochloride in-
1. Strömberg C, et al. Pulmonary infiltrations induced by tolfenam- 3. Tietjen DP. Recurrence and specificity of nephrotic syndrome jection with selected drugs and solutions. Am J Health-Syst
ic acid. Lancet 1987; ii: 685. due to tolmetin. Am J Med 1989; 87: 354–5. Pharm 2005; 62: 1299–1302.
 Tolfenamic Acid/Tramadol Hydrochloride 131
Stability. Oral suspensions of tramadol hydrochloride pressants and SSRIs. A similar pattern has been reported in the Interactions
5 mg/mL, prepared by mixing crushed tablets with a strawberry USA3 and Australia.4-6 For interactions associated with opioid analgesics, see
syrup and Ora-Plus (1:1) or with Ora-Sweet and Ora-Plus (1:1) A debilitating CNS-mediated reaction to an initial dose of trama-
were found to be stable for at least 90 days when stored either in p.103.
dol has been described in a patient.7 Symptoms, which lasted
the refrigerator or at room temperature.1 Oral suspensions con- about 4 hours, included ataxia, dilatation of the pupils, numbness Carbamazepine is reported to diminish the analgesic
taining tramadol hydrochloride 7.5 mg/mL and paracetamol in all limbs, tremulousness, and dysphoria. Although the exact activity of tramadol by reducing serum concentrations.
65 mg/mL, prepared by mixing the crushed tablets of a combina- mechanism of the reaction was not known, it was suggested that
tion preparation with the above vehicles, were also found to be
The risk of seizures is increased if tramadol is used
since the patient was an extensive metaboliser with very high ac-
stable for at least 90 days when stored under similar conditions.2 tivity of the cytochrome P450 isoenzyme CYP2D6, high con-
with other drugs that have the potential to lower the sei-
1. Wagner DS, et al. Stability of oral liquid preparations of trama- centrations of the active O-desmethyl metabolite were the cause. zure threshold. See also Effects on the CNS under Ad-
dol in strawberry syrup and a sugar-free vehicle. Am J Health- The patient recovered with no sequelae. It is possible that this verse Effects, above.
Syst Pharm 2003; 60: 1268–70.
represents a case of the serotonin syndrome, since tramadol is Tramadol inhibits reuptake of noradrenaline and serot-
2. Johnson CE, et al. Stability of tramadol hydrochloride–acetami-
known to be associated with this condition, particularly at high
nophen (Ultracet) in strawberry syrup and in a sugar-free vehi-
doses or when given with other drugs that raise serotonin con-
onin and enhances serotonin release and there is the
cle. Am J Health-Syst Pharm 2004; 61: 54–7.
centrations.4 possibility that it may interact with other drugs that en-
Dependence and Withdrawal 1. CSM/MCA. Tramadol (Zydol)—psychiatric reactions. Current hance monoaminergic neurotransmission including
As for Opioid Analgesics, p.101.
Problems 1995; 21: 2. Also available at: lithium, tricyclic antidepressants, and SSRIs; it should
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_
FILE&dDocName=CON2015618&RevisionSelectionMethod= not be given to patients receiving MAOIs or within 14
Tramadol may have lower potential for producing de- LatestReleased (accessed 26/06/08) days of their discontinuation.
pendence than morphine. 2. CSM/MCA. Tramadol—(Zydol, Tramake and Zamadol). Cur-
rent Problems 1996; 22: 11. Also available at: ◊ Metabolism of tramadol is mediated by the cytochrome P450
◊ A WHO expert committee1 considered in 2003 that the availa- http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ isoenzyme CYP2D6. Use with specific inhibitors of this en-
ble information on tramadol was not sufficient to warrant inter- FILE&dDocName=CON2023218&RevisionSelectionMethod= zyme, such as quinidine, may increase concentrations of trama-
national control. Studies in animals indicated that tramadol pro- LatestReleased (accessed 26/06/08) dol and lower concentrations of its active metabolite but the clin-
duced little tolerance, had mild withdrawal symptoms, and a 3. Kahn LH, et al. Seizures reported with tramadol. JAMA 1997; ical consequences of this effect are unclear.
lower abuse potential than codeine and pentazocine. Subse- 278: 1661.
quently, when reviewed in 2006, the committee2 considered that, 4. Adverse Drug Reactions Advisory Committee (ADRAC). Tra- Anticoagulants. For reports of the effect of tramadol on oral
madol—four years experience. Aust Adverse Drug React Bull anticoagulants, see Analgesics under Interactions of Warfarin,
despite an increase in its use, tramadol continued to show a low 2003; 22: 1–2. Also available at: http://www.tga.health.gov.au/
level of abuse and concluded that there was not sufficient evi- p.1427.
adr/aadrb/aadr0302.pdf (accessed 26/06/08)
dence to justify a further review. 5. Labate A, et al. Tramadol and new-onset seizures. Med J Aust Antidepressants. For reference to possible cases of serotonin
Nevertheless, there have been reports3-8 of dependence and 2005; 182: 42–3. syndrome associated with use of tramadol and SSRIs, see Opioid
abuse, particularly in opioid-dependent persons, and of with- 6. Boyd IW. Tramadol and seizures. Med J Aust 2005; 182: 595–6. Analgesics under Interactions of Fluoxetine, p.397.
drawal symptoms. In October 1996, the UK CSM9 commented 7. Gleason PP, et al. Debilitating reaction following the initial dose
of tramadol. Ann Pharmacother 1997; 31: 1150–2. 5-HT3-receptor antagonists. The pre-operative use of
that since June 1994 they had received reports of drug depend- ondansetron has been noted to reduce the postoperative analge-
ence in 5 patients and withdrawal symptoms associated with tra- Effects on the respiratory system. Respiratory depression sic efficacy of tramadol.1,2 In one study,1 the cumulative dose of
madol in 28 patients, which corresponded to a reporting rate of has been reported after tramadol infusion anaesthesia,1 although tramadol was up to 35% greater in those patients who also
about 1 in 6000. Doses in excess of the recommended maximum in a postoperative study2 tramadol had no significant respiratory received ondansetron compared to those who received no
of 400 mg daily had been taken by 5 of the patients. The duration depressant effect when equianalgesic doses of morphine, penta- antiemetic. In addition there was no difference in the incidence
of treatment before onset of these effects ranged from 10 to 409 zocine, pethidine, piritramide, and tramadol were compared. of postoperative nausea and vomiting between the two groups.
days (average 3 months). Withdrawal symptoms reported were 1. Paravicini D, et al. Tramadol-infusionsanaesthesie mit Substitu- 1. De Witte JL, et al. The analgesic efficacy of tramadol is impaired
typically those of opioid withdrawal in general. A more recent tion von Enfluran und differenten Lachgaskonzentrationen. An- by concurrent administration of ondansetron. Anesth Analg
report from the Swedish Medical Products Agency10 stated that aesthesist 1985; 34: 20–7. 2001; 92: 1319–21.
between 1996 to 2005 they had received 71 reports of withdraw- 2. Fechner R, et al. Clinical investigations on the effect of mor- 2. Arcioni R, et al. Ondansetron inhibits the analgesic effects of
phine, pentazocine, pethidine, piritramide and tramadol on respi- tramadol: a possible 5-HT spinal receptor involvement in acute
al symptoms associated with tramadol; treatment duration ration. Anasth Intensivmed 1985; 26: 126–32. pain in humans. Anesth Analg 2002; 94: 1553–7.
ranged from 1 week to over 3 years at daily doses of between
50 mg to 2 g. Overdosage. In a multicentre case series,1 126 cases of trama-
1. WHO. WHO expert committee on drug dependence: thirty-third dol toxicity were reported between October 1995 and August Pharmacokinetics
report. WHO Tech Rep Ser 915 2003. Also available at: http:// 1996; of these, 87 involved exposure to tramadol alone. Com- Tramadol is readily absorbed after oral doses but is
libdoc.who.int/trs/WHO_TRS_915.pdf (accessed 26/06/08) mon symptoms included lethargy, nausea, tachycardia, and agi- subject to some first-pass metabolism. Mean absolute
2. WHO. WHO expert committee on drug dependence: thirty-forth tation; seizures were also noted. Respiratory depression was seen
report. WHO Tech Rep Ser 942 2006. Also available at: in only 2 patients. The inhibitory effects of tramadol on
bioavailability is about 70 to 75% after oral use and
http://libdoc.who.int/trs/WHO_TRS_942_eng.pdf (accessed 100% after intramuscular injection. Plasma protein
26/06/08) monoamine reuptake, rather than its opioid effects, was consid-
3. Rodriguez Villamañan JC, et al. Withdrawal syndrome after ered to result in much of its toxicity. A similar pattern of toxicity binding is about 20%. Tramadol is metabolised by N-
long-term treatment with tramadol. Br J Gen Pract 2000; 50: has also been seen in a more recent report.2 In 190 tramadol-only and O-demethylation via the cytochrome P450 isoen-
406. exposures reported between January 1999 and July 2001, the
4. Yates WR, et al. Tramadol dependence with no history of sub- zymes CYP3A4 and CYP2D6 and glucuronidation or
main symptoms of overdosage were CNS depression, nausea
stance abuse. Am J Psychiatry 2001; 158: 964.
and vomiting, tachycardia, and seizures. Again, the incidence of sulfation in the liver. The metabolite O-desmethyltra-
5. Brinker A, et al. Abuse, dependence, or withdrawal associated
with tramadol. Am J Psychiatry 2002; 159: 881. respiratory depression was rare, with only 1 case reported. madol is pharmacologically active. Tramadol is excret-
6. Skipper GE, et al. Tramadol abuse and dependence among phy- 1. Spiller HA, et al. Prospective multicenter evaluation of tramadol ed mainly in the urine, predominantly as metabolites.
sicians. JAMA 2004; 292: 1818–19. exposure. J Toxicol Clin Toxicol 1997; 35: 361–4. Tramadol is widely distributed, crosses the placenta,
7. Soyka M, et al. Tramadol use and dependence in chronic non- 2. Marquardt KA, et al. Tramadol exposures reported to statewide
cancer pain patients. Pharmacopsychiatry 2004; 37: 191–2. poison control system. Ann Pharmacother 2005; 39: 1039–44. and appears in small amounts in breast milk. The elim-
8. Ripamonti C, et al. Withdrawal syndrome after delayed trama- ination half-life is about 6 hours.
dol intake. Am J Psychiatry 2004; 161: 2326–7.
9. CSM/MCA. Tramadol—(Zydol, Tramake and Zamadol). Cur- Precautions Children. References.
rent Problems 1996; 22: 11. Also available at: http:// As for Opioid Analgesics in general, p.103. 1. Murthy BVS, et al. Pharmacokinetics of tramadol in children af-
w w w. m h r a . g o v. u k / h o m e / i d c p l g ? I d c S e r v i c e = G E T _ ter i.v. or caudal epidural administration. Br J Anaesth 2000; 84:
FILE&dDocName=CON2023218&RevisionSelectionMethod= Tramadol should be used with caution in patients with 346–9.
LatestReleased (accessed 26/06/08)
10. Läkemedelsverket (Medical Products Agency—Sweden). Ut- renal or hepatic impairment and should be avoided if 2. Payne KA, et al. Pharmacokinetics of oral tramadol drops for
postoperative pain relief in children aged 4 to 7 years—a pilot
sättningsreaktioner av tramadol—ett större problem än förvän- renal impairment is severe. Removal by haemodialysis study. Anesth Prog 2003; 49: 109–12.
tat? (issued 14 November, 2006). Available at: http://
www.lakemedelsverket.se/Tpl/NewsPage____5449.aspx (ac- is reported to be minimal at 7%. 3. Zwaveling J, et al. Pharmacokinetics of rectal tramadol in post-
operative paediatric patients. Br J Anaesth 2004; 93: 224–7.
cessed 26/06/08) Tramadol should be used with care in patients with a 4. Garrido MJ, et al. Population pharmacokinetic/pharmacodynam-
history of epilepsy or those susceptible to seizures. See ic modelling of the analgesic effects of tramadol in pediatrics.
Adverse Effects and Treatment also Effects on the CNS under Adverse Effects, above. Pharm Res 2006; 23: 2014–23.
5. Saudan S, Habre W. Particularités pharmacologiques du trama-
As for Opioid Analgesics in general, p.102. dol chez l’enfant. Ann Fr Anesth Reanim 2007; 26: 560–3.
Abuse. See under Dependence and Withdrawal, above.
Tramadol may produce fewer typical opioid adverse The elderly. Pharmacokinetic parameters in elderly patients
effects such as respiratory depression and constipation. Anaesthesia. Licensed product information warns against were found to be similar to those in younger patients.1
using tramadol during very light planes of general anaesthesia
In addition to hypotension, hypertension has occasion- because of possible intra-operative awareness, although it may
1. Likar R, et al. Pharmacokinetic and pharmacodynamic proper-
ties of tramadol IR and SR in elderly patients: a prospective, age-
ally occurred. be used intra-operatively provided anaesthesia is maintained group—controlled study. Clin Ther 2006; 28: 2022–39.
Effects on the CNS. The UK CSM1 commented in February with a potent volatile or intravenous anaesthetic. Intra-operative Metabolism. Production of the active metabolite O-desmethyl-
1995 that since June 1994 they had received reports of 15 pa- awareness was reported in 65% of a group of 20 patients when tramadol is dependent on the cytochrome P450 isoenzyme
tients who had experienced confusion and/or hallucinations used to provide analgesia during light general anaesthesia with CYP2D6, which exhibits genetic polymorphism.1,2 For a refer-
while taking tramadol. The majority of the reactions developed 1 nitrous oxide and intermittent enflurane.1 However, in a study2 of ence to a debilitating CNS-mediated reaction in a patient who
to 7 days after starting treatment and in most patients resolved 51 patients given tramadol during stable light continuous isoflu- was an extensive metaboliser with high CYP2D6 activity, see Ef-
rapidly on withdrawal. It was noted that psychiatric reactions rane-nitrous oxide anaesthesia there was no clinically significant fects on the CNS under Adverse Effects, above.
comprised about 10% of all reactions reported with tramadol. lightening of anaesthesia and others have commented that during
1. Poulsen L, et al. The hypoalgesic effect of tramadol in relation
extensive use of tramadol intra-operatively over several years,
In a later comment2 in October 1996, the CSM noted that 27 re- to CYP2D6. Clin Pharmacol Ther 1996; 60: 636–44.
there had not been any incidence of recall in any patient treated 2. Pedersen RS, et al. Enantioselective pharmacokinetics of trama-
ports of convulsions and one of worsening epilepsy had been re-
at their clinic.3 dol in CYP2D6 extensive and poor metabolizers. Eur J Clin
ceived, which corresponded to a reporting rate of about 1 in Pharmacol 2006; 62: 513–21.
7000. Of the 5 patients receiving intravenous tramadol, 2 had 1. Lehmann KA, et al. Zur Bedeutung von Tramadol als intraoper-
ativem Analgetikum: eine randomisierte Doppelblindstudie im
been given doses equivalent to 1.45 and 4 g daily, well in excess
of those recommended (see also Overdosage, below). Of the pa-
Vergleich zu Placebo. Der Anaesthetist 1985; 34: 11–19. Uses and Administration
2. Coetzee JF, et al. Effect of tramadol on depth of anaesthesia. Br
tients receiving oral tramadol, the majority were taking other J Anaesth 1996; 76: 415–18. Tramadol hydrochloride is an opioid analgesic (p.104).
drugs known to cause convulsions, including tricyclic antide- 3. Budd K. Tramadol. Br J Anaesth 1995; 75: 500. It also has noradrenergic and serotonergic properties
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
132 Analgesics Anti-inflammatory Drugs and Antipyretics
that may contribute to its analgesic activity. Tramadol madolor; Tramal; Tramamed; Tramastad; Tramundal; Tramundin; Belg.: a concentration of 10 to 20% for the relief of muscular and rheu-
Contramal; Doctramado; Dolzam; Tradonal; Tramium; Braz.: Anangor; matic pain. It has also been used as a sunscreen.
is used for moderate to severe pain. Dorless; Sensitram; Sylador; Timasen†; Trabilin; Tramadon; Tramal; Tramal-
Tramadol hydrochloride is given by mouth, intrave- iv; Zamadol; Chile: Manol; Minidol; Timarol; Tramal; Zodol; Cz.: Mabron; Percutaneous absorption. In contrast to methyl salicylate,
Noax Uno; Protradon; Trabar†; Tradef; Tradonal†; Tralgit; Tramabene; which undergoes considerable absorption and produces high
nously, or rectally as a suppository. The intramuscular Tramagit; Tramal; Tramundin; Denm.: Dolol; Mandolgin; Nobligan; Tadol;
subcutaneous and dermal concentrations of salicylic acid after
route has also been used. It may also be given by infu- Tradolan; Fin.: Tradolan; Tramadin; Tramagetic; Tramal; Trambo; Fr.: Biodal-
gic; Contramal; Monocrixo; Orozamudol; Takadol; Topalgic; Trasedal†; Za- application to intact skin, concentrations of salicylic acid after
sion or as part of a patient-controlled analgesia system. mudol; Zumalgic; Ger.: Amadol; Jutadol; T-long; Tial; Tradol†; Trama; Tra- topical application of trolamine salicylate were substantially
Usual oral doses are 50 to 100 mg every 4 to 6 hours. ma-Dorsch†; Tramabeta; Tramadoc; Tramadolor; Tramadura; Tramagetic†; lower in tissue1 and undetectable in serum.2
Tramagit; Tramal; Tramundin; Travex One; Gr.: Tramal; Hong Kong: Acug-
1. Cross SE, et al. Is there tissue penetration after application of
Tramadol hydrochloride may also be given orally as a esic; Mabron; Sefmal; Tradonal†; Tramal; Tramo; Hung.: Adamon; Con-
topical salicylate formulations? Lancet 1997; 350: 636.
tramal; Ralgen; Tramadolor; Tramalgic; India: Contramal; Tramacip;
modified-release preparation once or twice daily. The Tramazac; TRD-Contin; Urgendol; Indon.: Andalpha; Bellatram; Camigesik; 2. Morra P, et al. Serum concentrations of salicylic acid following
total oral daily dosage should not exceed 400 mg. Contram; Dolana; Dolgesik; Dolocap; Forgesic; Kamadol; Katrasic; Nonal- topically applied salicylate derivatives. Ann Pharmacother
ges; Nufapotram; Orasic; Pinorec; Radol; Simatral; Tradosik; Tradyl; Tragesik; 1996; 30: 935–40.
Preparations containing tramadol hydrochloride with Tramal; Trasik; Traumasik; Trunal; Tugesal; Zumatram; Irl.: Biodol; By-Madol; Preparations
other analgesics such as paracetamol are also used. Tradol; Tramake; Tramapine; Tramex; Xymel; Zamadol; Zydol; Israel: Tra-
Proprietary Preparations (details are given in Part 3)
bar; Tramadex; Tramal; Ital.: Adamon; Contramal; Fortradol; Fraxidol;
A dose of 50 to 100 mg may be given every 4 to 6 Prontalgin; Tradonal; Traflash; Tralodie; Tramalin; Malaysia: Acugesic; Anal- Arg.: Geniol Flex†; Austral.: Dencorub Arthritis; Goanna Arthritis Cream;
ab; Mabron; Pengesic; Sefmal; Tracidol; Tramada; Tramal†; Tramundin; Metsal AR Analgesic; Canad.: Antiphlogistine Rub A-535 No Odour; As-
hours by intramuscular or intravenous injection over 2 Mex.: Durodor; Nobligan; Prontofort; Tradol; Tralic; Tramed; Trexol; Vel- percreme; Bengay No Odor; Myoflex; Mex.: Myoflex; Singapore: Metsal
to 3 minutes, or by intravenous infusion. For the treat- drol; Neth.: Doltard; Theradol; Tradonal; Tramagetic; Tramal; Tramelene; AR Analgesic; Spain: Bexidermil; USA: Analgesia Creme; Aspercreme;
Norw.: Nobligan; Tradolan; Tramagetic; NZ: Tramal; Tramedo; Zytram; Coppertone Tan Magnifier; Flex-Power Performance Sports; Mobisyl; My-
ment of postoperative pain, the initial dose is 100 mg Philipp.: Dolmal; Dolotral; Dolpaz; Milador; Pengesic; Peptrad; Siverol; oflex; Sportscreme; Tropical Blend Tan Magnifier.
followed by 50 mg every 10 to 20 minutes if necessary TDL; Tolma; Tradonal; Tramal; Tramkor; Tramundin; Unitral; Pol.: Poltram; Multi-ingredient: Arg.: Duo Minoxi†; Canad.: Myoflex Extra Strength
to a total maximum (including the initial dose) of Tramahexal; Tramal; Tramcod; Tramundin; Port.: Dolpar; Gelotralib; Nobli- Ice.
gan; Paxilfar ; Tramal; Tramy; Travex; Zydol; Zytram; Rus.: Mabron
250 mg in the first hour. Thereafter, doses are 50 to (Маброн); Sintradon (Синтрадон); Tramal (Трамал); S.Afr.: Dolotram;
100 mg every 4 to 6 hours up to a total daily dose of Tramahexal; Tramal; Tramazac; Singapore: Mabron; Pengesic; Sefmal; Tra-
dol†; Tramal; Tramium; Spain: Adolonta; Ceparidin; Dolodol; Sofrodol; Valdecoxib (BAN, USAN, rINN)
600 mg. Tioner; Tradonal; Tralgiol; Zytram; Swed.: Nobligan; Tiparol; Tradolan;
Switz.: Dolotramine; Ecodolor; Tramal; Tramundin; Thai.: Amanda; Am- SC-65872; Valdécoxib; Valdecoxibum; Valdekoksib. p-(5-Methyl-
Usual rectal doses by suppository are 100 mg up to 4 mitram; Anadol; Analab; Mabron†; Madol; Madola; Millidol; Paindol†; Phar- 3-phenyl-4-isoxazolyl)benzenesulfonamide.
times daily. madol; Rofy; Sefmal; Tamolan; Tracine; Tradolgesic; Tradonal; Tramadil;
Tramal; Tramamed; Tramax; Tramoda; Trosic; Volcidol-S; Turk.: Contramal; Вальдекоксиб
For details of doses in children and in patients with he- Tramadolor; UK: Dromadol; Larapam; Mabron; Nobligan; Tradorec; Tra- C 16 H 14N 2 O 3 S = 314.4.
patic or renal impairment, see below. make; Tramulief; Zamadol; Zeridame; Zydol; USA: Ultram; Venez.: Tramal. C AS — 181695-72-7.
Multi-ingredient: Arg.: Calmador Plus; Tramacet; Austria: Zaldiar; ATC — M01AH03.
◊ References. Belg.: Zaldiar; Braz.: Ultracet; Canad.: Tramacet; Chile: Cronus; Minidol ATC Vet — QM01AH03.
1. Scott LJ, Perry CM. Tramadol: a review of its use in periopera- Plus; Zafin; Zaldiar; Cz.: Zaldiar; Fr.: Ixprim; Zaldiar; Ger.: Zaldiar; Hong
tive pain. Drugs 2000; 60: 139–76. Kong: Ultracet; India: Tolydol; Tramacip Plus; Ultrazac; Malaysia: Ultrac-
2. McClellan K, Scott LJ. Tramadol/paracetamol. Drugs 2003; 63: et; Mex.: Gammadol; Sinergix; Tramacet; Zaldiar; Neth.: Tilalgin; Zaldiar;
1079–86. Correction. ibid.; 1636. Philipp.: Dolcet; Pol.: Zaldiar; Port.: Tilalgin; Zaldiar; Rus.: Zaldiar
3. Bennett RM, et al. Tramadol and acetaminophen combination (Залдиар); S.Afr.: Tramacet; Singapore: Ultracet; Spain: Pazital; Pontalsic;
tablets in the treatment of fibromyalgia pain: a double-blind, Zaldiar; Switz.: Zaldiar; Thai.: Ultracet; UK: Tramacet; USA: Ultracet;
randomized, placebo-controlled study. Am J Med 2003; 114: Venez.: Ultracet; Zaldiar.
537–45.
4. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin O
Pharmacokinet 2004; 43: 879–923. N
5. Leppert W, Luczak J. The role of tramadol in cancer pain treat- Trimeperidine Hydrochloride (BANM, rINNM) S NH2
ment—a review. Support Care Cancer 2005; 13: 5–17. O
6. Close BR. Tramadol: does it have a role in emergency medi- Hidrocloruro de trimeperidina; Promedol (trimeperidine); O
cine? Emerg Med Australas 2005; 17: 73–83. Promedolum (trimeperidine); Trimépéridine, Chlorhydrate de;
7. Cepeda MS, et al. Tramadol for osteoarthritis. Available in The Trimeperidini Hydrochloridum. 1,2,5-Trimethyl-4-phenyl-4-pip- CH3
Cochrane Database of Systematic Reviews; Issue 3. Chichester:
John Wiley; 2006 (accessed 26/06/08). eridyl propionate hydrochloride.
8. Hollingshead J, et al. Tramadol for neuropathic pain. Available Тримеперидина Гидрохлорид Profile
in The Cochrane Database of Systematic Reviews; Issue 3. C 17 H 25NO 2 ,HCl = 311.8. Valdecoxib is an NSAID (p.96) reported to be a selective inhibi-
Chichester: John Wiley; 2006 (accessed 26/06/08). tor of cyclo-oxygenase-2 (COX-2). It was given orally in the
9. Keating GM. Tramadol sustained-release capsules. Drugs 2006; C AS — 64-39-1 (trimeperidine); 125-80-4 (trimeperidine
66: 223–30. hydrochloride). treatment of osteoarthritis and rheumatoid arthritis, and for the
10. Hair PI, et al. Tramadol extended-release tablets. Drugs 2006; pain of dysmenorrhoea. The risk of serious skin reactions with
66: 2017–27. valdecoxib, in addition to its cardiovascular adverse effects (see
11. Lee EY, et al. Tramadol 37.5-mg/acetaminophen 325-mg com- CH3 below), prompted its general withdrawal worldwide in April
bination tablets added to regular therapy for rheumatoid arthritis 2005.
pain: a 1-week, randomized, double-blind, placebo-controlled
trial. Clin Ther 2006; 28: 2052–60. N CH3 Effects on the cardiovascular system. The short-term use
12. Freeman R, et al. Randomized study of tramadol/acetami- of parecoxib and valdecoxib after coronary artery bypass graft
nophen versus placebo in painful diabetic peripheral neuropa- O surgery has been associated with an increased risk of adverse ef-
thy. Curr Med Res Opin 2007; 23: 147–61.
H3C CH3 fects such as myocardial infarction, deep-vein thrombosis, pul-
Administration in children. In the UK, tramadol hydrochlo- O monary embolism, and stroke.1 When compared with patients in
ride is licensed for the management of moderate to severe pain in the placebo group, the risk of such effects was almost 4 times
children 12 years of age and older; usual adult doses may be giv- greater in those who had received intravenous parecoxib for 3
en (see above). However, in some other European countries it is days followed by oral valdecoxib for the next 7 days. Those pa-
licensed in younger children although the age range permitted tients who received oral valdecoxib only for 7 days postopera-
can vary: for example, in France, a usual dose in those aged 3 (trimeperidine) tively had a non-significant increase in risk for adverse cardio-
years and over is 1 to 2 mg/kg orally, which may be repeated 3 or vascular effects.
4 times daily, whereas in Germany, similar doses are permitted in Profile The adverse cardiovascular effects associated with valdecoxib
children as young as 1 year old. Tramadol has also been given Trimeperidine hydrochloride is an opioid analgesic (p.101) with treatment were one of the reasons the drug was generally with-
parenterally to children in doses similar to those used orally. actions and uses similar to those of pethidine (p.113). drawn in April 2005.
Some references on the use of tramadol in children. 1. Nussmeier NA, et al. Complications of the COX-2 inhibitors
1. Finkel JC, et al. An evaluation of the efficacy and tolerability of parecoxib and valdecoxib after cardiac surgery. N Engl J Med
oral tramadol hydrochloride tablets for the treatment of postsur- 2005; 352: 1081–91.
gical pain in children. Anesth Analg 2002; 94: 1469–73. Trolamine Salicylate (pINNM)
2. Demiraran Y, et al. A comparison of the postoperative analgesic Effects on the skin. Toxic epidermal necrolysis developed in a
efficacy of single-dose epidural tramadol versus morphine in
Salicilato de trietanolamina; Triethanolamine Salicylate; patient who took valdecoxib for 8 days, despite stopping the drug
children. Br J Anaesth 2005; 95: 510–13. Trolamine, Salicylate de; Trolamini Salicylas. at the first signs of a rash and starting treatment with oral pred-
3. Bozkurt P. Use of tramadol in children. Paediatr Anaesth 2005; Троламина Салисилат nisolone;1 the patient had a history of hypersensitivity to sulfon-
15: 1041–7. amides. Health Canada2 noted in January 2004 that it had re-
4. Chu Y-C, et al. Intraoperative administration of tramadol for
C 13 H 21NO 6 = 287.3.
postoperative nurse-controlled analgesia resulted in earlier C AS — 2174-16-5. ceived 5 reports of serious cutaneous adverse reactions
awakening and less sedation than morphine in children after car- associated with valdecoxib over less than 1 year from marketing
diac surgery. Anesth Analg 2006; 102: 1668–73. of the drug in December 2002. However, none of these were ery-
Administration in hepatic or renal impairment. A dos- O thema multiforme, Stevens-Johnson syndrome, or toxic epider-
age interval of 12 hours is recommended for tramadol usage in mal necrolysis although such reactions had been reported to
OH other regulatory authorities. In December 2004, the EMEA3 stat-
severe hepatic impairment. The dosage interval should also be OH
increased to 12 hours in patients with a creatinine clearance (CC) N ed that it had received reports of all 3 reactions, as well as exfo-
less than 30 mL/minute; in the USA licensed product informa- HO OH liative dermatitis; most of them had occurred within the first 2
tion suggests that the maximum oral dose should not exceed OH weeks of starting treatment and the incidence rate appeared
200 mg daily in these patients. Tramadol should not be given to greater for valdecoxib than other selective COX-2 inhibitors.
patients with more severe renal impairment (CC less than Pharmacopoeias. In US. The EMEA also noted that use of parecoxib (a prodrug of val-
10 mL/minute). USP 31 (Trolamine Salicylate). A compounded mixture of decoxib, see p.111) had been associated with erythema multi-
trolamine and salicylic acid in propylene glycol. pH of a 5% so- forme.
Preparations lution in water is between 6.5 and 7.5. Store in airtight containers The increased risk of serious skin reactions with valdecoxib
BP 2008: Tramadol Capsules. in a cool place. treatment was one of the reasons the drug was generally with-
Proprietary Preparations (details are given in Part 3) drawn in April 2005.
Arg.: Adamon†; Calmador; Nobligan; Trama-Klosidol; Tramal; Tramalan†;
Profile 1. Glasser DL, Burroughs SH. Valdecoxib-induced toxic epidermal
Austral.: Tramahexal; Tramal; Tramedo; Zydol; Austria: Adamon; Con- Trolamine salicylate is a salicylic acid derivative used similarly necrolysis in a patient allergic to sulfa drugs. Pharmacotherapy
tramal; Cromatodol; Dolol; Lanalget; Nycodol; Tradolan; Tramabene; Tra- to methyl salicylate (p.85) in topical rubefacient preparations in 2003; 23: 551–3.
 Trimeperidine Hydrochloride/Ziconotide 133
2. Health Canada. Valdecoxib (Bextra ): severe cutaneous reac- Profile Adverse Effects and Precautions
tions. Can Adverse React News 2004; 14 (1): 1–2. Also available Viminol hydroxybenzoate has analgesic and antipyretic proper- The most common adverse effects reported with ziconotide have
at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/ ties. The equivalent of 400 mg of viminol has been given daily in included dizziness, nausea and vomiting, nystagmus, abnormal
pdf/medeff/carn-bcei_v14n1-eng.pdf (accessed 29/08/08)
3. EMEA. EMEA public statement on valdecoxib (Bextra/Valdyn) divided doses by mouth. gait, blurred vision, headache, elevated creatine kinase levels,
and parecoxib sodium (Dynastat/Rayzon): cardiovascular risks Preparations and asthenia. Cognitive impairment, particularly confusion and
in coronary artery bypass graft (CABG) surgery and serious ad- impaired memory, is also very common, and typically develops
verse skin reactions (issued 15th December, 2004). Available at: Proprietary Preparations (details are given in Part 3)
Braz.: Dividol; Ital.: Dividol. after several weeks of treatment. Severe CNS symptoms such as
h t t p : / / w w w. e m e a . e u r o p a . e u / p d f s / h u m a n / p r e s s / p u s / hallucinations, paranoid reactions, speech disorders, aphasia,
20480204en.pdf (accessed 29/08/08)
and decreased alertness may occur but convulsions, stroke, delir-
Preparations ium, encephalopathy, and coma have been reported less com-
Proprietary Preparations (details are given in Part 3) Zaltoprofen (rINN) monly. Creatine kinase may be elevated, and monitoring of
Belg.: Bextra†; Braz.: Bextra†; Canad.: Bextra†; Chile: Bextra†; Cz.: CN-100; Zaltoprofène; Zaltoprofeno; Zaltoprofenum; ZC-102. blood concentrations is recommended, but clinical myopathy or
Bextra†; Fin.: Bextra†; Fr.: Bextra†; Ger.: Bextra†; Gr.: Bextra†; Hong rhabdomyolysis is uncommon. Ziconotide may cause or exacer-
Kong: Bextra†; India: Bioval†; Valdiff†; Valdixx†; Valdone†; Valus†; Vorth†; (±)-10,11-Dihydro-α-methyl-10-oxodibenzo[b,f]thiepin-2-acetic
Indon.: Bextra†; Irl.: Bextra†; Malaysia: Bextra†; Neth.: Kudeq†; Norw.: acid. bate depression. Patients with a history of psychosis should not
Bextra†; NZ: Bextra†; Port.: Bextra†; S.Afr.: Bextra†; Singapore: Bex- be treated with ziconotide.
Зальтопрофен
tra†; Swed.: Bextra†; Switz.: Bextra†; Thai.: Bextra†; UK: Bextra†; USA:
Bextra†; Venez.: Bextra†. C 17 H 14 O 3 S = 298.4. ◊ References.
Multi-ingredient: India: Valus Insta†; Valus-XT†; Vectra-P†; Vorth Insta†;
C AS — 89482-00-8. 1. Penn RD, Paice JA. Adverse effects associated with the intrath-
Vorth-XT†. ecal administration of ziconotide. Pain 2000; 85: 291–6.
Uses and Administration
O Ziconotide is a synthetic form of a peptide derived from the ven-
Vedaprofen (BAN, USAN, rINN) om of the cone shell Conus magus (a sea snail). It is reported to
O be a neurone-specific calcium-channel blocker. Ziconotide is
CERM-10202; PM-150; Vedaprofeeni; Védaprofène; Vedapro-
OH given as a continuous intrathecal infusion in the management of
feno; Vedaprofenum. (±)-4-Cyclohexyl-α-methyl-1-naphthalene- severe chronic pain in patients who are intolerant of or refractory
acetic acid. S to more conventional treatments (see Choice of Analgesic, p.2).
Ведапрофен CH3 Ziconotide is given intrathecally as the acetate; doses may be
C 19 H 22O 2 = 282.4. expressed in terms of the base or the acetate. In the EU, the initial
C AS — 71109-09-6. dose (expressed in terms of the base) is 2.4 micrograms daily ad-
ATC Vet — QM01AE90. Pharmacopoeias. In Jpn.
justed according to response, in increments of up to
Profile 2.4 micrograms, to a maximum daily dose of 21.6 micrograms.
Zaltoprofen is an NSAID (p.96) that has been given in an oral Licensed product information recommends that the interval be-
dose of 80 mg three times daily for pain and musculoskeletal and tween dose increases is at least 2 days. In the USA, the initial
HO joint disorders. dose (expressed in terms of the acetate) should be no more than
O ◊ References. 2.4 micrograms daily, adjusted according to response. Dose in-
1. Ishizaki T, et al. Pharmacokinetic profile of a new nonsteroidal creases of up to 2.4 micrograms two or three times a week are
anti-inflammatory agent, CN-100, in humans. Drug Invest 1991; permitted, over a period of at least 3 weeks, up to a maximum
3: 1–7. daily dose of 19.2 micrograms.
CH3 2. Hatori M, Kokubun S. The long-term efficacy and tolerability of
the new anti-inflammatory agent zaltoprofen in rheumatoid ar- Ziconotide has been tried in other conditions such as head trau-
thritis. Curr Med Res Opin 1998; 14: 79–87. ma.
Profile 3. Hase K, et al. The effect of zaltoprofen on physiotherapy for lim-
Vedaprofen, a propionic acid derivative, is an NSAID used in ited shoulder movement in breast cancer patients: a single-blind- ◊ References.
veterinary medicine for the treatment of inflammation and pain. ed before-after trial. Arch Phys Med Rehabil 2006; 87: 1618–22. 1. Verweij BH, et al. Mitochondrial dysfunction after experimental
and human brain injury and its possible reversal with a selective
Preparations N-type calcium channel antagonist (SNX-111). Neurol Res 1997;
Proprietary Preparations (details are given in Part 3) 19: 334–9.
Viminol Hydroxybenzoate (rINNM) Mex.: Soleton. 2. Jain KK. An evaluation of intrathecal ziconotide for the treat-
ment of chronic pain. Expert Opin Invest Drugs 2000; 9:
Diviminol Hydroxybenzoate; Hidroxibenzoato de viminol; Vimi- 2403–10.
nol, Hydroxybenzoate de; Viminoli Hydroxybenzoas; Z-424 3. Wermeling D, et al. Pharmacokinetics and pharmacodynamics of
(viminol). 1-[1-(2-Chlorobenzyl)pyrrol-2-yl]-2-(di-sec-butyl)ami- Ziconotide (USAN, rINN) intrathecal ziconotide in chronic pain patients. J Clin Pharmacol
noethanol 4-hydroxybenzoate. CI-1009; ω-Conotoxin M VIIA; SNX-111; Ziconotida; Ziconoti- 2003; 43: 624–36.
dum. L-Cysteinyl-L-lysylglycyl-L-lysylglycl-L-alanyl-L-lysyl-L-cystei- 4. Staats PS, et al. Intrathecal ziconotide in the treatment of refrac-
Виминола Гидроксибензоат tory pain in patients with cancer or AIDS: a randomized control-
C 21 H 31ClN 2 O,C 7 H 6 O 3 = 501.1. nyl-L-seryl-L-arginyl-L-leucyl-L-methionyl-L-tyrosyl-L-α-aspartyl-L- led trial. JAMA 2004; 291: 63–70.
C AS — 21363-18-8 (viminol); 21466-60-4 (viminol hy- cysteinyl-L-cysteinyl-L-threonylglycyl-L-seryl-L-cysteinyl-L-arginyl-L- 5. Wermeling DP. Ziconotide, an intrathecally administered N-type
droxybenzoate); 23784-10-3 (viminol hydroxybenzoate). serylglycyl-L-lysyl-L-cysteinamide cyclic(1→16),(8→20),(15→25)- calcium channel antagonist for the treatment of chronic pain.
ATC — N02BG05. tris(disulfide). Pharmacotherapy 2005; 25: 1084–94.
ATC Vet — QN02BG05. 6. Rauck RL, et al. A randomized, double-blind, placebo-control-
Зиконотид led study of intrathecal ziconotide in adults with severe chronic
C 102 H 172N 36 O 32S 7 = 2639.1. pain. J Pain Symptom Manage 2006; 31: 393–406.
C AS — 107452-89-1. 7. Lynch SS, et al. Intrathecal ziconotide for refractory chronic
ATC — N02BG08. pain. Ann Pharmacother 2006; 40: 1293–1300.
H 3C CH3 ATC Vet — QN02BG08. 8. Wermeling DP, Berger JR. Ziconotide infusion for severe chron-
CH3 ic pain: case series of patients with neuropathic pain. Pharmaco-
N Ziconotide Acetate (rINNM) therapy 2006; 26: 395–402.
9. Lyseng-Williamson KA, Perry C. Ziconotide. CNS Drugs 2006;
Cl N Acetato de ziconotida; Ziconotide, Acétate de; Ziconotidi Ace- 20: 331–8.
CH3 tas.
Preparations
OH Зиконотида Ацетат
Proprietary Preparations (details are given in Part 3)
C 102 H 172N 36 O 32S 7 , C 2 H 4 O 2 = 2699.2.
Cz.: Prialt; Fr.: Prialt; Neth.: Prialt; Port.: Prialt; UK: Prialt; USA: Prialt.
(viminol) ATC — N02BG08.
ATC Vet — QN02BG08.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
Anthelmintics
Ancylostomiasis, p.134 The nematode infections can be divided into filarial in- Trematode (or fluke) infections are caused by parasit-
Angiostrongyliasis, p.134 fections, intestinal infections, and tissue infections. ic worms of the class Trematoda. There are 4 catego-
Ascariasis, p.134
Capillariasis, p.135 Filarial nematodes are endemic in large areas of the ries of fluke which are pathogenic in man; the blood
Clonorchiasis, p.135 tropics and produce considerable morbidity. The adult flukes Schistosoma spp., the intestinal flukes Fasciol-
Cutaneous larva migrans, p.135 opsis, Heterophyes, Metagonimus, and Nanophyetus
Cysticercosis, p.135 worms may live for several years, releasing large num-
Diphyllobothriasis, p.136 bers of motile embryos known as microfilariae into the spp., the liver flukes Clonorchis, Fasciola, and
Dracunculiasis, p.136 blood or skin, depending on the species. Transmission Opisthorchis spp., and the lung flukes Paragonimus
Echinococcosis, p.136 spp. Symptoms are usually only seen in heavy infec-
Enterobiasis, p.136 is usually by biting insects, which form the intermedi-
Fascioliasis, p.136 ate host. In some endemic areas multiple infections tions and commonly include fever, pain, and eosin-
Fasciolopsiasis, p.136 with filarial nematodes are common. ophilia.
Gnathostomiasis, p.136
Heterophyiasis, p.136 Filarial nematode infections include: Trematode infections include:
Hookworm infections, p.136 • loiasis • intestinal fluke infections
Hymenolepiasis, p.136 • lymphatic filariasis
Intestinal fluke infections, p.136 • liver fluke infections
Liver fluke infections, p.137 • mansonella infections
Loiasis, p.137
• lung fluke infections
• onchocerciasis.
Lung fluke infections, p.137 • schistosomiasis.
Lymphatic filariasis, p.137 Intestinal nematode infections (roundworms) are very
Mansonella infections, p.137 common especially in developing countries in the trop-
Metagonimiasis, p.137 ics and subtropics. Children are particularly at risk and Ancylostomiasis
Nanophyetiasis, p.137 See under Hookworm Infections, below. Larvae of Ancy-
Necatoriasis, p.137 these infections contribute to morbidity through mal-
Onchocerciasis, p.137 nutrition, vitamin deficiencies, diarrhoea, anaemia, and lostoma spp. are also a cause of cutaneous larva migrans
Opisthorchiasis, p.138 pneumonia. Poor sanitation and sewage disposal per- (see below).
Paragonimiasis, p.138
Schistosomiasis, p.138
petuate infections with soil-borne nematodes. Often
Strongyloidiasis, p.138 several different worm infections are endemic in the Angiostrongyliasis
Syngamosis, p.138 same region, resulting in mixed infections. When this Two forms of angiostrongyliasis are recognised and both
Taeniasis, p.139 occurs, broad-spectrum anthelmintics may be used to are due to accidental infection with species of the animal
Toxocariasis, p.139
Trichinosis, p.139 reduce the overall infection burden in the population nematode Angiostrongylus.
Trichostrongyliasis, p.139 (see under Ascariasis, below). Infection with the larvae of the rat lungworm A. cantonen-
Trichuriasis, p.139 sis causes an eosinophilic meningoencephalitis. Transmis-
Intestinal nematode infections include:
• angiostrongyliasis sion follows ingestion of raw or undercooked snails or
This chapter describes the important helminth or worm crustaceans, or of contaminated vegetables. The disease is
infections that occur in man (see Table 1, p.135) and • ascariasis
generally self-limiting.
the anthelmintics used to treat them. • capillariasis
• enterobiasis Intestinal infection with A. costaricensis can cause eosin-
ophilic gastro-enteritis. It most commonly occurs in chil-
Choice of Anthelmintic • hookworm infections dren after ingestion of vegetables contaminated by infect-
Helminth infections are among the most common in- • strongyloidiasis ed slugs. Surgical resection of the affected bowel may be
fections in man, affecting a large proportion of the • trichostrongyliasis necessary. Mebendazole and albendazole have been tried
world’s population, mainly in tropical regions. In de- • trichuriasis. in the management of both these infections. However, an-
veloping countries they pose a large threat to public The tissue nematodes represent a miscellaneous group thelmintic drugs have not been shown to be effective and
health, and contribute to the prevalence of malnutri- causing a variety of pathological conditions in man. In in A. cantonensis infection, severe host reaction to the
cutaneous larva migrans and toxocariasis, the nema- dying larvae may result. Most patients will in fact have a
tion, anaemia, eosinophilia, and pneumonia. Helminth self-limited course and recover completely. Symptomatic
infections causing severe morbidity include lymphatic todes have a primary animal host and the human dis-
treatment with analgesics, corticosteroids, and removal of
filariasis (a cause of elephantiasis), onchocerciasis (riv- ease is caused by infection with infective larvae which CSF may relieve pressure in A. cantonensis meningitis.1
er blindness), and schistosomiasis. These infections do not subsequently mature in man. Trichinosis and 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
can affect the majority of populations in endemic areas gnathostomiasis affect a number of carnivorous ani- Rochelle NY: The Medical Letter, 2007.
with major economic and social consequences. WHO mals and man is an incidental host. Syngamosis is pri-
is making strenuous efforts to control a number of marily an infection of domestic fowl and wild birds al-
Ascariasis
these infections in endemic areas. Control of these in- though infection in man has been reported rarely. In Ascariasis is an infection caused by Ascaris lumbricoides,
fections in both individuals and populations depends dracunculiasis, man is the primary (definitive) host. the common or giant roundworm. The term roundworm is
not only on the use of chemotherapeutic agents but also Although these diseases are not generally fatal they also applied to nematodes in general. It is usually an infec-
on preventing transmission by advice on food prepara- cause a considerable degree of morbidity and treatment tion of the small intestine but on rare occasions there may
tion and hygiene, the provision of adequate sanitation is complicated by the lack of effective, non-toxic sys- be severe ectopic infections. It is commonly found in the
and sewage treatment (especially where sewage is used temic anthelmintics. tropics and especially in rural areas. Eggs are excreted in
as fertiliser), the provision of safe potable water sup- Tissue nematode infections include: the faeces and can remain viable in moist soil for several
years. On ingestion of mature eggs the larvae hatch and
plies, and effective vector control. • angiostrongyliasis
penetrate the intestinal wall. They migrate in the blood-
The worms that cause infection in man generally fall • cutaneous larva migrans stream via the liver to the lungs where they enter the alve-
either into the phylum Nematoda, which includes the • dracunculiasis oli. The larvae then move up the bronchial tree and are
nematodes or roundworms, or into the phylum Platy- • gnathostomiasis swallowed. The mature adult develops in the intestines,
helminthes, which includes the cestodes or tapeworms • syngamosis and it has been estimated that a gravid female is produced
and the trematodes or flukes. • toxocariasis about 2 months after infection. The life span of the adult
• trichinosis. worm is 1 to 2 years. Ascariasis may be asymptomatic.
The nematodes (or roundworms) are a large group of When symptoms of intestinal infection do occur they in-
worms, some of which are capable of producing infec- The cestodes (flatworms, segmented worms, or tape- clude anorexia, abdominal pain, and diarrhoea; nutritional
tions in man. In many cases man is the primary (defin- worms) cause infection in man in most parts of the deficiency may result. The pulmonary stage may cause
itive) host but human infections caused by parasites for world. Man may be the primary host, harbouring the pneumonitis and bronchospasm often accompanied by
which animals are the primary hosts also occur. Nem- adult worm in the intestine, or an intermediate host eosinophilia. Heavy infections can cause intestinal or bil-
atodes do not generally multiply in man; strongyloidia- carrying the larval form. With the exception of Hyme- iary obstruction. Migration of the worm from the small in-
sis is an exception as re-infection can occur without en- nolepis nana the adult worms do not usually multiply testine can produce ectopic infection of the genito-urinary
vironmental re-exposure. Nematode infections are within the same host. However, larval forms may be tract, lungs, liver, or heart. Such infections are rare but
produced and, as with infection or ingestion of these serious.
most common in warm, moist climates, but some spe-
cies of nematode can tolerate cool or arid conditions forms, systemic infection may develop. Treatment is with a benzimidazole carbamate derivative
and infective forms can persist in the environment for Cestode infections include: such as albendazole or mebendazole1-3 with both drugs be-
ing equally highly effective. Pyrantel embonate3 and le-
long periods. An understanding of the life cycle of the • cysticercosis
vamisole are alternatives, while the potential of nitazoxa-
infective species is necessary for diagnostic tests to be • diphyllobothriasis nide for the treatment of ascariasis is being investigated.1
made at appropriate times, usually to coincide with the • echinococcosis Ivermectin has also been used.2 Such broad-spectrum ther-
infective stage of the cycle, and for the choice of appro- • hymenolepiasis apy can be useful if the patient is suffering from a mixed
priate control measures. • taeniasis. intestinal nematode infection. Drugs such as tiabendazole
134
 Anthelmintics 135
Cysticercosis
Table 1. Helminths: classification and diseases. Infection with the pork tapeworm, Taenia solium may re-
sult in taeniasis (intestinal infection with adult tape-
Group Helminth Common Name Clinical infection worms—see below) or cysticercosis (tissue infection with
larval forms). Cysticercosis may develop after ingestion of
Nematodes Brugia malayi lymphatic filariasis (Malayan, brugian) T. solium eggs in food or water contaminated with infected
(filarial) Brugia timori lymphatic filariasis (Timorian, brugian) human faecal material, or as a result of auto-infection in
Loa loa eye-worm loiasis intestinal carriers of adult tapeworms. Ingested eggs re-
Mansonella spp. Mansonella infections lease larvae that may penetrate the intestinal wall to be car-
ried via the bloodstream to skeletal muscles, heart, eyes,
Onchocerca volvulus onchocerciasis (river blindness)
brain, and spinal cord where they form encapsulated cysts
Wuchereria bancrofti lymphatic filariasis (bancroftian) (cysticerci). Human cysticercosis is associated with pover-
ty and endemic in areas where hygiene is poor and sanita-
Nematodes Ancylostoma duodenale Old World hookworm ancylostomiasis tion inadequate.
(intestinal) Angiostrongylus costaricensis angiostrongyliasis
Infection is typically subclinical, but symptoms may de-
Ascaris lumbricoides* common roundworm, ascariasis velop when the encysted larvae die and elicit an inflamma-
giant roundworm tory reaction. Clinical features depend on the number, size,
Capillaria philippinensis capillariasis location, and stage of development of the cysticerci, as
Enterobius vermicularis* threadworm, pinworm enterobiasis well as on the host’s immune response. Cysts in the CNS
Necator americanus New World hookworm necatoriasis (neurocysticercosis) may result in seizures and head-
Strongyloides stercoralis sometimes called strongyloidiasis aches, and are a common cause of epilepsy in endemic ar-
threadworm in USA eas. Other symptoms include confusion, attention deficit,
Trichostrongylus spp. trichostrongyliasis and ataxia. Hydrocephalus and intracranial hypertension
Trichuris trichiura* whipworm trichuriasis
may result from obstruction of CSF flow. Cysts in the spi-
nal cord, eyes, or heart may also cause serious morbidity.
Nematodes Ancylostoma spp. dog/cat hookworm cutaneous larva migrans (creeping eruption) Treatment of neurocysticercosis consists of managing
(tissue) Angiostrongylus cantonensis angiostrongyliasis seizures with antiepileptics. Antiepileptics can usually be
Dracunculus medinensis guinea-worm dracunculiasis (dracontiasis)
discontinued if patients have been seizure-free for more
than 2 years.1
Gnathostoma spinigerum gnathostomiasis
Syngamus spp. gapeworm syngamosis The use of anthelmintics in the treatment of neurocysticer-
cosis remains controversial.1-3 Live cysticerci usually do
Toxocara spp.* toxocariasis (visceral larva migrans, ocular
not provoke seizures whereas dead or dying parasites can
larva migrans) elicit an inflammatory response, seizures, and transient
Trichinella spiralis* trichinosis (trichinellosis) neurological effects, hence treatment does not necessarily
reduce seizure frequency. Patients with viable or degener-
Cestodes Diphyllobothrium latum broad fish tapeworm diphyllobothriasis ating parenchymal cysts and those with extraparenchymal
(tapeworms) Echinococcus spp. echinococcosis (hydatid disease) cysts (such as subarachnoid cysts, including giant cysts
Hymenolepis nana dwarf tapeworm hymenolepiasis and racemose forms) may benefit from anthelmintics.1,3,4
Taenia saginata* beef tapeworm taeniasis Anthelmintics are of little or no benefit in patients with in-
Taenia solium* pork tapeworm cysticercosis (larval form), taeniasis (adult active, calcified lesions, and are contra-indicated in pa-
worm) tients with cysticercotic encephalitis as they may exacer-
bate intracranial hypertension.1,2 A double-blind, placebo-
Trematodes Clonorchis sinensis Chinese liver fluke clonorchiasis controlled study in patients with seizures due to viable pa-
renchymal cysts confirmed that albendazole therapy (with
(flukes) Fasciola hepatica liver fluke fascioliasis
dexamethasone) was safe and decreased the burden of par-
Fasciolopsis buski intestinal fluke fasciolopsiasis asites and the number of generalised seizures.5 Albenda-
Heterophyes heterophyes intestinal fluke heterophyiasis zole is now considered to be the drug of choice, but prazi-
Metagonimus yokogawi intestinal fluke metagonimiasis quantel may also be used.1,4,6 Adjunctive corticosteroids
Nanophyetus salmincola intestinal fluke nanophyetiasis are recommended for parenchymal infections if there are
Opisthorchis spp. liver fluke opisthorchiasis numerous cysts, or if neurological symptoms or intracrani-
Paragonimus spp. oriental lung fluke paragonimiasis al hypertension develops after starting treatment. Patients
Schistosoma spp. blood fluke schistosomiasis with subarachnoid cysticercosis should also be given ad-
junctive corticosteroids. However, use of corticosteroids
with praziquantel may be complicated by a pharmacoki-
NOTE: Infections due to worms marked with an asterisk may occur in temperate climates. Infections due to other worms are
netic interaction— see Corticosteroids, under Interactions
generally limited to tropical or localised areas, but may occur in travellers who have visited those areas. of Praziquantel p.154 for further details. If hydrocephalus
is present, surgical removal of cysts or ventricular shunting
may be indicated.1 Detailed consensus guidelines for the
with little or no activity against Ascaris should be avoided Clonorchiasis treatment of neurocysticercosis have been developed.2
for the initial treatment of mixed infections since they may See under Liver Fluke Infections, below.
stimulate the worm to migrate to a different body site. Prevention of infection with T. solium is possible by
Mass treatment programmes may be necessary in endemic avoiding ingestion of undercooked pork and food and wa-
areas to reduce the overall burden of disease.1 Cutaneous larva migrans ter contaminated with human faeces. Ideally, prevention
Cutaneous larva migrans (creeping eruption) occurs when measures should include adequate sanitation, sewage
1. Bethony J, et al. Soil-transmitted helminth infections: ascariasis, man becomes infected with the larvae of animal hook- treatment, and abattoir inspection. Those already infected
trichuriasis, and hookworm. Lancet 2006; 367: 1521–32.
worms, usually Ancylostoma braziliense or A. caninum, with T.solium and their close contacts should be treated
2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New hookworms of cats and dogs. Other hookworms may also
Rochelle NY: The Medical Letter, 2007.
with anthelmintics in order to interrupt or reduce the cycle
be involved or may cause other infections (see Hookworm of direct person-to-person transmission. Universal or se-
3. Keiser J, Utzinger J. Efficacy of current drugs against soil-trans-
mitted helminth infections: systematic review and meta-analysis.
Infections, below). The larvae penetrate the skin and then lected treatment of human taeniasis with praziquantel has
JAMA 2008; 299: 1937–48. migrate causing characteristic trails in the skin. This mi- significantly reduced the prevalence in areas where T. so-
gration can persist for several months and can be a source lium infection is endemic.3,7
of intense pruritus. Occasionally larvae migrate to the 1. Takayanagui OM. Therapy for neurocysticercosis. Expert Rev
Capillariasis lungs causing eosinophilia and pulmonary symptoms. Al- Neurother 2004; 4: 129–39.
Capillariasis is caused by infection with Capillaria philip- bendazole or ivermectin may be given by mouth and may 2. García HH, et al. Current consensus guidelines for treatment of
pinensis, a nematode endemic in the Philippines and be better tolerated than oral tiabendazole; tiabendazole can neurocysticercosis. Clin Microbiol Rev 2002; 15: 747–56. Also
available at: http://cmr.asm.org/cgi/reprint/15/4/747.pdf (ac-
southern Thailand. Infection in man is through eating raw also be applied topically but is of limited value for multiple cessed 09/08/07)
or undercooked freshwater fish containing infective lar- lesions. 3. García HH, et al. Taenia solium cysticercosis. Lancet 2003; 362:
vae. The larvae mature in the intestines and the adults pro- Infection with Gnathostoma spinigerum or Strongyloides 547–56.
duce both eggs and infective larvae so that auto-infection stercoralis can also cause cutaneous larva migrans (see 4. Del Brutto OH, et al. Meta-analysis: cysticidal drugs for neuro-
occurs and heavy infections can result. Symptoms are cysticercosis— albendazole and praziquantel. Ann Intern Med
Gnathostomiasis and Strongyloidiasis, below). Ocular and 2006; 145: 43–51.
mostly gastrointestinal, with abdominal pain, vomiting, visceral larva migrans are features of toxocariasis (see be- 5. Garcia HH, et al. A trial of antiparasitic treatment to reduce the
and severe prolonged diarrhoea leading to cachexia and low). rate of seizures due to cerebral cysticercosis. N Engl J Med 2004;
muscle wasting. The infection has a mortality rate of be- 350: 249–58.
tween 20 and 30% if untreated. Prolonged treatment with References. 6. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
mebendazole or, alternatively, albendazole, is necessary.1 1. Caumes E. Treatment of cutaneous larva migrans. Clin Infect Dis Rochelle NY: The Medical Letter, 2007.
2000; 30: 811–14. 7. WHO. Control of neurocysticercosis. Geneva: WHO, 2003. Also
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New 2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New available at: http://www.who.int/gb/ebwha/pdf_files/WHA56/
Rochelle NY: The Medical Letter, 2007. Rochelle NY: The Medical Letter, 2007. ea5610.pdf (accessed 09/08/07)

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
136 Anthelmintics
Diphyllobothriasis of the cyst contents. Concomitant chemotherapy is recom- Hookworm infections
Diphyllobothriasis is an intestinal infection with the fish mended. Infections with the hookworms Ancylostoma duodenale
tapeworm Diphyllobothrium latum and other Diphyllo- E. multilocularis infection (alveolar echinococcosis) is (ancylostomiasis) and Necator americanus (necatoriasis)
bothrium spp. and is acquired in man through ingestion of more invasive and is characterised by a tumour-like infil- are a major cause of iron-deficiency anaemia in large areas
raw, infected, freshwater fish. The infection is rarely trative growth; it usually requires both surgery and long- of the tropics and sub-tropics, especially in rural commu-
symptomatic. However, because the adult worm competes term treatment with a benzimidazole, such as albendazole, nities. Eggs deposited in warm moist soil hatch into larvae
for vitamin B12, some patients may develop megaloblastic although some patients have improved on albendazole which develop further into the infective form. Infection is
anaemia with its associated neurological symptoms. Con- alone. normally by penetration through the skin although it may
centrations of other vitamins may also be reduced. Treat- be by ingestion. The larvae migrate to the lungs and are
References.
ment is with a single dose of praziquantel; niclosamide is subsequently swallowed and mature to the adult form in
1. Kumar A, Chattopadhyay TK. Management of hydatid disease
an alternative.1 Vitamin supplements should also be given of the liver. Postgrad Med J 1992; 68: 853–6. the small intestine. Eggs appear in the faeces about 6 to 8
to correct any deficiencies. 2. Wen H, et al. Diagnosis and treatment of human hydatidosis. Br weeks after infection and the adult worm may live for sev-
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New J Clin Pharmacol 1993; 35: 565–74. eral years. A. duodenale larvae are capable of remaining
Rochelle NY: The Medical Letter, 2007. 3. WHO Informal Working Group on Echinococcosis. Guidelines dormant in the tissues, only maturing to the adult when cli-
for treatment of cystic and alveolar echinococcosis in humans. matic conditions are favourable. Symptoms correspond to
Bull WHO 1996; 74: 231–42.
4. Reuter S, et al. Benzimidazoles in the treatment of alveolar echi- the stage of infection. Visitors to endemic areas may devel-
Dracunculiasis nococcosis: a comparative study and review of the literature. J op intense pruritus, erythema, and papulovesicular erup-
Dracunculiasis (dracontiasis, guinea-worm infection) is Antimicrob Chemother 2000; 46: 451–6. tion at the site of infection, known as ground itch. Migra-
caused by infection with the nematode Dracunculus med- 5. Mcmanus DP, et al. Echinococcosis. Lancet 2003; 362: tion through the lungs during the first infection may cause
inensis. It has been endemic in parts of Africa and Asia but 1295–1304.
6. Smego RA, et al. Percutaneous aspiration-injection-reaspiration
pneumonitis and bronchospasm with accompanying eosin-
is increasingly coming under control and the hope is that it ophilia. The main symptoms of intestinal infection are
drainage plus albendazole or mebendazole for hepatic cystic
will soon be eradicated.1 The disease is transmitted echinococcosis: a meta-analysis. Clin Infect Dis 2003; 37: iron-deficiency anaemia and severe hypoalbuminaemia.
through drinking water containing larvae that develop in 1073–83. In addition, abdominal pain, diarrhoea, and weight loss
freshwater crustaceans. The larvae penetrate the intestinal 7. Smego RA, Sebanego P. Treatment options for hepatic cystic may occur.
mucosa and mature in connective tissue. The adult female echinococcosis. Int J Infect Dis 2005; 9: 69–76.
8. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New Treatment is usually with a benzimidazole carbamate de-
migrates to the subcutaneous tissues, normally of the legs, Rochelle NY: The Medical Letter, 2007. rivative such as mebendazole or albendazole,1-3 and such
after about 1 year. Ulceration of the overlying skin releases
broad-spectrum therapy can also be useful if the patient
larvae which are ingested by the crustacean host to com-
Enterobiasis has a mixed intestinal nematode infection. Albendazole
plete the life cycle. The first symptom is the lesion caused
Enterobiasis is an infection with Enterobius vermicularis may be more effective than mebendazole.4 Other an-
by the emerging worm, although a generalised hypersensi-
(pinworm, threadworm). It is one of the few intestinal thelmintics used in hookworm infections include levami-
tivity reaction may also occur. Secondary infection is a
nematodes which is common in temperate climates and is sole or pyrantel embonate,2-4 but these may be less effec-
common complication.
particularly common in young children. Like trichuriasis it tive against N. americanus than against A. duodenale.
The most effective method of controlling dracunculiasis is Iron-deficiency anaemia caused by hookworm infections
is an infection of the large intestine and transmission fol-
by provision of safe drinking water. The WHO eradication responds rapidly to oral iron therapy; folic acid supple-
lows ingestion or inhalation of mature eggs. The larvae
campaign is based on health education, and the provision ments may be necessary in some patients. Mass treatment
mature in the gut in about 2 months. The eggs are not re-
of safe water by measures including water treatment with programmes may be necessary in endemic areas to reduce
leased into the gut contents but the mature female migrates
pesticides such as temefos and encouraging the use of
to the anus at night and lays its eggs on the perianal and the overall burden of infection.2,5
domestic filters. 1. Hotez PJ, et al. Hookworm infection. N Engl J Med 2004; 351:
perineal skin. The eggs become infective within 6 hours.
799–807.
There is no effective direct drug therapy against any stage Diagnosis is based on detecting eggs around the anus. The 2. Bethony J, et al. Soil-transmitted helminth infections: ascariasis,
in man. The traditional treatment is removal of the adult most common symptom is perianal itching but many in- trichuriasis, and hookworm. Lancet 2006; 367: 1521–32.
worm by gentle traction sometimes over several weeks. fections are asymptomatic. Rarely ectopic disease such as 3. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
Metronidazole or tiabendazole may provide symptomatic appendicitis or salpingitis may occur. The adult worm has Rochelle NY: The Medical Letter, 2007.
benefit in the management of dracunculiasis although they a life span of about 6 weeks and, if re-infection can be pre- 4. Keiser J, Utzinger J. Efficacy of current drugs against soil-trans-
mitted helminth infections: systematic review and meta-analy-
have no direct anthelmintic effect. They are thought to act vented, the infection is self-limiting. While additional hy- sis. JAMA 2008; 299: 1937–48.
by weakening the anchorage of the worms within the sub- giene measures can prevent re-infection, treatment of the 5. Idris MA, et al. Effective control of hookworm infection in
cutaneous tissues, thus allowing them to be removed more whole family with an anthelmintic should remain the main school children from Dhofar, Sultanate of Oman: a four-year ex-
quickly. perience with albendazole mass chemotherapy. Acta Trop 2001;
therapeutic response; more than one course may be re- 80: 139–43.
1. WHO. Dracunculiasis eradication. Available at: http:// quired.
www.who.int/dracunculiasis/en/ (accessed 16/07/08) Treatment is with a benzimidazole carbamate derivative,
such as albendazole or mebendazole, or with pyrantel em- Hymenolepiasis
bonate.1 Such broad-spectrum therapy can be useful if the Hymenolepiasis is an infection of the intestine with Hyme-
Echinococcosis nolepis nana, or dwarf tapeworm. Infection is acquired
Echinococcosis, or hydatid disease, in man is infection patient is suffering from a mixed intestinal nematode in-
fection. Other anthelmintics used in enterobiasis include through ingestion of eggs in contaminated food or water or
with the larval stage of the cestode Echinococcus granulo- on hands and can be passed directly from person to person.
sus or E. multilocularis. These two species cause distinct piperazine or pyrvinium embonate.
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
It is more common in children. Clinical symptoms occur
forms of the disease known as cystic echinococcosis and Rochelle NY: The Medical Letter, 2007. in heavy infections and include diarrhoea and abdominal
alveolar echinococcosis respectively. Various animals are pain. Treatment is with a single dose of praziquantel. Nita-
involved in the transmission of the disease, man becoming zoxanide may be used as an alternative.1
infected through ingestion of eggs from contaminated fae- Fascioliasis 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
ces. The eggs hatch in the intestine and the embryos pene- See under Liver Fluke Infections, below. Rochelle NY: The Medical Letter, 2007.
trate the intestinal wall and invade body organs, usually the
liver. The embryo develops into a cyst which slowly in-
creases in size and may remain intact for many years. Fasciolopsiasis Intestinal fluke infections
Symptomatic infection usually only occurs when the cyst See under Intestinal Fluke Infections, below. The intestinal fluke infections fasciolopsiasis, hetero-
is large enough to cause obstruction or to compress adja- phyiasis, metagonimiasis, and nanophyetiasis are
cent structures, or if rupture occurs. Where possible, surgi- caused by Fasciolopsis buski, Heterophyes heterophyes
Gnathostomiasis and some other Heterophyes spp., Metagonimus yokoga-
cal removal of the intact cyst is the first line of treatment. Gnathostomiasis is an infection with, in most cases, the wai, and Nanophyetus salmincola respectively. Fasciolop-
In cystic echinococcosis, drugs may be given locally or larval form of the nematode Gnathostoma spinigerum, al- siasis, heterophyiasis, and metagonimiasis are endemic in
systemically before surgery to kill infective larvae within though other Gnathostoma spp. have been identified. G. the Far East and Southeast Asia, and heterophyiasis is also
the cyst and reduce the risk of further infection. They are spinigerum inhabits the stomach of cats and dogs. Eggs common in the Middle East. Nanophyetiasis has occurred
also given postoperatively if a cyst ruptures during sur- shed in their faeces are ingested by freshwater crustaceans increasingly in the Pacific Northwest of the USA. Fasciol-
gery. Local injection of a larvicidal agent such as alcohol, and hatch into larvae which are ingested by fish or other opsiasis is caused by the ingestion of infected aquatic
cetrimide, or hypertonic saline has been used. Chemother- animals; man acquires the infection by consumption of the plants, while undercooked or raw infected fish are the
apy is also used as an adjunct or when surgery is not pos- raw or undercooked flesh of these secondary hosts. Once sources of H. heterophyes, M. yokogawai, and N. salmin-
sible. The preferred drug for associated systemic treatment ingested the larva penetrates the gut wall and migrates via cola infections.
is albendazole. Mebendazole may be used, although some the liver to other tissues including skin, eyes, and CNS.
Rarely, dermal infiltration may result in cutaneous larva Fasciolopsiasis is usually asymptomatic, but heavy infec-
have suggested it is not as effective as albendazole. Prazi- tions can cause diarrhoea, abdominal pain, and, rarely, in-
quantel has also been reported to be effective. Albendazole migrans (above).
testinal obstruction and an allergic oedematous reaction.
may be a suitable alternative to surgery as initial treatment The preferred treatment of gnathostomiasis is surgical re- Metagonimiasis is also generally asymptomatic but may
in uncomplicated cases; use with cimetidine (to inhibit its moval of the gnathostome but this is rarely possible. Al- cause mild diarrhoea, while pain and mucous diarrhoea are
metabolism) may increase its effectiveness. bendazole or, alternatively, ivermectin, may be used.1 common in heterophyiasis. Similar gastrointestinal symp-
A further option when surgery is not possible is the PAIR 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New toms plus eosinophilia occur in nanophyetiasis. Eggs of M.
Rochelle NY: The Medical Letter, 2007.
(puncture/aspiration/injection/re-aspiration) procedure yokogawai and H. heterophyes may rarely penetrate the
which consists of ultrasound-guided cyst puncture fol- bowel wall and enter the bloodstream to be deposited in
lowed by aspiration of the cyst fluid, local injection of al- Heterophyiasis various organs, leading to serious complications such as
cohol or hypertonic saline into the cyst, and re-aspiration See under Intestinal Fluke Infections, below. heart failure or fatal embolism in the heart or brain.
 Anthelmintics 137
Treatment of intestinal fluke infections is with praziquan- Lung fluke infections poorly vascularised tissues and therefore rigorous hygiene,
tel.1,2 The lung fluke infection paragonimiasis is caused by skin care, physiotherapy, and other measures to promote
1. WHO. Control of foodborne trematode infections. WHO Tech Paragonimus spp., commonly P. westermani, and occurs lymph flow in the affected areas are recommended; in
Rep Ser 849 1995. Available at: http://libdoc.who.int/trs/ in Asia, Africa, and Central or South America. The disease some cases antibiotics are needed. Large hydroceles and
WHO_TRS_849_(part1).pdf and http://libdoc.who.int/trs/ is transmitted by the ingestion of raw infected freshwater scrotal elephantiasis are generally not reversible with drug
WHO_TRS_849_(part2).pdf (accessed 16/07/08)
crabs or crayfish, or from drinking infected water. therapy and usually require surgical intervention after a
2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
Rochelle NY: The Medical Letter, 2007. The flukes mature in the lungs where they cause local treatment course with diethylcarbamazine.
necrosis, haemorrhage, inflammation, and fibrosis. Symp- Filaria have been shown to contain Wolbachia endobacte-
toms of paragonimiasis include fever, pain, and chest com- ria which are essential for larval development and adult
Liver fluke infections plaints, but most light to moderate infections are asympto- worm fertility and viability. This symbiotic dependency
Fasciola hepatica, Opisthorchis viverrini, O. felineus, and matic. The worms may also develop at other sites, has provided a new approach in the treatment of filariasis,
Clonorchis sinensis are liver flukes transmitted by the in- particularly the brain where they can cause epilepsy, and oral doxycycline for 8 weeks has resulted in a reduc-
gestion of infected aquatic plants, grasses or water (F. symptoms of cerebral tumours, or cerebral embolism, tion in adult worms and prolonged reduction in microfila-
hepatica), or raw or undercooked fish (Opisthorchis spp., which may be fatal. raemia.5
C. sinensis). Fascioliasis is primarily a disease of sheep Treatment is with praziquantel or bithionol.1 Triclabenda- Tropical pulmonary eosinophilia responds to a 3-week
and cattle and human infections may occur wherever these zole has been studied. course of diethylcarbamazine but patients may relapse and
animals are raised, whereas clonorchiasis and opisthorch- 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New require re-treatment. Filarial arthritis responds rapidly to
iasis are seen mainly in Southeast Asia and eastern Europe. Rochelle NY: The Medical Letter, 2007. treatment with diethylcarbamazine.
Fascioliasis in the acute phase is usually characterised by In communities where lymphatic filariasis is endemic
fever, gastrointestinal symptoms, pain due to liver enlarge- Lymphatic filariasis mass treatment of the entire community is the basis of the
ment, and marked eosinophilia, but these symptoms de- Lymphatic filariasis is a parasitic disease caused by filarial Global Programme to Eliminate Lymphatic Filariasis.2
cline as the worms enter their final habitat in the bile ducts. nematodes. The three species of filariae that cause lym- The primary goal is to eliminate microfilariae from the
Acute symptoms occur rarely with clonorchiasis and phatic filariasis are Wuchereria bancrofti (bancroftian blood of infected individuals thereby interrupting trans-
opisthorchiasis and infections tend to be asymptomatic for filariasis), Brugia malayi, and B. timori (brugian filariasis, mission. The programme recommends a single dose of 2
many years. Adult flukes live in the bile ducts and symp- also known as Malayan and Timorian filariasis respective- drugs (albendazole plus either diethylcarbamazine or iver-
toms of biliary-tract obstruction appear after repeated or ly). Adult worms produce larvae (microfilariae) which en- mectin) given once-yearly for 4 to 6 years.2,3 Albendazole
heavy infections with liver flukes. Cholangiocarcinoma ter the peripheral bloodstream and through mosquito vec- plus ivermectin is used in areas where onchocerciasis or
(bile-duct cancer) is now generally accepted to be associ- tors infective larvae may be transmitted from person to loiasis are also endemic. An alternative approach is the use
ated with liver fluke infection although its exact pathogen- person. The larvae migrate from the skin to the lymphatic of diethylcarbamazine-medicated salt for 6 to 12 months
esis is unclear. system where they mature into adult worms that may live throughout the community at risk.
Praziquantel is used for the treatment of most liver fluke for several years. Development of lymphatic filariasis re- Ongoing vector control should be carried out before or
infections.1,2 Bithionol is more effective than praziquantel quires multiple bites from infected mosquitoes over a pro- during peak transmission season, in order to consolidate
in fascioliasis and has been the preferred treatment, al- longed period of time (months to years); consequently, the effects of mass chemotherapy. People living in or vis-
though in the USA the CDC considers triclabendazole to people living in endemic areas are at greatest risk of devel- iting endemic areas are advised to sleep under a mosquito
be the treatment of choice; dehydroemetine has also been oping the disease. net and use mosquito repellent on exposed skin between
used, and nitazoxanide2 may be effective. Filarial infection is usually contracted in childhood and dusk and dawn.
most infections are initially asymptomatic, although near- 1. Cox FEG, et al. (eds). Topley and Wilson’s microbiology and mi-
Praziquantel remains the treatment of choice for clonorch- ly all those infected will have some degree of subclinical
crobial infections: parasitology. 10th ed. London: Hodder Ar-
iasis and opisthorchiasis.1,2 Albendazole is a suggested al- lymphatic and kidney damage. Infection may remain oc-
nold, 2005.
2. WHO. Eliminate filariasis: attack poverty—a green light from the
ternative for clonorchiasis.2 cult or species- and body-site-dependent symptoms may Global Alliance. Geneva: WHO, 2000. Also available at: http://
1. WHO. Control of foodborne trematode infections. WHO Tech whqlibdoc.who.int/hq/2000/WHO_CDS_CPE_CEE_2000.5.pdf
follow. Acute inflammatory reactions to immature and (accessed 03/08/07)
Rep Ser 849 1995. Available at: http://libdoc.who.int/trs/
WHO_TRS_849_(part1).pdf and http://libdoc.who.int/trs/ dead or dying adult worms in the lymphatic system are re- 3. Tisch DJ, et al. Mass chemotherapy options to control lymphatic
WHO_TRS_849_(part2).pdf (accessed 16/07/08) ferred to as adenolymphangitis, and are characterised by filariasis: a systematic review. Lancet Infect Dis 2005; 5:
episodic attacks of fever, malaise, and inflammation of the 514–23.
2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New 4. Critchley J, et al. International Filariasis Review Group. Alben-
Rochelle NY: The Medical Letter, 2007. inguinal lymph nodes, testis, and spermatic cord, and focal dazole for lymphatic filariasis. Available in The Cochrane Data-
lymphoedema. These acute episodes usually resolve spon- base of Systematic Reviews; Issue 4. Chichester: John Wiley;
taneously after about a week, but can recur several times a 2005 (accessed 02/10/06).
Loiasis year. Chronic filariasis may develop 10 to 15 years after
5. Taylor MJ, et al. Macrofilaricidal activity after doxycycline
Loiasis is an infection with the filarial nematode Loa loa treatment of Wuchereria bancrofti: a double-blind, randomised
initial symptoms and results from recurrent inflammation placebo-controlled trial. Lancet 2005; 365: 2116–21.
which occurs in areas of Central and West Africa. It is with subsequent damage to the lymphatic system, leading
transmitted by the biting tabanid fly Chrysops. The infec- to impaired lymph drainage and lymphoedema. Manifes-
tive larvae mature to adult worms which migrate through Mansonella infections
tations include mild to massive enlargement of the legs, Infections with the filarial nematodes Mansonella per-
subcutaneous tissues and occasionally the subconjunctiva. arms, breasts, or genitals (testicular hydrocele or swelling
Symptoms include pruritus, swelling, and pain, with occa- stans, M. ozzardi, and M. streptocerca are generally
of the vulva), chyluria, and elephantiasis (grossly swollen asymptomatic but symptoms including malaise, fever,
sional subcutaneous swellings, often on the arms or legs, limbs with thickened, hard, rough, and fissured skin).
that are characteristic of the disease. Passage of a worm joint pain, and meningeal symptoms have been described.
Lymphangitis may result from secondary bacterial infec- Infection is transmitted by biting midges and flies. Treat-
through the subconjunctiva produces intense conjunctivi- tions.
tis. Eosinophilia may be severe, especially in visitors from ment with diethylcarbamazine may be effective depending
non-endemic areas. Other complications include renal dis- Occult filariasis refers to filarial infection in which micro- on the infecting species (although it has no effect in M. oz-
ease, endomyocardial fibrosis, encephalopathy, and peri- filariae are not detected in the peripheral blood but may be zardi infections1). Mebendazole may be effective alone1 or
pheral neuropathy. found in other body fluids and tissues. It is rare and is with levamisole or diethylcarbamazine2 in M. perstans; al-
thought to result from a hypersensitivity reaction to filarial bendazole is considered the drug of choice in this infec-
Diethylcarbamazine is used for treatment;1 it is effective antigens. Clinical manifestations include tropical pulmo- tion.1 Ivermectin has been suggested for M. ozzardi
against the microfilariae, larval forms, and a proportion of nary eosinophilia, glomerulopathies, endomyocardial infections1 and may be the drug of choice for M. strep-
adult worms. In some cases, treatment has been associated fibrosis, filarial arthritis, and filarial granulomas in the tocerca.
with acute encephalitis, particularly in patients with heavy breast. 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
microfilaraemia. It has been assumed that this is related to There is no entirely satisfactory treatment for individuals Rochelle NY: The Medical Letter, 2007.
blockage of capillaries in the brain and meninges and for with lymphatic filariasis. Current treatments are effective 2. Bregani ER, et al. Comparison of different anthelmintic drug
this reason small doses of diethylcarbamazine are given in- regimens against Mansonella perstans filariasis. Trans R Soc
against microfilariae, and thus prevent disease transmis- Trop Med Hyg 2006; 100: 458–63.
itially, with a corticosteroid and antihistamine, gradually sion, but have little or no effect on the adult worms and do
increasing to full therapeutic doses over several days. not halt the progression of symptoms once the disease has
However this does not eliminate the risk of encephalitis developed. Diethylcarbamazine removes circulating mi- Metagonimiasis
entirely and the role of the microfilariae in this syndrome crofilariae and is partially effective against the adult worm See under Intestinal Fluke Infections, above.
has been questioned. Albendazole may be useful where di- and is considered the treatment of choice.1 Treatment may
ethylcarbamazine cannot be used, but repeated courses trigger acute lymphangitis, and diethylcarbamazine should Nanophyetiasis
may be needed.1 Some consider that ivermectin could be not be given during an acute episode as it may cause fur- See under Intestinal Fluke Infections, above.
used1 but, as with diethylcarbamazine, there is concern ther worm death and thus exacerbate the inflammatory re-
over its potential neurotoxic effects in patients with heavy sponse. Ivermectin is only active against microfilariae and
microfilaraemia. is mainly used in areas also endemic for onchocerciasis or
Necatoriasis
See under Hookworm Infections, above.
Diethylcarbamazine is also used for prophylaxis1 but it has loiasis. Albendazole plus either of these two drugs is con-
been suggested that it should be reserved for subjects at sidered to increase their effectiveness and such combina-
high risk of exposure. Vector control is regarded as im- tions are recommended for mass treatment programmes.2 Onchocerciasis
practical and methods aimed at reducing contact with the However, systematic reviews of randomised studies3,4 Onchocerciasis (river blindness) is a parasitic disease
vector such as window screens and protective clothing are found insufficient evidence to either confirm or reject the caused by infection with the filarial nematode Onchocerca
recommended. observation that albendazole with diethylcarbamazine or volvulus. It is endemic in large areas of West and Central
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New ivermectin is more effective than either drug given alone. Africa, areas of Latin America, and Yemen. It is particular-
Rochelle NY: The Medical Letter, 2007. Secondary infections with bacteria and fungi occur in ly prevalent near fast flowing rivers, the breeding ground
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
138 Anthelmintics
of the blackfly which is the vector of the parasite. After infection and was the main strategy for onchocerciasis 3. Saconato H, Atallah A. Interventions for treating schistosomia-
sis mansoni. Available in The Cochrane Database of Systematic
infection, the larvae mature into adult worms in fibrous control before the introduction of ivermectin. However, Reviews; Issue 3. Chichester: John Wiley; 1999 (accessed
nodules, usually in the subcutaneous tissue. The adult fe- despite initial success fly re-invasion became a problem, 16/05/05).
male worms release large numbers of microfilariae which as the flight range of the vector was longer than expect- 4. WHO. Schistosomiasis. Available at: http://www.who.int/tdr/
migrate from the nodules into other tissues, most notably ed.13 diseases/schisto/diseaseinfo.htm (accessed 15/06/06)
the skin and the eyes. Death of microfilariae in the eyes 5. Ross AGP, et al. Schistosomiasis. N Engl J Med 2002; 346:
1. Saint André A, et al. The role of endosymbiotic Wolbachia bac-
teria in the pathogenesis of river blindness. Science 2002; 295: 1212–20.
causes severe inflammation and scarring that may lead to 6. Gryseels B, et al. Human schistosomiasis. Lancet 2006; 368:
1892–5.
lesions in the eyes and impaired vision. There is some ev- 2. Hoerauf A, et al. Onchocerciasis. BMJ 2003; 326: 207–10. 1106–18.
idence that antigens released from symbiotic Wolbachia 3. Udall DN. Recent updates on onchocerciasis: diagnosis and 7. De Clercq D, et al. Efficacy of artesunate against Schistosoma
bacteria within the microfilariae also play a role.1-3 Re- treatment. Clin Infect Dis 2007; 44: 53–60. mansoni infections in Richard Toll, Senegal. Trans R Soc Trop
4. WHO. Onchocerciasis and its control: report of a WHO expert Med Hyg 2000; 94: 90–1.
peated infection over several years may result in irreversi- committee on onchocerciasis control. WHO Tech Rep Ser 852 8. Utzinger J, et al. Oral artemether for prevention of Schistosoma
ble blindness. In the skin the dying microfilariae trigger a 1995. Also available at: http://libdoc.who.int/trs/ mansoni infection: randomised controlled trial. Lancet 2000;
subcutaneous inflammatory response that causes intense WHO_TRS_852.pdf (accessed 03/10/07) 355: 1320–5.
itching. Over time the skin becomes swollen and thick- 5. WHO. Onchocerciasis (river blindness). Available at: http:// 9. Borrmann S, et al. Artesunate and praziquantel for the treatment
www.who.int/blindness/partnerships/onchocerciasis_home/en/ of Schistosoma haematobium infections: a double-blind, rand-
ened (lizard skin) and may lose some of its elasticity and index.html (accessed 15/06/06) omized, placebo-controlled study. J Infect Dis 2001; 184:
pigment (leopard skin). 6. Pond B. Distribution of ivermectin by health workers. Lancet 1363–6.
1990; 335: 1539.
Onchocerciasis is controlled either by treating the infected 7. Gardon J, et al. Effects of standard and high doses of ivermectin
patient, thereby reducing the transmission of the infection on adult worms of Onchocerca volvulus: a randomised control- Strongyloidiasis
from the human host to the vector, or by interrupting the led trial. Lancet 2002; 360: 203–10.
Strongyloidiasis1 is an infection of the small intestine
transmission from vector to human. The drug of choice for 8. Osei-Atweneboana MY, et al. Prevalence and intensity of On-
chocerca volvulus infection and efficacy of ivermectin in en- caused by Strongyloides stercoralis, known as thread-
the treatment of onchocerciasis is ivermectin.2-5 A single demic communities in Ghana: a two-phase epidemiological worm in the USA. It generally occurs in the tropics and
oral dose of ivermectin rapidly eliminates microfilariae study. Lancet 2007; 369: 2021–9.
subtropics and can also occur in some areas of South and
from the skin and more gradually eliminates them from the 9. The Mectizan Expert Committee and Technical Consultative
Committee. Recommendations for the treatment of onchocer- East Europe, Japan, and the USA. In contrast with other
cornea and anterior chamber of the eye.4 It has little effect ciasis with Mectizan in areas co-endemic for onchocerciasis intestinal nematodes, the eggs of S. stercoralis hatch be-
on the adult worms although it suppresses release of mi- and loiasis. 2004. Available at: http://www.mectizan.org/
fore leaving the gastrointestinal tract, and can cause au-
crofilariae for several cycles. Ivermectin therefore only library/EnglishMECTCCLoaRecs-June04.pdf (accessed
14/09/07) toinfection, particularly in immunocompromised patients.
controls the disease; it does not cure or eradicate it. Control 10. Cotreau MM, et al. The antiparasitic moxidectin: safety, tolera- Larvae reaching the soil can either mature into free-living
of the disease in endemic areas relies upon the use of iver- bility, and pharmacokinetics in humans. J Clin Pharmacol
adults or remain in an infective larval stage. Infective lar-
mectin every 12 months in Africa (and every 6 months in 2003; 43: 1108–15.
11. Hoerauf A, et al. Endosymbiotic bacteria in worms as targets for vae cause infection by penetrating the skin. The larvae mi-
Central and South America) and this may be combined a novel chemotherapy in filariasis. Lancet 2000; 355: 1242–3. grate to the lungs, move up the bronchial tree to be swal-
with vector control (below). Because the adult worms live 12. Hoerauf A, et al. Depletion of wolbachia endobacteria in On- lowed, and finally penetrate the mucosa of the small
for about 15 years, treatment will need to be continued for chocerca volvulus by doxycycline and microfilaridermia after
ivermectin treatment. Lancet 2001; 357: 1415–6. intestine where they mature. Eggs are deposited about 28
many years. Ivermectin is donated by Merck through the 13. Thylefors B, Alleman M. Towards the elimination of onchocer- days after initial infection.
Mectizan Expert Committee (MEC) for human use in ciasis. Ann Trop Med Parasitol 2006; 100: 733–46.
community-wide mass treatment programmes in all coun- Infection may be asymptomatic, but commonly patients
tries in which onchocerciasis is endemic, where it is given have symptoms relating to the stages of infection. Penetra-
to all but pregnant women, breast-feeding mothers of re- Opisthorchiasis tion of larvae through the skin causes intense pruritus and
cently born babies, children weighing less than 15 kg, and See under Liver Fluke Infections, above. an erythematous rash. The rash may follow the course of
those unable to walk or otherwise seriously ill.6 For further migration and is one of the causes of cutaneous larva mi-
details, see under Ivermectin, p.146. Increasing the fre- grans (above). An inflammatory response to migration
Paragonimiasis
quency of the standard doses of ivermectin to every 3 through the lungs may be seen and may include pneumo-
See under Lung Fluke Infections, above.
months appears to increase efficacy compared with annual nitis and bronchospasm. In heavy infections, which are
treatments.7 Evidence from Ghana suggests that ivermec- most common in immunocompromised patients as a result
tin-resistant populations of parasites are emerging and that Schistosomiasis of autoinfection, massive pulmonary invasion can occur
its ability to suppress skin microfilariae repopulation is re- Schistosomiasis (bilharziasis) is a parasitic infection resulting in fatal alveolar haemorrhage. Abdominal symp-
duced over time in some communities.8 caused by Schistosoma spp., largely S. mansoni, S. japon- toms include colicky pain, diarrhoea, and vomiting, lead-
icum, and S. haematobium, and to a lesser extent S. inter- ing to nutritional deficiencies and weight loss. Eosin-
In areas where onchocerciasis and loiasis are co-endemic, ophilia may also be present. Disseminated disease may
calatum and S. mekongi. The disease is seen mainly in Af-
care should be taken because ivermectin may cause seri- occur in immunocompromised patients and produce se-
rica, Asia, South America, and the Caribbean, where it is a
ous adverse effects, including encephalopathy, in some pa- vere pulmonary and abdominal symptoms, shock, enceph-
hazard to individuals exposed to fresh water containing the
tients with high Loa loa microfilaraemias (see Incidence of alopathy, meningitis, and Gram-negative septicaemia.
intermediate host, infected freshwater snails.
Adverse Effects, under Ivermectin, p.145). The Mectizan Since strongyloidiasis is commonly fatal in these patients,
Expert Committee and the Technical Consultative Free-swimming cercariae are released from the snail and
penetrate human skin causing a pruritic papular rash in vulnerable patients from endemic areas should be
Committee9 have implemented recommendations for iver- screened regularly and treated promptly at the first sign of
mectin mass treatment programmes of onchocerciasis in sensitised individuals (swimmer’s itch). Parasites mature
in the lungs and liver within about 6 weeks, then migrate infection.
areas co-endemic for loiasis.
to the blood vessels, the bladder, or intestines. Mature Ivermectin is considered to be the treatment of choice.1,2
Before the introduction of ivermectin in 1988, diethylcar-
female worms produce eggs which are excreted in urine or Tiabendazole was widely used, and still is in some coun-
bamazine was the usual treatment for onchocerciasis, but
stools, or become lodged in tissues, and immunological re- tries, but albendazole is more effective and better tolerated.
it is no longer recommended by WHO.4 The major limita-
action to these eggs results in disease. The acute reaction Mebendazole has also been suggested but it must be given
tions to its use are the severe allergic reaction (the Mazzotti
to egg deposition has been termed Katayama fever, a self- for longer periods than albendazole since it has only a lim-
reaction) associated with its microfilaricidal action, aggra-
limiting but sometimes fatal illness resembling serum ited effect on migrating larvae. A combination of ivermec-
vation of existing ocular lesions or precipitation of new
sickness and most frequently seen in S. japonicum infec- tin and albendazole has been suggested in disseminated
ones, and the need to give repeated courses of treatment for
tion. The chronic phase of infection is often asymptomatic disease.2 These broad-spectrum anthelmintics (except tia-
continued suppression of the disease.4 Suramin has also
for many years, but usually results in granuloma formation bendazole) are also useful if the patient is suffering from a
been used in the treatment of onchocerciasis and is effec-
and fibrosis in tissues where eggs are deposited, such as mixed intestinal nematode infection.
tive against adult worms.4 However, its use is restricted be-
the liver, lungs, intestines, or urinary tract, the site depend- 1. Segarra-Newnham M. Manifestations, diagnosis, and treatment
cause of its toxicity. Moxidectin is an anthelmintic used in of Strongyloides stercoralis infection. Ann Pharmacother 2007;
ing on the infecting species.
veterinary medicine and is currently being evaluated for 41: 1992–2001.
human use.10 Amocarzine has also been evaluated in on- Praziquantel is used for the treatment of chronic 2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
chocerciasis.4 schistosomiasis1-6 and is effective against all species of Rochelle NY: The Medical Letter, 2007.
Recently it has been shown that adult worms contain Wol- schistosomes. Metrifonate and oxamniquine have been
bachia endobacteria, which are essential for adult worm used as alternatives against S. haematobium1,2 and S.
mansoni1,3-5 respectively. Artemisinin derivatives used
Syngamosis
fertility and viability. This symbiotic dependency on Wol- Syngamosis, or gapeworm infection, is caused by Synga-
bachia has provided a new approach in the treatment of alone or in combination with praziquantel are also under
mus and Mammomonogamus spp. and is mainly an infec-
onchocerciasis. Treatment with oral doxycycline daily for investigation for S. mansoni infection6-8 and S. haemato-
tion of domestic fowl and wild birds and mammals, al-
bium.9
6 weeks has been shown to sterilise adult worms for the 4- though infection in man has been reported very rarely.1-6
month study period.11 When given with a single dose of Niclosamide is used as a molluscicide for the treatment of Man may become infected by eating foods contaminated
ivermectin, embryogenesis is interrupted for at least 18 water in schistosomiasis control programmes. Copper sul- with infective larvae which penetrate the intestinal wall
months.12 The long doxycycline treatment regimen is not fate or sodium pentachlorophenate have also been used but and migrate to the lungs, where they mature into adult
suitable for mass treatment programmes, but it may be to a lesser extent. worms. The major symptom is cough, due to irritation of
used with ivermectin for treatment of patients who perma- Schistosomiasis vaccines are in development. the bronchi and increased mucus production. The infection
nently leave an endemic area. 1. WHO. The control of schistosomiasis: second report of the may be confused with asthma. Tiabendazole and meben-
WHO expert committee. WHO Tech Rep Ser 830 1993. Available dazole have been used successfully to treat the infection in
In non-endemic areas ivermectin may be given every 3 to at: http://libdoc.who.int/trs/WHO_TRS_830.pdf (accessed
6 months depending on the recurrence of symptoms or 16/07/08) man.
presence of microfilariae. 2. Squires N. Interventions for treating schistosomiasis haemato- 1. Timmons RF, et al. Infection of the respiratory tract with Mam-
bium. Available in The Cochrane Database of Systematic Re- momanogamus (Syngamus) laryngeus: a new case in Largo,
Vector control with larvicides, continued for the life span views; Issue 3. Chichester: John Wiley; 1997 (accessed Florida, and a summary of previously reported cases. Am Rev
of an adult worm, is used to interrupt the transmission of 16/05/05). Respir Dis 1983; 128: 566–9.
 Anthelmintics/Albendazole 139
2. Gardiner CH, Schantz PM. Mammomonogamus infection in a Trichostrongyliasis Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet.
human: report of a case. Am J Trop Med Hyg 1983; 32: 995–7. Ph. Eur. 6.2 (Albendazole). A white to faintly yellowish pow-
Trichostrongyliasis is an infection of the small intestine
3. Leers WD, et al. Syngamosis, an unusual cause of asthma: the der. Practically insoluble in water and in alcohol; very slightly
first reported case in Canada. Can Med Assoc J 1985; 132: caused by Trichostrongylus spp. including T. colubri-
269–70. formis. Trichostrongylus spp. are normally parasites of soluble in dichloromethane; freely soluble in anhydrous formic
4. Nosanchuk JS, et al. Case report of and description of parasite in herbivores, but infections in man have been found. They acid. Protect from light.
Mammomonogamus laryngeus (human syngamosis) infection. J USP 31 (Albendazole). A white to faintly yellowish powder.
Clin Microbiol 1995; 33: 998–1000.
have a similar life cycle to Ancylostoma duodenale (see Practically insoluble in water and in alcohol; very slightly solu-
5. Turner P, et al. A case of human syngamosis. Travel Med Infect Hookworm Infections, above). Pyrantel embonate, alben- ble in ether and in dichloromethane; freely soluble in anhydrous
Dis 2003; 1: 231–3. dazole, or mebendazole are recommended for the treat- formic acid. Store in airtight containers.
6. Castaño JC, et al. Reporte del primer caso humano de infección ment of trichostrongyliasis.1 Successful treatment with
parasitaria por Mammomonogamus laryngeus en Colombia. Bi- ivermectin has occurred in areas where widespread use of
omedica 2006; 26: 337–41. Adverse Effects and Precautions
benzimidazole carbamate derivatives in grazing animals As for Mebendazole, p.148.
has led to resistance to these drugs.2
Taeniasis 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
Incidence of adverse effects. Although generally well-toler-
Taeniasis is an infection of the intestine with beef tape- Rochelle NY: The Medical Letter, 2007. ated, the following adverse reactions were reported in the first
worm, Taenia saginata, or pork tapeworm, T. solium, ac- 2. Ralph A, et al. Abdominal pain and eosinophilia in suburban
phase of WHO-coordinated studies1 involving 30 patients given
quired through ingestion of contaminated raw or under- goat keepers. Med J Aust 2006; 184: 467–9. Correction. ibid.; high-dose therapy with albendazole for the treatment of cystic
185: 49. [title] echinococcosis (hydatid disease): raised serum-transaminase
cooked meat. The larval form of T. solium can cause the levels (2 patients), reduced leucocyte counts (1), gastrointestinal
systemic infection cysticercosis (see above). symptoms (1), allergic conditions (1), and loss of hair (1). Treat-
Infection with the adult worm usually produces symptoms Trichuriasis ment was stopped in a further patient with alveolar echinococco-
only when the worm reaches a size that can cause obstruc- Trichuriasis is an infection of the large intestine with Tri- sis because of depressed bone-marrow activity. In the second
tion or related problems. Segments of the worm containing churis trichiura, sometimes known as whipworm. Distri- phase of these studies,2 of 109 patients given albendazole for
eggs may be excreted in the faeces so maintaining the bution is worldwide, but most infections occur in the trop- cystic echinococcosis, 20 had adverse effects; similar findings
cycle of reproduction. Treatment is with a single dose of ics and subtropics. Eggs are excreted in the faeces and can were reported with mebendazole. The range of effects with al-
bendazole was: elevation of transaminases (5 patients), abdomi-
praziquantel,1 which has the advantage of also being ac- remain viable in the soil for extended periods. Under opti- nal pain and other gastrointestinal symptoms (7), severe head-
tive, in higher doses, against the larval form of T. solium. mum conditions the eggs become infective in about 2 to 4 ache (4), loss of hair (2), leucopenia (2), fever and fatigue (1),
Niclosamide is also effective but is only active against weeks. After ingestion, larvae are released from the eggs thrombocytopenia (1), and urticaria and itching (1). Albendazole
adult worms. and develop within the wall of the small intestine for about had to be withdrawn in 5 patients because of adverse effects, al-
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New 3 to 10 days, before migrating to the lumen of the large though in 3 the withdrawal was only temporary.
Rochelle NY: The Medical Letter, 2007. intestine where they remain attached to the mucosal lining. 1. Davis A, et al. Multicentre clinical trials of benzimidazolecar-
Eggs are detectable in the faeces about 1 to 3 months after bamates in human echinococcosis. Bull WHO 1986; 64: 383–8.
2. Davis A, et al. Multicentre clinical trials of benzimidazolecar-
Toxocariasis infection. Trichuriasis is often asymptomatic, but heavy bamates in human cystic echinococcosis (phase 2). Bull WHO
Toxocariasis1 is infection with the larval form of Toxocara infection can result in anaemia, diarrhoea, and rectal pro- 1989; 67: 503–8.
canis or, less commonly, T. cati. The adult worms live in lapse. Effects on growth. A multiple-dose regimen of albendazole in
the intestines of dogs and cats respectively, and man be- Treatment is with a benzimidazole carbamate derivative children with asymptomatic trichuriasis has been reported to be
comes infected when eggs excreted in animal faeces are such as albendazole or mebendazole1-3 and such broad- associated with impaired growth in those with low levels of in-
ingested. Once ingested the eggs hatch and the larvae mi- spectrum therapy can be useful if the patient is suffering fection.1 However it was considered that this should not prevent
grate from the intestine to other organs, most commonly from a mixed intestinal nematode infection. Ivermectin2 the use of single doses in mass treatment programmes.2
1. Forrester JE, et al. Randomised trial of albendazole and pyrantel
the liver, lung, and eye. Most infections are asymptomatic and nitazoxanide4 are alternatives. However, a systematic in symptomless trichuriasis in children. Lancet 1998; 352:
but two clinical syndromes, ocular larva migrans and vis- review3 considered the treatment of trichuriasis to be un- 1103–8.
ceral larva migrans, can occur, usually in children. satisfactory with current drugs. 2. Winstanley P. Albendazole for mass treatment of asymptomatic
trichuris infections. Lancet 1998; 352: 1080–1.
Ocular larva migrans occurs when larvae invade the eye 1. Bethony J, et al. Soil-transmitted helminth infections: ascariasis,
causing a granuloma which may impair vision and can trichuriasis, and hookworm. Lancet 2006; 367: 1521–32. Effects on the liver. In a series of 40 patients given albenda-
cause blindness. There is no specific treatment.2 An- 2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New zole for echinococcosis, 7 developed abnormalities in liver func-
thelmintics such as albendazole or tiabendazole, corticos- Rochelle NY: The Medical Letter, 2007. tion tests during therapy.1 Six had a hepatocellular type of abnor-
3. Keiser J, Utzinger J. Efficacy of current drugs against soil-trans- mality attributable to albendazole; the seventh had cholestatic
teroids, ocular surgery, and laser photocoagulation have mitted helminth infections: systematic review and meta-analy- jaundice which was probably not due to albendazole. See also
been used but assessment of their efficacy is difficult be- sis. JAMA 2008; 299: 1937–48. Incidence of Adverse Effects, above for reports of raised serum-
cause of the variable natural course of the disease. 4. Juan JO, et al. Comparative clinical studies of nitazoxanide, al- transaminase levels.
The clinical symptoms of visceral larva migrans depend bendazole and praziquantel in the treatment of ascariasis, trichu- Albendazole should only be used in the treatment of echinococ-
riasis and hymenolepiasis in children from Peru. Trans R Soc
upon the organs involved but commonly include cough, Trop Med Hyg 2002; 96: 193–6. cosis if there is constant medical supervision with regular moni-
wheezing, fever, and hepatomegaly. Encephalitis and sei- toring of serum-transaminase concentrations and of leucocyte
zures may occur and there is usually eosinophilia. Acute and platelet counts. Patients with liver damage should be treated
infection normally resolves without treatment.3 However, with reduced doses of benzimidazole carbamates, if at all.2
severe or prolonged infections may be treated with alben- Abamectin (USAN, rINN) 1. Morris DL, Smith PG. Albendazole in hydatid disease—hepato-
cellular toxicity. Trans R Soc Trop Med Hyg 1987; 81: 343–4.
dazole;4 mebendazole or tiabendazole have also been Abamectina; Abamectine; Abamectinum; MK-0936. A mixture 2. Davis A, et al. Multicentre clinical trials of benzimidazolecar-
used.1,4 of abamectin component B1a and abamectin component B1b. bamates in human cystic echinococcosis (phase 2). Bull WHO
1. Despommier D. Toxocariasis: clinical aspects, epidemiology, 1989; 67: 503–8.
medical ecology, and molecular aspects. Clin Microbiol Rev Абамектин Pregnancy. Albendazole is teratogenic in some animals and
2003; 16: 265–72. there are no adequate and well controlled studies in human preg-
C AS — 65195-55-3 (component B 1a ); 65195-56-4 (com-
2. Shields JA. Ocular toxocariasis: a review. Surv Ophthalmol
1984; 28: 361–81. ponent B 1b ). nancy. Albendazole is therefore usually contra-indicated during
3. Gillespie SH. Human toxocariasis. Commun Dis Rep 1993; 3: ATC Vet — QP54AA02. pregnancy and licensed product information cautions against be-
R140–R143. coming pregnant while taking albendazole or within one month
4. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New Profile of completing treatment.
Rochelle NY: The Medical Letter, 2007. Abamectin is an avermectin anthelmintic used in veterinary
medicine for nematode infections. It is also used as a systemic Interactions
veterinary ectoparasiticide.
Trichinosis Anthelmintics. The plasma concentration of albendazole sul-
Trichinosis (trichinellosis) is an infection caused by foxide has been increased by praziquantel,1 although the practi-
Trichinella spiralis. Man becomes infected through inges- cal consequences of this were considered uncertain.
tion of raw or undercooked meat, usually pork, containing 1. Homeida M, et al. Pharmacokinetic interaction between praziqu-
infective larvae. The larvae mature into adult worms in the Albendazole (BAN, USAN, rINN) antel and albendazole in Sudanese men. Ann Trop Med Parasitol
1994; 88: 551–9.
small intestine and the mature females deposit larvae Albendatsoli; Albendazol; Albendazolas; Albendazolum; SKF-
which migrate in the blood to skeletal muscle and some- Antiepileptics. Phenytoin, carbamazepine, and phenobarbital
62979. Methyl 5-propylthio-1H-benzimidazol-2-ylcarbamate. appear to induce the oxidative metabolism of albendazole via the
times to the myocardium. Symptoms usually occur only in cytochrome P450 isoenzyme CYP3A by roughly the same ex-
heavy infections. Invasion of the intestines by the matur- Альбендазол
tent, resulting in significantly reduced concentrations of albenda-
ing adult worms can cause diarrhoea, abdominal pain, and C 12 H 15 N 3 O 2 S = 265.3. zole sulfoxide. This interaction is likely to be clinically signifi-
vomiting followed about a week later by hypersensitivity C AS — 54965-21-8. cant when albendazole is used to treat systemic worm infections,
reactions to the migrating larvae. These may include eosin- ATC — P02C A03. and increased doses of albendazole would be needed.1 The inter-
ophilia, fever, muscle pain, periorbital oedema and, more action is probably not clinically significant when albendazole is
rarely, encephalitis, myocarditis, or pneumonia which may ATC Vet — QP52AC11. used for intestinal worm infections.
be fatal. 1. Lanchote VL, et al. Pharmacokinetic interaction between alben-
dazole sulfoxide enantiomers and antiepileptic drugs in patients
All patients with confirmed or suspected infection should H with neurocysticercosis. Ther Drug Monit 2002; 24: 338–45.
be treated to prevent the continued production of larvae. N Corticosteroids. Plasma concentrations of the active metabo-
Albendazole or mebendazole are considered to be the an- NH lite of albendazole (albendazole sulfoxide) were reported to be
thelmintics of choice. A corticosteroid should be given for H 3C raised by about 50% in a study in 8 patients receiving dexameth-
severe hypersensitivity reactions.1 S N OCH3 asone.1
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New O 1. Jung H, et al. Dexamethasone increases plasma levels of alben-
Rochelle NY: The Medical Letter, 2007. dazole. J Neurol 1990; 237: 279–80.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
140 Anthelmintics
Histamine H2-antagonists. Concentrations of albendazole secutive days; this may be repeated after 3 weeks if Gnathostomiasis. Albendazole has been reported to be effec-
sulfoxide have been found to be raised in bile and hydatid cyst necessary. tive in the treatment of gnathostomiasis (p.136). Doses of
fluid when albendazole was given with cimetidine, which may 400 mg once or twice daily have been given for 2 or 3 weeks.1-4
increase effectiveness in the treatment of echinococcosis.1 Albendazole has also been used to treat giardiasis 1. Kraivichian P, et al. Albendazole for the treatment of human gna-
1. Wen H, et al. Initial observation on albendazole in combination (p.824); suggested doses are 400 mg daily by mouth thostomiasis. Trans R Soc Trop Med Hyg 1992; 86: 418–21.
with cimetidine for the treatment of human cystic echinococco- for 5 days. 2. Suntharasamai P, et al. Albendazole stimulates outward migra-
sis. Ann Trop Med Parasitol 1994; 88: 49–52. tion of Gnathostoma spinigerum to the dermis in man. Southeast
Ascariasis. Albendazole is used as an alternative to mebenda- Asian J Trop Med Public Health 1992; 23: 716–22.
zole in the treatment of ascariasis (p.134). Both drugs are equally 3. Nontasut P, et al. Comparison of ivermectin and albendazole
Pharmacokinetics treatment for gnathostomiasis. Southeast Asian J Trop Med Pub-
highly effective with a cure rate greater than 98% reported for
Absorption of albendazole from the gastrointestinal albendazole in one study.1
lic Health 2000; 31: 374–7.
4. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
tract is poor but may be enhanced by a fatty meal. 1. Albonico M, et al. A randomized controlled trial comparing me- Rochelle NY: The Medical Letter, 2007.
Albendazole rapidly undergoes extensive first-pass bendazole and albendazole against Ascaris, Trichuris and hook-
worm infections. Trans R Soc Trop Med Hyg 1994; 88: 585–9. Hookworm infections. Hookworm infections (p.136) are
metabolism. Its principal metabolite albendazole sulfox- commonly treated with benzimidazole carbamates such as al-
ide has anthelmintic activity and a plasma half-life of Capillariasis. Albendazole in a dose of 400 mg daily for 10
bendazole. In 77 patients with light necatoriasis (Necator ameri-
days has been suggested1 as an alternative to mebendazole for
about 8.5 hours. Albendazole sulfoxide is widely dis- the treatment of capillariasis (p.135).
canus infection) albendazole, in a single 400-mg dose, produced
tributed throughout the body including into the bile and an 84% cure rate and an 82% reduction in egg count in those
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
patients not cured.1 In another study,2 although the cure rate was
the CSF. It is about 70% bound to plasma protein. Al- Rochelle NY: The Medical Letter, 2007.
only 56.8% after a single 400-mg dose of albendazole this was
bendazole sulfoxide is eliminated in the bile; only a Cutaneous larva migrans. Albendazole has been reported1-4 superior to treatment with mebendazole which had a cure rate of
small amount appears to be excreted in the urine. to be effective in the treatment of cutaneous larva migrans 22.4%. A further study3 comparing albendazole with mebenda-
(p.135) and is an alternative to tiabendazole or ivermectin. Al- zole and pyrantel in the treatment of necatoriasis also found al-
◊ References. bendazole, generally in a dose of 400 mg daily for three1 or five2 bendazole to be the most effective.
1. Marriner SE, et al. Pharmacokinetics of albendazole in man. Eur days, has alleviated the discomfort of cutaneous larva migrans;
J Clin Pharmacol 1986; 30: 705–8. Albendazole is given in mass treatment programmes to reduce
treatment for seven days may be more effective and has not been the overall burden of infection.1,4
2. Morris DL, et al. Penetration of albendazole sulphoxide into hy- associated with an increased incidence of adverse effects.4 A
datid cysts. Gut 1987; 28: 75–80. 1. Nahmias J, et al. Evaluation of albendazole, pyrantel, bephe-
3. Steiger U, et al. Albendazole treatment of echinococcosis in hu-
single dose of 400 mg has also been effective.3 An ointment con- nium, pyrantel-praziquantel and pyrantel-bephenium for single-
mans: effects on microsomal metabolism and drug tolerance. taining albendazole 10%, applied 3 times a day for 10 days, was dose mass treatment of necatoriasis. Ann Trop Med Parasitol
Clin Pharmacol Ther 1990; 47: 347–53. reported to be effective in treating cutaneous larva migrans in 2 1989; 83: 625–9.
4. Jung H, et al. Clinical pharmacokinetics of albendazole in pa- young children.5 2. Albonico M, et al. A randomized controlled trial comparing me-
tients with brain cysticercosis. J Clin Pharmacol 1992; 32: 1. Jones SK, et al. Oral albendazole for the treatment of cutaneous bendazole and albendazole against Ascaris, Trichuris and hook-
28–31. larva migrans. Br J Dermatol 1990; 122: 99–101. worm infections. Trans R Soc Trop Med Hyg 1994; 88: 585–9.
5. Jung H, et al. Clinical pharmacokinetics of albendazole in chil- 2. Sanguigni S, et al. Albendazole in the therapy of cutaneous larva 3. Sacko M, et al. Comparison of the efficacy of mebendazole, al-
dren with neurocysticercosis. Am J Ther 1997; 4: 23–6. migrans. Trans R Soc Trop Med Hyg 1990; 84: 831. bendazole and pyrantel in treatment of human hookworm infec-
3. Oriheula AR, Torres JR. Single dose of albendazole in the treat- tions in the southern region of Mali, West Africa. Trans R Soc
ment of cutaneous larva migrans. Arch Dermatol 1990; 126: Trop Med Hyg 1999; 93: 195–203.
Uses and Administration 398–9. 4. Idris MA, et al. Effective control of hookworm infection in
Albendazole is a benzimidazole carbamate an- 4. Veraldi S, Rizzitelli G. Effectiveness of a new therapeutic regi- school children from Dhofar, Sultanate of Oman: a four-year ex-
men with albendazole in cutaneous larva migrans. Eur J Derma- perience with albendazole mass chemotherapy. Acta Trop 2001;
thelmintic structurally related to mebendazole (p.148) 80: 139–43.
tol 1999; 9: 352–3.
and with similar activity. It is used in relatively high 5. Caumes E. Efficacy of albendazole ointment on cutaneous larva Loiasis. Albendazole has been investigated1,2 to reduce micro-
doses in the treatment of the cestode infections cyst- migrans in 2 young children. Clin Infect Dis 2004; 38: 1647–8.
filariasis in patients infected with Loa loa (see Loiasis, p.137)
icercosis and echinococcosis (hydatid disease). In Cysticercosis. The use of anthelmintics in the treatment of neu- with modest success.
some countries albendazole is used in the treatment of rocysticercosis (see Cysticercosis, p.135) remains controversial, 1. Klion AD, et al. Albendazole in human loiasis: results of a dou-
but if indicated albendazole is considered to be the drug of ble-blind, placebo-controlled trial. J Infect Dis 1993; 168:
single and mixed intestinal nematode infections in- choice.1-3 The dose of albendazole originally used was the same 202–6.
cluding ascariasis, enterobiasis, hookworm, strongy- as that used in echinococcosis, typically about 15 mg/kg daily 2. Tabi TE, et al. Human loiasis in a Cameroonian village: a dou-
loidiasis, and trichuriasis. It may also be used in the orally for 1 month. There is now some evidence that shorter ble-blind, placebo-controlled, crossover clinical trial of a three-
day albendazole regimen. Am J Trop Med Hyg 2004; 71: 211–15.
treatment of angiostrongyliasis, capillariasis, gnathos- courses of treatment may be appropriate in some forms of neuro-
tomiasis, and trichostrongyliasis. Albendazole may be cysticercosis. A study4 confirmed that a 10-day course of alben- Lymphatic filariasis. Albendazole is used in the management
dazole 400 mg twice daily, together with dexamethasone, was of lymphatic filariasis (p.137). In endemic areas mass treatment
effective in the treatment of the tissue nematode infec- safe and decreased the burden of parasites and the number of of the entire population (excluding neonates, pregnant women,
tions cutaneous larva migrans, toxocariasis, and trichi- generalised seizures in patients with viable parenchymal cysts. and debilitated individuals) can reduce the intensity of transmis-
nosis and has been tried in loiasis, and, with other an- Albendazole has also been reported to be effective for extrapa- sion and the incidence of disease. The Global Programme to
thelmintics, in mass treatment programmes in areas renchymal infection, such as subarachnoid, ventricular,2,5,6 and eliminate Lymphatic Filariasis launched by WHO, with other in-
where lymphatic filariasis is endemic. For discussions spinal cord cysticercosis,2 but the longer treatment period of 1 ternational agencies, advocates a single dose of albendazole
month with a dose of 15 mg/kg daily is usually used. Alternative- 400 mg with either a single dose of ivermectin 150 to
of these infections and their treatment, see under ly, a higher dose of albendazole for a shorter time may be consid- 200 micrograms/kg (if there is co-endemic loiasis or onchocer-
Choice of Anthelmintic (p.134), and under the individ- ered. A study5 of 36 patients with subarachnoid and intraven- ciasis) or with a single dose of diethylcarbamazine 6 mg/kg (if
ual headings below. tricular cysticercosis found that 30 mg/kg daily for 8 days was there is no co-endemic loiasis or onchocerciasis); these doses are
safe and more effective than 15 mg/kg daily for 8 days, both reg- given once each year for at least 5 years.
In the treatment of echinococcosis, albendazole is giv- imens being given with corticosteroids.
en orally with meals in a dose of 400 mg twice daily for Microsporidiosis. Albendazole has been tried1-6 in the treat-
1. Sotelo J, Jung H. Pharmacokinetic optimisation of the treatment ment of the protozoal infection microsporidiosis (p.826) in pa-
28 days for patients weighing over 60 kg. A dose of of neurocysticercosis. Clin Pharmacokinet 1998; 34: 503–15.
tients with AIDS. Albendazole has also been used empirically in
2. Takayanagui OM. Therapy for neurocysticercosis. Expert Rev
15 mg/kg daily in two divided doses (to a maximum Neurother 2004; 4: 129–39. the treatment of HIV-associated infections and complications
total daily dose of 800 mg) is used for patients weigh- 3. Del Brutto OH, et al. Meta-analysis: cysticidal drugs for neuro- (p.857).
ing less than 60 kg. For cystic echinococcosis, the 28- cysticercosis: albendazole and praziquantel.Ann Intern Med 1. Blanshard C, et al. Treatment of intestinal microsporidiosis with
2006; 145: 43–51. albendazole in patients with AIDS. AIDS 1992; 6: 311–13.
day course may be repeated after 14 days without treat- 4. Garcia HH, et al. A trial of antiparasitic treatment to reduce the 2. Dieterich DT, et al. Treatment with albendazole for intestinal
ment to a total of 3 treatment cycles. For alveolar echi- rate of seizures due to cerebral cysticercosis. N Engl J Med 2004; disease due to Enterocytozoon bieneusi in patients with AIDS. J
350: 249–58. Infect Dis 1994; 169: 178–82.
nococcosis, cycles of 28 days of treatment followed by 5. Góngora-Rivera F, et al. Albendazole trial at 15 or 30 mg/kg/day 3. Franzen C, et al. Intestinal microsporidiosis with Septata intesti-
14 days without treatment may need to continue for for subarachnoid and intraventricular cysticercosis. Neurology nalis in a patient with AIDS—response to albendazole. J Infect
2006; 66: 436–8. 1995; 31: 237–9.
months or years. 6. Proaño JV, et al. Medical treatment for neurocysticercosis char- 4. Dore GJ, et al. Disseminated microsporidiosis due to Septata in-
In the treatment of neurocysticercosis, US licensed acterized by giant subarachnoid cysts. N Engl J Med 2001; 345: testinalis in nine patients infected with the human immunodefi-
879–85. ciency virus: response to therapy with albendazole. Clin Infect
product information recommends doses of albendazole Dis 1995; 21: 70–6.
for parenchymal cysts similar to the doses used in echi- Echinococcosis. Albendazole is used in the treatment of echi-
nococcosis (p.136) as an adjunct to, or instead of, surgery. It is 5. Molina J-M, et al. Albendazole for treatment and prophylaxis of
nococcosis (see above); the recommended duration of generally preferred to mebendazole.
microsporidiosis due Encephalitozoon intestinalis in patients
with AIDS: a randomized double-blind controlled trial. J Infect
treatment is 8 to 30 days. Current expert opinion also References. Dis 1998; 177: 1373–7.
favours similar doses of 15 mg/kg daily but with a du- 1. Teggi A, et al. Therapy of human hydatid disease with mebenda- 6. Tremoulet AH, et al. Albendazole therapy for Microsporidium
zole and albendazole. Antimicrob Agents Chemother 1993; 37: diarrhea in immunocompetent Costa Rican children. Pediatr In-
ration of treatment of only 8 days for parenchymal dis- 1679–84. fect Dis J 2004; 23: 915–18.
ease and about 1 month for subarachnoid disease. For 2. Gil-Grande LA, et al. Randomised controlled trial of efficacy of
albendazole in intra-abdominal hydatid disease. Lancet 1993; Strongyloidiasis. Albendazole is generally preferred to tiaben-
further information on dosage regimens, see Cysticer- dazole or mebendazole in the treatment of strongyloidiasis
342: 1269–72.
cosis, below. 3. Wen H, et al. Initial observation on albendazole in combination (p.138) although ivermectin is now generally considered to be
Albendazole is given orally, usually as a single dose, in with cimetidine for the treatment of human cystic echinococco- the drug of choice. Both drugs have been used together in dis-
sis. Ann Trop Med Parasitol 1994; 88: 49–52. seminated disease.
the treatment of single or mixed intestinal nematode 4. Wen H, et al. Albendazole chemotherapy for human cystic and
alveolar echinococcosis in north-western China. Trans R Soc References.
infections. The usual dose for adults and children aged 1. Rossignol JF, Maisonneuve H. Albendazole: placebo-controlled
Trop Med Hyg 1994; 88: 340–3.
2 years or over with ascariasis, enterobiasis, hook- 5. Liu Y, et al. Continuous long-term albendazole therapy in in- study in 870 patients with intestinal helminthiasis. Trans R Soc
worm infections, or trichuriasis is 400 mg as a single traabdominal cystic echinococcosis. Chin Med J (Engl) 2000; Trop Med Hyg 1983; 77: 707–11.
113: 827–32. 2. Chanthavanich P, et al. Repeated doses of albendazole against
dose. In enterobiasis, the dose may be repeated in 1 to 6. Keshmiri M, et al. Albendazole versus placebo in treatment of strongyloidiasis in Thai children. Southeast Asian J Trop Med
4 weeks. Some consider that children of 1 to 2 years of echinococcosis. Trans R Soc Trop Med Hyg 2001; 95: 190–4. Public Health 1989; 20: 221–6.
age may be given 200 mg for enterobiasis. In strongy- 7. Falagas ME, Bliziotis IA. Albendazole for the treatment of hu- 3. Mojon M, Nielsen PB. Treatment of Strongyloides stercoralis
man echinococcosis: a review of comparative clinical trials. Am with albendazole: a cure rate of 86 per cent. Zentralbl Bakteriol
loidiasis, 400 mg is given once or twice daily for 3 con- J Med Sci 2007; 334: 171–9. Mikrobiol Hyg [A] 1987; 263: 619–24.
 Albendazole/Trivalent Antimony Compounds 141
4. Archibald LK, et al. Albendazole is effective treatment for Stibophen
chronic strongyloidiasis. Q J Med 1993; 86: 191–5.
5. Pornsuriyasak P, et al. Disseminated strongyloidiasis successful-
Estibofeno; Fouadin; Stibophenum. Bis[4,5-dihydroxybenzene-
H
ly treated with extended duration ivermectin combined with al- N 1,3-disulphonato(4−)-O4,O5]antimonate(5−) pentasodium hep-
bendazole: a case report of intractable strongyloidiasis. South- S tahydrate.
east Asian J Trop Med Public Health 2004; 35: 531–4.
Стибофен
6. Singthong S, et al. Randomized comparative trial of two high-
dose albendazole regimens for uncomplicated human strongyloi- O 2N N N C 12 H 4 Na 5 O 16S 4 Sb,7H 2 O = 895.2.
diasis. Southeast Asian J Trop Med Public Health 2006; 37 (sup- H C AS — 15489-16-4 (stibophen heptahydrate).
pl 3): 32–4. N ATC — P02BX03.
CH3
Toxocariasis. Albendazole is one of the drugs that might be
used for the treatment of toxocariasis (p.139) and in a small NOTE.Amocarzine has sometimes been referred to as thiocar- O O
study1 it produced improvement similar to that achieved with tia- Na+
-
O O- Na+
bamazine. S S
bendazole but with fewer problems. O O
1. Stürchler D, et al. Thiabendazole vs albendazole in treatment of Profile O Sb O
toxocariasis: a clinical trial. Ann Trop Med Parasitol 1989; 83: Amocarzine is an antifilarial anthelmintic that is active against O O-
473–8. the adult worms of Onchocerca volvulus. It has been studied for
Na+
the oral treatment of onchocerciasis (p.137). O S O O S O
Trichinosis. Albendazole may be effective in the treatment of
trichinosis (p.139). A retrospective study in 44 patients with ◊ References. O- Na+ O- Na+
trichinosis comparing albendazole treatment with tiabendazole 1. Poltera AA, et al. Onchocercacidal effects of amocarzine (CGP
found that, while the two drugs were of comparable efficacy, al- 6140) in Latin America. Lancet 1991; 337: 583–4. Adverse Effects and Treatment
bendazole was the better tolerated.1 Albendazole has been used 2. Cooper PJ, et al. Onchocerciasis in Ecuador: evolution of chori- Trivalent antimony compounds are more toxic than pentavalent
to treat a patient infected with Trichinella pseudospiralis, an oretinopathy after amocarzine treatment. Br J Ophthalmol 1996; antimonials such as sodium stibogluconate, possibly because
organism related to T. spiralis, the usual cause of trichinosis.2 80: 337–42. they are excreted much more slowly. The most serious adverse
1. Cabié A, et al. Albendazole versus thiabendazole as therapy for 3. Awadzi K, et al. The safety and efficacy of amocarzine in Afri- effects are on the heart and liver. There are invariably ECG
trichinosis: a retrospective study. Clin Infect Dis 1996; 22: can onchocerciasis and the influence of ivermectin on the clini- changes during treatment, but hypotension, bradycardia, and car-
1033–5. cal and parasitological response to treatment. Ann Trop Med Par-
asitol 1997; 91: 281–96.
diac arrhythmias are more serious. Sudden death or cardiovascu-
2. Andrews JRH, et al. Trichinella pseudospiralis in humans: de- lar collapse may occur at any time. Elevated liver enzyme values
scription of a case and its treatment. Trans R Soc Trop Med Hyg are common; liver damage with hepatic failure and death is more
1994; 88: 200–3. likely in patients with pre-existing hepatic disease.
Trichostrongyliasis. Albendazole in a single dose of 400 mg Trivalent Antimony Compounds Adverse effects immediately after intravenous use of trivalent
has been suggested1 as an alternative to pyrantel embonate or antimonials, in particular the tartrates, have included coughing,
mebendazole in the treatment of trichostrongyliasis (p.139). Compuestos de antimonio trivalente. chest pain, pain in the arms, vomiting, abdominal pain, fainting,
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
and collapse, especially after rapid injection. Extravasation dur-
Rochelle NY: The Medical Letter, 2007. Antimony Potassium Tartrate ing injection is extremely painful because of tissue damage. An
anaphylactoid reaction characterised by an urticarial rash, husky
Trichuriasis. Albendazole is used in the treatment of trichuria- Antim. Pot. Tart.; Antimónico potásico, tartrato; Antymonu voice, and collapse has been reported after the sixth or seventh
sis (p.139). It is normally given in a single dose and is often used potasu winian; Brechweinstein; Kalii Stibyli Tartras; Potassium An- intravenous injection of a course of treatment.
in mixed intestinal nematode infections.1 However, it has been timonyltartrate; Stibii et Kalii Tartras; Tartar Emetic; Tartarus Stib- Numerous less immediate adverse effects have occurred includ-
reported1-3 that in children with mixed intestinal worm infections iatus. Dipotassium bis{μ-[2,3-dihydroxybutanedioato(4-)- ing gastrointestinal disturbances, muscular and joint pains,
single doses of albendazole are ineffective in eliminating Tri- O1,O2:O3,O4]}-diantimonate(2-) trihydrate; Dipotassium bis[μ- arthritis, pneumonia, dyspnoea, headache, dizziness, weakness,
churis trichiura and multiple doses are required to produce tartrato(4-)]diantimonate(2-) trihydrate. pruritus, skin rashes, facial oedema, fever, haemolytic anaemia,
worthwhile reductions in egg production. Treatment for 3 days and kidney damage.
has been used4 (but for a suggestion that such regimens may be Антимонил-тартрат Калия
Large oral doses of antimony compounds have an emetic action.
associated with impaired growth in less heavily infected chil- C 8 H 4 K 2 O 12 Sb 2,3H 2O = 667.9. Continuous treatment with small doses of antimony may give
dren, see Effects on Growth under Adverse Effects, above). C AS — 11071-15-1 (anhydrous antimony potassium tar- rise to symptoms of subacute poisoning similar to those of chron-
Combined use of albendazole with ivermectin may prove use- trate); 28300-74-5 (antimony potassium tartrate trihy- ic arsenical poisoning.
ful.5 drate). Treatment of severe poisoning with antimony compounds is sim-
1. Hall A, Anwar KS. Albendazole and infections with Trichuris ilar to that for arsenic poisoning (p.2261); dimercaprol may be of
trichiura and Giardia intestinalis. Southeast Asian J Trop Med
Public Health 1991; 22: 84–7. benefit.
O O
2. Hall A, Nahar Q. Albendazole and infections with Ascaris lum- ◊ References.
bricoides and Trichuris trichiura in children in Bangladesh. 1. Stemmer KL. Pharmacology and toxicology of heavy metals: an-
Trans R Soc Trop Med Hyg 1994; 88: 110–12. timony. Pharmacol Ther 1976; 1: 157–60.
3. Albonico M, et al. A randomized controlled trial comparing me- O O O O
bendazole and albendazole against Ascaris, Trichuris and hook- K+ Sb- Sb -
K+ Precautions
worm infections. Trans R Soc Trop Med Hyg 1994; 88: 585–9. O O O O Trivalent antimony therapy has generally been superseded by
4. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New less toxic treatment. It is contra-indicated in the presence of lung,
Rochelle NY: The Medical Letter, 2007. heart, liver, or kidney disease. Intravenous injections should be
5. Ismail MM, Jayakody RL. Efficacy of albendazole and its com- O O given very slowly and stopped if coughing, vomiting, or subster-
binations with ivermectin or diethylcarbamazine (DEC) in the nal pain occurs; extravasation should be avoided.
treatment of Trichuris trichiura infections in Sri Lanka. Ann Trop Pharmacopoeias. In US. Some antimony compounds such as the tartrates cause severe
Med Parasitol 1999; 93: 501–4.
USP 31 (Antimony Potassium Tartrate). Odourless, colourless, pain and tissue necrosis and should not be given by intramuscu-
Preparations transparent crystals or white powder. The crystals effloresce on lar or subcutaneous injection.
exposure to air and do not readily rehydrate even on exposure to Breast feeding. The American Academy of Pediatrics1 states
USP 31: Albendazole Tablets. high humidity. Soluble 1 in 12 of water, 1 in 3 of boiling water, that there have been no reports of any clinical effect on the infant
Proprietary Preparations (details are given in Part 3) and 1 in 15 of glycerol; insoluble in alcohol. Its solutions are acid associated with the use of antimony by breast-feeding mothers,
Arg.: Vastus; Austral.: Eskazole; Zentel; Austria: Eskazole; Braz.: Alba-3; to litmus. and that therefore it may be considered to be usually compatible
Albel; Alben†; Albendrox†; Albendy†; Albenix†; Albentel; Albenzonil; Al- with breast feeding.
bezin†; Alib†; Alin; Alzoben†; Bentiamin†; Benzol; Imavermil; Mebenix;
Monozol; Neo Bendazol; Parasin; Parazol; Totelmin†; Verdazol†; Vermiclase; Antimony Sodium Tartrate 1. American Academy of Pediatrics. The transfer of drugs and oth-
Vermital; Zentel; Zolben; Zoldan†; Chile: Ceprazol; Vermoil; Zentel; Cz.: er chemicals into human milk. Pediatrics 2001; 108: 776–89.
Zentel; Fr.: Zentel; Ger.: Eskazole; Gr.: Eskazole; Zentel; India: Albezole; Antim. Sod. Tart.; Antimónico sódico, tartrato; Sodium Antimo- Correction. ibid.; 1029. Also available at:
Bendex; Combantrin-A; Emanthal; Nemozole; Olworm; Zentel; Israel: Es- nyltartrate; Stibium Natrium Tartaricum. Disodium bis{μ-[2,3-di- h t tp : // a a pp o l ic y. a a p p u bl i c a t i on s . o rg /c gi / c o n te nt / f u ll /
kazole; Ital.: Zentel; Malaysia: Albendol; Champs D-Worms; Thelban†; hydroxybutanedioato(4-)-O1,O2:O3,O4]}diantimonate(2-); Diso- pediatrics%3b108/3/776 (accessed 02/06/04)
Vemizol; Zentel; Zoben; Mex.: Albensil; Aldamin; Alfazol; Bendapar;
Bradelmin; Dazocan; Dazolin; Dezabil; Digezanol; Entoplus; Eskazole; Eural- dium bis{μ-[L-(+)-tartrato(4-)]}diantimonate(2-). Glucose-6-phosphate dehydrogenase deficiency. In the
ben; Flatezol†; Gascop; Helmisons; Kolexan; Loveral; Lurdex; Olbendital; Ri- event of trivalent antimony compounds being used, patients with
vazol; Serbendazol; Synparyn; Tenibex; Veranzol; Vermilan†; Vermin Plus;
Антимонил-тартрат Натрия G6PD deficiency should be excluded. WHO lists stibophen1
Vermisen; Zelfin; Zenaxin; Zentel; Neth.: Eskazole; Philipp.: Zentel; Pol.: C 8 H 4 Na 2 O 12 Sb 2 = 581.6. among the anthelmintics to be avoided in patients with this defi-
Zentel; Port.: Zentel; Rus.: Nemozole (Немозол); S.Afr.: Bendex; Zentel;
Singapore: Alzental; Zentel; Spain: Eskazole; Switz.: Zentel; Thai.: Aben- C AS — 34521-09-0. ciency.
tel; Albatel; Alben; Albenda; Alda†; Alfuca; Alzol; Anthel†; Gendazel; Laben- 1. WHO. Glucose-6-phosphate dehydrogenase deficiency. Bull
da; Leo-400; Manoverm; Masaworm†; Mesin; Mycotel; Vermixide; Zeben; Pharmacopoeias. In Int. (as C4H4NaO7Sb = 308.8) and US. WHO 1989; 67: 601–11.
Zela; Zentel; Zenzera; Turk.: Andazol; UAE: Albenda; USA: Albenza; Ven- USP 31 (Antimony Sodium Tartrate). Odourless, colourless,
ez.: Albezol; Albicar; Bevindazol; Helal; Sostril; Taron; Vendazol; Zentel. transparent crystals or white powder. The crystals effloresce on Pharmacokinetics
exposure to air. Freely soluble in water; insoluble in alcohol. Antimony compounds are poorly absorbed from the gastrointes-
Multi-ingredient: Mex.: Oxal. tinal tract. They are slowly excreted, mainly in the urine, after
parenteral doses. Antimony accumulates in the body during
Sodium Stibocaptate (BAN, rINN) treatment and persists for several months afterwards. Trivalent
Antimony Sodium Dimercaptosuccinate; Estibocaptato de sodio; antimony has a greater affinity for cell proteins than for plasma
Amocarzine (rINN) proteins.
Natrii Stibocaptas; Ro-4-1544/6; Sb-58; Stibocaptate; Stibocap-
Amocarzina; Amocarzinum; CGP-6140. 4-Methyl-4′-(p-ni- tate de Sodium; TWSb/6. Antimony sodium meso-2,3-dimercap- Uses and Administration
troanilino)thio-1-piperazinecarboxanilide. tosuccinate. The formula varies from Trivalent antimony compounds were used in the treatment of the
Амокарзин C12H11NaO12S6Sb2 = 806.1 to C12H6Na6O12S6Sb2 = 916.0. protozoal infection leishmaniasis until the advent of the less toxic
pentavalent compounds. They continued to be used in the treat-
C 18 H 21N 5 O 2 S = 371.5. Натрия Стибокаптат ment of schistosomiasis, but have now been superseded by less
C AS — 36590-19-9. C AS — 3064-61-7 (C 12 H 6 Na 6 O 12S 6Sb 2 ). toxic and more easily given drugs such as praziquantel.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
142 Anthelmintics
Antimony sodium tartrate was formerly used as an emetic. The Bithionol (BAN, rINN) Profile
sodium tartrate and potassium tartrate have also been used as ex- Cambendazole is a benzimidazole carbamate anthelmintic struc-
Bithionololum; Bithionolum; Bitionol; Bitionolol; Bitionololi. 2,2′-
pectorants. turally related to tiabendazole (p.156). It is used in the treatment
Thiobis(4,6-dichlorophenol). of strongyloidiasis.
Preparations Битионол
Preparations
Proprietary Preparations (details are given in Part 3) C 12 H 6Cl 4 O 2 S = 356.1.
C AS — 97-18-7. Proprietary Preparations (details are given in Part 3)
Multi-ingredient: Thai.: Brown Mixture. Braz.: Cambem†.
ATC — D10AB01; P02BX01.
ATC Vet — QD10AB01; QP52AG07. Multi-ingredient: Braz.: Exelmin†.

Ascaridole
Cl Cl Chenopodium Oil
Ascaridol. 1-Isopropyl-4-methyl-2,3-dioxabicyclo[2.2.2]oct-5-
ene. OH Aceite de quenopodio; Aetheroleum Chenopodii; Esencia de
Quenopodio Vermifuga; Oil of American Wormseed; Wurmsa-
Аскаридол menöl.
C 10 H 16 O 2 = 168.2. Cl S Cl Амброзиевое Масло; Маревое Масло
C AS — 512-85-6. C AS — 8006-99-3.
OH
Profile
Pharmacopoeias. Fr. includes bithionol oxide for veterinary Chenopodium oil is distilled with steam from the fresh flowering
use. and fruiting plants, excluding roots, of Chenopodium ambrosio-
CH3 ides var. anthelminticum. It contains ascaridole. It was formerly
H 3C Adverse Effects used as an anthelmintic for the expulsion of roundworms (As-
O O Adverse effects in patients taking bithionol by mouth include an- caris) and hookworms. It is toxic and has caused numerous fatal-
CH3 orexia, nausea, vomiting, abdominal discomfort, diarrhoea, sali- ities.
vation, dizziness, headache, and skin rashes.
Handling. Chenopodium oil may explode when heated.
Profile Photosensitivity reactions have occurred in persons using soap
Ascaridole is the active principle of chenopodium oil (p.142) and containing bithionol. Cross-sensitisation with other halogenated
has the same actions. disinfectants has also occurred.
Uses and Administration Clorsulon (BAN, USAN, rINN)
Handling. Ascaridole is an unstable liquid which is liable to ex- Bithionol is a chlorinated bis-phenol with bactericidal and an-
plode when heated or when treated with organic acids. Clorsulón; Clorsulone; Clorsulonum; MK-401. 4-Amino-6-
thelmintic properties. It is active against most trematodes (trichlorovinyl)benzene-1,3-disulphonamide.
(flukes). Bithionol is used in preference to praziquantel in fasci-
Клорсулон
oliasis (see Liver Fluke Infections, p.137) and is also used in
paragonimiasis (see Lung Fluke Infections, p.137) as an alterna- C 8 H 8 Cl 3 N 3 O 4 S 2 = 380.7.
Bephenium Hydroxynaphthoate (BAN, rINN) tive to praziquantel. It may be given in an oral dose of 30 to C AS — 60200-06-8.
Bephenii Hydroxynaphthoas; Béphénium, Hydroxynaphtoate de; 50 mg/kg on alternate days for 10 to 15 doses. Alternatively, for
Hidroxinaftoato de befenio; Naphthammonum. Benzyldime- fascioliasis, WHO recommends a regimen of 30 mg/kg daily for
5 days. H2N
thyl(2-phenoxyethyl)ammonium 3-hydroxy-2-naphthoate. O
Bithionol was formerly used topically as a bactericide but this S
Бефения Гидроксинафтоат use has declined because of photosensitivity reactions. O
Cl O
C 28 H 29 NO 4 = 443.5. Preparations
C AS — 7181-73-9 (bephenium); 3818-50-6 (bephenium S NH2
Proprietary Preparations (details are given in Part 3)
hydroxynaphthoate). Cl
Multi-ingredient: Arg.: Fonergine. O
ATC — P02CX02.
Cl NH2

CH3 Bromofenofos (rINN) Pharmacopoeias. In US for veterinary use only.

O COO USP 31 (Clorsulon). A white to off-white powder. Slightly sol-
N Bromfenofos; Bromofénofos; Bromofenofós; Bromofenofosum;
uble in water; freely soluble in acetonitrile and in methyl alcohol;
Bromophenophos; Bromphenphos. 3,3′,5,5′-Tetrabromo-2,2′-
very slightly soluble in dichloromethane.
CH3 OH biphenyldiolmono(dihydrogen phosphate).
Бромофенофос Profile
Clorsulon is an anthelmintic used in veterinary medicine for the
Pharmacopoeias. In Int. C 12 H 7Br 4 O 5 P = 581.8. treatment of liver fluke infections.
C AS — 21466-07-9.
Profile ATC Vet — QP52AB02.
Bephenium hydroxynaphthoate is an anthelmintic formerly used
in the treatment of hookworm infections, ascariasis, and tricho-
strongyliasis. Closantel (BAN, USAN, rINN)
Br Closantelum; R-31520. 5′-Chloro-4′-(4-chloro-α-cyanobenzyl)-
3,5-di-iodosalicyl-o-toluidide.
OH Клозантел
Betanaphthol C 22 H 14Cl 2 I 2 N 2 O 2 = 663.1.
Br
β-Naftol; 2-Naftol; Naphthol. Naphth-2-ol. Br C AS — 57808-65-8.
HO ATC Vet — QP52AG09.
Бета-нафтол O
C 10 H 8 O = 144.2. P
O
C AS — 135-19-3. OH Br Cl
I
Profile O CH3
OH Bromofenofos is an organophosphorus compound (see Organo-
phosphorus Insecticides, p.2047) used as an anthelmintic in vet-
erinary medicine for the treatment of fluke infections. HN
I OH
Pharmacopoeias. In Pol. and Swiss. Cl N
Cambendazole (BAN, USAN, rINN)
Profile
Cambendazol; Cambendazolum; MK-905. Isopropyl 2-(thiazol-4-
Betanaphthol was formerly used as an anthelmintic in hook-
worm and tapeworm infections, but it has been superseded by yl)-1H-benzimidazol-5-ylcarbamate. Closantel Sodium (BANM, rINNM)
less toxic and more efficient drugs. Камбендазол Closantel sódico; Closantel sodique; Closantelum natricum;
Betanaphthol has a potent parasiticidal effect and has been used C 14 H 14N 4 O 2 S = 302.4. Klosanteelinatrium; Klosantel sodná sůl; Klosantelnatrium; Natrii
topically in the treatment of scabies, ringworm, and other skin C AS — 26097-80-3. Closantelum; R-34828.
diseases. ATC Vet — QP52AC08. Натрий Клозантел
Betanaphthyl benzoate has been used in preparations for the C 22 H 14Cl 2 I 2 N 2 O 2 Na = 686.1.
treatment of gastrointestinal disorders. H Pharmacopoeias. In Eur. (see p.vii) as the dihydrate for veter-
N inary use.
Preparations CH3 O S Ph. Eur. 6.2 (Closantel Sodium Dihydrate for Veterinary Use;
Proprietary Preparations (details are given in Part 3) Closantel Sodium Dihydrate BP(Vet) 2008). A yellow, slightly
Multi-ingredient: Arg.: Hekabetol; Austria: Salvyl. H 3C O N N N hygroscopic, powder. It exhibits polymorphism. Very slightly
H soluble in water; freely soluble in alcohol; soluble in methyl al-
cohol. Store in airtight containers. Protect from light.
 Ascaridole/Diethylcarbamazine Citrate 143
Profile Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US. normally excluded when diethylcarbamazine is used in
Closantel is an anthelmintic used in veterinary medicine for the Ph. Eur. 6.2 (Diethylcarbamazine Citrate). A white or almost mass treatment schedules.
treatment of fluke and nematode infections. white, crystalline, slightly hygroscopic powder. Very soluble in
Effects on the eyes. Loss of eyesight was reported in 11 wom- water; soluble in alcohol; practically insoluble in acetone. Store Pregnancy. Pregnant women are normally excluded when di-
en who received closantel (Flukiver) in mistake for a gynaeco- in airtight containers. ethylcarbamazine is used in mass treatment schedules.
logical product.1 Sight was restored after closantel was stopped USP 31 (Diethylcarbamazine Citrate). A white, crystalline, Animal studies1 suggest that the uterine hypermotility induced by
but incapacitating eye pain remained. slightly hygroscopic powder, odourless or has a slight odour. diethylcarbamazine is mediated via prostaglandin synthesis; this
1. ’t Hoen E, et al. Harmful human use of donated veterinary drug. Very soluble in water; sparingly soluble in alcohol; practically in- might explain the mechanism of the abortifacient action previ-
Lancet 1993; 342: 308–9. soluble in acetone, in chloroform, and in ether. Store in airtight ously reported.2
containers.
1. Joseph CA, Dixon PAF. Possible prostaglandin-mediated effect
of diethylcarbamazine on rat uterine contractility. J Pharm Phar-
Diamfenetide (BAN, rINN) Adverse Effects macol 1984; 36: 281–2.
Diamfenetida; Diamfénétide; Diamfenetidum; Diamphenethide. Adverse effects directly attributable to diethylcar- 2. Subbu VSV, Biswas AR. Ecbolic effect of diethyl carbamazine.
Indian J Med Res 1971; 59: 646–7.
β,β′-Oxybis(aceto-p-phenetidide). bamazine include nausea and vomiting. Headache, diz-
Диамфенетид ziness, and drowsiness may occur. Renal impairment. For a study on the effects of renal impair-
C 20 H 24N 2 O 5 = 372.4. ment on the pharmacokinetics of diethylcarbamazine, see under
Hypersensitivity reactions arise from the death of the Pharmacokinetics, below.
C AS — 36141-82-9.
microfilariae. These can be serious, especially in on-
chocerciasis where there may also be sight-threatening Pharmacokinetics
O
O
O
O
O
ocular toxicity; fatalities have been reported. Encepha- Diethylcarbamazine is readily absorbed from the gas-
litis may be exacerbated in patients with loiasis and fa- trointestinal tract and also through the skin and con-
H C N N CH talities have occurred.
H H junctiva. It is widely distributed in tissues and is mainly
◊ Reactions occurring during diethylcarbamazine treatment of excreted in the urine unchanged and as the N-oxide
Profile lymphatic filariasis are basically of 2 types: pharmacological metabolite. Urinary excretion and hence plasma half-
Diamfenetide is an anthelmintic that has been used in veterinary dose-dependent responses and a response of the infected host to
medicine for the control of fascioliasis in sheep. life is dependent on urinary pH. About 5% of a dose is
the destruction and death of parasites.1
eliminated in the faeces.
• Reactions of the first type include weakness, dizziness, lethar-
gy, anorexia, and nausea. They begin within 1 to 2 hours of Disposition. A pharmacokinetic study in 6 patients with
Dichlorophen (BAN, rINN) taking diethylcarbamazine, and persist for a few hours. onchocerciasis1 indicated that diethylcarbamazine is absorbed
Dichlorophène; Dichlorophenum; Diclorofeno; Di-phenthane- • Reactions of the second type are less likely to occur and are quickly and almost completely from the gastrointestinal tract,
70; G-4. 2,2′-Methylenebis(4-chlorophenol). less severe in bancroftian than in brugian filariasis. They may and is eliminated largely as unchanged drug in urine, with rela-
be systemic or local, both with or without fever. tively small amounts being excreted as the N-oxide metabolite.
Дихлорофен After a single radioactively labelled oral dose of diethylcar-
C 13 H 10Cl 2 O 2 = 269.1. Systemic reactions may occur a few hours after the first oral bamazine citrate 0.5 mg/kg given as an aqueous solution, peak
C AS — 97-23-4. dose of diethylcarbamazine and generally do not last for more plasma concentrations of 100 to 150 nanograms/mL were
ATC — P02DX02. than 3 days. They include headache, aches in other parts of the achieved in 1 to 2 hours, followed by a sharp decline, then a
ATC Vet — QP52AG01. body, joint pain, dizziness, anorexia, malaise, transient haem- marked secondary rise 3 to 6 hours after dosing, followed by a
aturia, allergic reactions, vomiting, and sometimes attacks of steady decline. The half-life ranged from 9 to 13 hours. Urinary
bronchial asthma in asthmatic patients. Fever and systemic re- excretion of diethylcarbamazine and diethylcarbamazine N-ox-
OH OH actions are positively associated with microfilaraemia. Sys- ide was complete within 96 hours; between 4 and 5% of the dose
temic reactions are reduced if diethylcarbamazine is given in was recovered in the faeces. Disposition was similar in 5 healthy
spaced doses or in repeated small doses. They eventually subjects given a single 50-mg tablet of diethylcarbamazine cit-
cease spontaneously and interruption of treatment is rarely rate. Peak plasma concentrations were initially 80 to
necessary; symptomatic treatment with antipyretics or analge- 200 nanograms/mL, with a secondary rise 3 to 9 hours after dos-
sics may be helpful. ing, the terminal half-life ranged from 5 to 13 hours, and urinary
Cl Cl Local reactions tend to occur later in the course of treatment excretion of unchanged diethylcarbamazine and the N-oxide was
and last longer; they also disappear spontaneously and inter- complete within 48 hours.
Pharmacopoeias. In Br. and Fr. ruption of treatment is not necessary. Local reactions include
When an alkaline urinary pH was maintained, the elimination
BP 2008 (Dichlorophen). A white or slightly cream-coloured lymphadenitis, abscess, ulceration, and transient lymphoede-
half-life of diethylcarbamazine and the area under the plasma
powder with a not more than slightly phenolic odour. Practically ma; funiculitis and epididymitis may also occur in bancroftian
concentration versus time curve were significantly increased
insoluble in water; freely soluble in alcohol; very soluble in ether. filariasis.
compared with when an acidic urinary pH was maintained.2
Profile It has been suggested that the release of interleukin-6 may be im-
1. Edwards G, et al. Diethylcarbamazine disposition in patients
Dichlorophen is an anthelmintic that was used in the treatment of plicated in diethylcarbamazine’s adverse effects in patients with with onchocerciasis. Clin Pharmacol Ther 1981; 30: 551–7.
infection by tapeworms but has been superseded by praziquantel lymphatic filariasis.2 2. Edwards G, et al. The effect of variations in urinary pH on the
or niclosamide. In most patients with onchocerciasis, the microfilaricidal activi- pharmacokinetics of diethylcarbamazine. Br J Clin Pharmacol
ty of diethylcarbamazine leads to a series of events with dermal, 1981; 12: 807–12.
Dichlorophen also has antifungal and antibacterial activity and
has been used topically in the treatment of fungal infections and ocular, and systemic components, known as the Mazzotti reac- Renal impairment. Results in patients with chronic renal im-
as a germicide in soaps and cosmetics. tion, within minutes to hours after its use.3 pairment and in healthy subjects, given a single 50-mg oral dose
Preparations • Clinical manifestations can be severe, dangerous, and debili- of diethylcarbamazine citrate, indicated that the plasma half-life
tating. Systemic reactions include increased itching, rash, of diethylcarbamazine is prolonged and its 24-hour urinary ex-
BP 2008: Dichlorophen Tablets.
headache, aching muscles, joint pain, painful swollen and cretion considerably reduced in those with moderate and severe
Proprietary Preparations (details are given in Part 3) tender lymph nodes, fever, tachycardia and hypotension, and degrees of renal impairment.1 Mean plasma half-lives in 7 pa-
Multi-ingredient: S.Afr.: Mycota†; UK: Mycota. vertigo. Most patients have eye discomfort in the first few tients with severe renal impairment (creatinine clearance less
hours after diethylcarbamazine treatment. Punctate keratitis than 25 mL/minute), in 5 patients with moderate renal impair-
can develop as can optic neuritis and visual field loss. ment (creatinine clearance between 25 and 60 mL/minute), and
WHO no longer recommends the use of diethylcarbamazine in in 4 healthy subjects, were 15.1, 7.7, and 2.7 hours, respectively.
Diethylcarbamazine Citrate onchocerciasis as safer alternatives exist. The patient with the longest plasma half-life of 32 hours did not
(BANM, rINNM) 1. WHO. Lymphatic filariasis: the disease and its control: fifth re-
have the poorest renal function, but it was considered likely that
port of the WHO expert committee on filariasis. WHO Tech Rep the abnormally slow elimination of diethylcarbamazine was due
Citrato de dietilcarbamazina; Diethylcarbam. Cit.; Diethylcar- to the high urinary pH (7) resulting from sodium bicarbonate
Ser 821 1992.
bamazine Acid Citrate; Diéthylcarbamazine, citrate de; Diethyl- 2. Yazdanbakhsh M, et al. Serum interleukin-6 levels and adverse therapy. A further patient with a half-life longer than expected
carbamazini citras; Diethylkarbamazin-citrát; Dietilkarbamazin- reactions to diethylcarbamazine in lymphatic filariasis. J Infect also had a less acidic urine.
citrát; Dietilkarbamazino citratas; Dietylkarbamazincitrat; Dietyy- Dis 1992; 166: 453–4.
1. Adjepon-Yamoah KK, et al. The effect of renal disease on the
likarbamatsiinisitraatti; Ditrazini Citras; RP-3799. NN-Diethyl-4- 3. WHO. WHO expert committee on onchocerciasis: third report. pharmacokinetics of diethylcarbamazine in man. Br J Clin Phar-
methylpiperazine-1-carboxamide dihydrogen citrate. WHO Tech Rep Ser 752 1987. macol 1982; 13: 829–34.
Диэтилкарбамазина Цитрат
C 10 H 21N 3 O,C 6 H 8 O 7 = 391.4. Precautions Uses and Administration
C AS — 90-89-1 (diethylcarbamazine); 1642-54-2 (di- Treatment with diethylcarbamazine should be closely Diethylcarbamazine is an anthelmintic used in the
ethylcarbamazine citrate). supervised since hypersensitivity reactions are com- treatment of lymphatic filariasis due to Wuchereria
ATC — P02CB02. mon and may be severe, especially in patients with on- bancrofti (bancroftian filariasis), Brugia malayi, or B.
chocerciasis or loiasis. Patients with onchocerciasis timori (both known as brugian filariasis and as Malay-
should be monitored for eye changes. (The use of di- an and Timorian filariasis respectively). It is also used
O
ethylcarbamazine to treat onchocerciasis is no longer in loiasis due to Loa loa. It was used in onchocerciasis
recommended.) In patients with heavy Loa loa infec- due to Onchocerca volvulus before ivermectin became
N N CH3
tion there is a small risk of encephalopathy and diethyl- available. Diethylcarbamazine is active against both
N carbamazine should be stopped at the first sign of cer- the microfilariae and adult worms of W. bancrofti, B.
H 3C CH3 ebral involvement. malayi, and Loa loa, but only against the microfilariae
(diethylcarbamazine) Infants, pregnant women, the elderly, and the debilitat- of O. volvulus. It has been tried in Mansonella infec-
ed, especially those with cardiac or renal disease, are tions and may be most effective against M. streptocer-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
144 Anthelmintics
ca. Diethylcarbamazine is also used in the treatment of Disophenol
toxocariasis (visceral larva migrans). For discussions Disofenol. 2,6-Diiodo-4-nitrophenol. O H C
of these infections and their treatment, see under C 6 H 3 I 2NO 3 = 390.9.
O
H C HN H C
Choice of Anthelmintic, p.134, and under the individ- C AS — 305-85-1. O

ual headings below. H C O

O
CH CH
H H
O O
Diethylcarbamazine is usually given orally as the cit- H C O
O
CH

rate. I H
H H
H C R
-O
In the treatment of lymphatic filariasis the recom- O O

mended dose of diethylcarbamazine citrate is 6 mg/kg N+ OH OH H

daily in 3 divided doses for 3 weeks, given in an initial O O

CH
dosage of 1 mg/kg daily and then gradually increased I H
OH
to 6 mg/kg daily over 3 days to reduce the incidence
and severity of hypersensitivity reactions due to the de- Profile Pharmacopoeias. In US.
struction of microfilariae. However, adverse effects of Disophenol is an anthelmintic used in veterinary medicine. USP 31 (Eprinomectin). Eprinomectin is a mixture of compo-
diethylcarbamazine may be reduced, without loss of nent B1a (C50H75NO14 = 914.1) and component B1b
(C49H73NO14 = 900.1). It contains not less than 90% of compo-
efficacy, by giving a single dose of 6 mg/kg at weekly nent B1a and not less than 95% of components B1a and B1b, cal-
or monthly intervals. In areas where lymphatic filaria- Doramectin (BAN, USAN, rINN) culated on the anhydrous, solvent-free, and antoxidant-free basis.
sis is endemic, mass treatment campaigns can reduce Antoxidants may be added. A white to off-white powder. Insol-
the intensity of transmission and incidence of disease. Doramectina; Doramectine; Doramectinum; Doramektiini; Do- uble in cold water. Store in airtight containers at 2° to 8°.
ramektin; UK-67994.
Diethylcarbamazine may also be used in the form of Profile
medicated salt to control lymphatic filariasis. For fur- Дорамектин Eprinomectin is an avermectin anthelmintic used in veterinary
ther details, see below. C AS — 117704-25-3. medicine for nematode infections. It is also used as a systemic
ATC Vet — QP54AA03. veterinary ectoparasiticide.
In the treatment of loiasis diethylcarbamazine citrate
6 mg/kg daily in 3 divided doses for 2 to 4 weeks has
been given. In heavy infections rapid killing of micro- H C
O Epsiprantel (BAN, rINN)
filariae can cause severe adverse effects including en- HO H C BRL-38705; Epsipranteeli; Epsiprantelum. 2-Cyclohexylcarbonyl-
O
cephalitis and treatment should start with very small 1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepin-4-one.
O
doses, increasing gradually over 4 days. A corticoster- H C O
H
CH
H
CH Эпсипрантел
oid has been given concurrently. In the prophylaxis of H C O
O O C 20 H 26N 2 O 2 = 326.4.
loiasis, a dose of 300 mg weekly is recommended by H O C AS — 98123-83-2.
H C ATC Vet — QP52AA04.
WHO.
O O
In the treatment of toxocariasis diethylcarbamazine OH H
citrate 9 mg/kg daily in 3 divided doses for 21 days has O
been given. Diethylcarbamazine is considered by some O
CH
to be the treatment of choice while others do not rec- H N
OH
ommend its use due to higher rates of severe adverse O N
effects. Profile
Doramectin is an avermectin anthelmintic used in veterinary
Administration. Diethylcarbamazine was first used as the medicine for nematode infections. It is also used as a systemic
chloride, but was subsequently produced as the dihydrogen cit- veterinary ectoparasiticide.
rate which contains only half its weight as base. In reporting dos-
es it was therefore important to indicate whether they referred to
a specific salt or to the base; unless otherwise stated, it could gen-
erally be assumed that the dose referred to the citrate.1 Profile
Embelia
1. WHO. Lymphatic filariasis: fourth report of the WHO expert Epsiprantel is an anthelmintic closely related to praziquantel. It
committee on filariasis. WHO Tech Rep Ser 702 1984. Available Vidang. is used in veterinary medicine.
at: http://libdoc.who.int/trs/WHO_TRS_702.pdf (accessed
16/07/08) Виданга
C AS — 550-24-3 (embelic acid).
Loiasis. Diethylcarbamazine is the main drug used in the man- Febantel (BAN, USAN, rINN)
agement of loiasis (p.137).
Bay-h-5757; Bay-Vh-5757; Febanteeli; Fébantel; Febantelum. 2′-
References. O [2,3-Bis(methoxycarbonyl)guanidino]-5′-phenylthio-2-methoxy-
1. Nutman TB, et al. Loa loa infection in temporary residents of acetanilide; Dimethyl {2-[2-(2-methoxyacetamido)-4-(phenylth-
endemic regions: recognition of a hyperresponsive syndrome OH io)phenyl]imidocarbonyl}dicarbamate.
with characteristic clinical manifestations. J Infect Dis 1986;
154: 10–18. Фебантел
2. Nutman TB, et al. Diethylcarbamazine prophylaxis for human C 20 H 22N 4 O 6 S = 446.5.
loiasis: results of a double-blind study. N Engl J Med 1988; 319:
HO C AS — 58306-30-2.
752–6. ATC Vet — QP52AC05.
O
3. Nutman TB, Ottesen EA. Diethylcarbamazine and human loia- H 3C
sis. N Engl J Med 1989; 320: 320.
4. Klion AD, et al. Effectiveness of diethylcarbamazine in treating H 3C
loiasis acquired by expatriate visitors to endemic regions: long- (embelic acid)
term follow-up. J Infect Dis 1994; 169: 604–10. O O

Lymphatic filariasis. Diethylcarbamazine is used in the man- Profile O HN

agement of lymphatic filariasis (p.137). In endemic areas mass Embelia consists of the dried fruits of Embelia ribes and E. ro- HN O CH3
treatment of the entire population (excluding neonates, pregnant busta ( = E. tsjeriamcottam) (Myrsinaceae), containing about
2.5% of embelic acid (embelin). It has been used in India and N
women, and debilitated individuals) can reduce the intensity of
transmission and the incidence of disease. In countries where other Asian countries for the expulsion of tapeworms.
there is no co-endemic loiasis or onchocerciasis, the Global Pro- Preparations NH
gramme to Eliminate Lymphatic Filariasis launched by WHO to-
gether with other international agencies, advocates a single dose Proprietary Preparations (details are given in Part 3)
of diethylcarbamazine citrate 6 mg/kg with a single dose of al- Multi-ingredient: India: Happy’tizer. S O O CH3
bendazole 400 mg, given once each year for at least 5 years. If
diethylcarbamazine-medicated salt is to be employed then intake
of salt needs to be on a daily basis for 6 to 12 months.
Eprinomectin (USAN, rINN) Pharmacopoeias. In Eur. (see p.vii) for veterinary use only.
Preparations Ph. Eur. 6.2 (Febantel for Veterinary Use; Febantel BP(Vet)
Eprinomectina; Éprinomectine; Eprinomectinum; Eprinomektiini; 2008). A white or almost white, crystalline powder. It exhibits
BP 2008: Diethylcarbamazine Tablets; Eprinomektin; MK-397. A mixture of eprinomectin component polymorphism. Practically insoluble in water; slightly soluble in
USP 31: Diethylcarbamazine Citrate Tablets. dehydrated alcohol; soluble in acetone.
B1a and eprinomectin component B1b.
Proprietary Preparations (details are given in Part 3) Profile
Эприномектин
Fr.: Notezine; Gr.: Hetrazan†; Notezine; India: Banocide; Hetrazan; Thai.: Febantel is an anthelmintic used in veterinary medicine for the
Diethizine. C AS — 159628-36-1 (eprinomectin); 123997-26-2 (epri-
nomectin); 133305-88-1 (component B 1a ); 133305-89-2 treatment of nematode infections of the gastrointestinal tract and
Multi-ingredient: India: Helmazan†; Unicarbazan. (component B 1b ). lungs and in tapeworm infections.
ATC Vet — QP54AA04.
 Disophenol/Ivermectin 145
Fenbendazole (BAN, USAN, rINN) Profile
Fenbendatsoli; Fenbendazol; Fenbendazolum; Hoe-881V. Methyl Haloxon is an organophosphorus compound (see Organophos-
phorus Insecticides, p.2047) used as an anthelmintic in veteri- H C
5-phenylthio-1H-benzimidazol-2-ylcarbamate. O
nary medicine. HO H C
Фенбендазол O
C 15 H 13N 3 O 2 S = 299.3. O
H C O CH CH
C AS — 43210-67-9. H H
ATC — P02C A06. O O
Hycanthone (USAN, rINN) H C O CH
ATC Vet — QP52AC13. H O
H H
Hicantona; Hycanthonum; NSC-134434; Win-24933. 1-(2-Di- H C R
ethylaminoethylamino)-4-hydroxymethylthioxanthen-9-one. O O
H O OH H
N Гикантон
N OCH3 C 20 H 24 N 2 O 2 S = 356.5. O
H CH
C AS — 3105-97-3. H
S N OH

Pharmacopoeias. In Eur. (see p.vii) and US for veterinary use

only. H3C CH3 Pharmacopoeias. In Eur. (see p.vii) and US.
Ph. Eur. 6.2 (Fenbendazole for Veterinary Use; Fenbendazole N Ph. Eur. 6.2 (Ivermectin). A mixture of ivermectin comp-
BP(Vet) 2008). A white or almost white powder. Practically in- onent H2B1a (5-O-demethyl-22,23-dihydroavermectin A1a;
OH C48H74O14 = 875.1) and ivermectin component H2B1b (5-O-
soluble in water; sparingly soluble in dimethylformamide; very
slightly soluble in methyl alcohol. Protect from light. HN demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-di-
USP 31 (Fenbendazole). A white to off-white powder. Practical- hydroavermectin A1a; C47H72O14 = 861.1).
ly insoluble in water; sparingly soluble in dimethylformamide; A white or yellowish-white, slightly hygroscopic, crystalline
very slightly soluble in methyl alcohol. Store at a temperature of O S powder. Practically insoluble in water; soluble in alcohol; freely
25°, excursions permitted between 15° and 30°. Protect from soluble in dichloromethane. Store in airtight containers.
light. USP 31 (Ivermectin). A mixture of component H2B1a (5-O-
demethyl-22,23-dihydro-avermectin A1a; C48H74O14 = 875.1)
Profile and component H2B1b (5-O-demethyl-25-de(1-methyl-
Fenbendazole is a benzimidazole carbamate anthelmintic struc-
propyl)-22,23-dihydro-25-(1-methylethyl)-avermectin A1a;
turally related to mebendazole (p.148). It is used in veterinary
medicine. C47H72O14 = 861.1). It may contain small amounts of suitable
Hycanthone Mesilate (rINNM) antoxidant and chelating agents.
A white to yellowish-white, slightly hygroscopic, crystalline
Hycanthone, Mésilate d’; Hycanthone Mesylate; Hycanthoni powder. Practically insoluble in water and in petroleum spirit;
Flubendazole (BAN, USAN, rINN) Mesilas; Hydroxylucanthone Methanesulphonate; Mesilato de hi- soluble in acetone and in acetonitrile; freely soluble in dichlo-
cantona. romethane and in methyl alcohol. Store in airtight containers at a
Flubendatsoli; Flubendazol; Flubendazolas; Flubendazolum; Fluor-
omebendazole; R-17889. Methyl 5-(4-fluorobenzoyl)-1H-benz- Гикантона Мезилат temperature of 2° to 8°. Where the use of an antoxidant is al-
lowed, store at 25°, excursions permitted between 15° and 30°.
imidazol-2-ylcarbamate. C 20 H 24 N 2 O 2 S,CH 3 SO 3 H = 452.6.
Флубендазол C AS — 23255-93-8.
C 16 H 12FN 3 O 3 = 313.3. Adverse Effects and Precautions
C AS — 31430-15-6. Profile
Hycanthone has been used as a schistosomicide in the individual The adverse effects reported with ivermectin in pa-
ATC — P02C A05.
ATC Vet — QP52AC12. or mass treatment of infection with Schistosoma haematobium tients with filariasis are generally consistent with a
and S. mansoni. mild Mazzotti reaction arising from its effect on micro-
Owing to its toxicity and concern about possible carcinogenicity, filariae. They include fever, pruritus, skin rashes, ar-
O mutagenicity, and teratogenicity, hycanthone has been replaced thralgia, myalgia, asthenia, orthostatic hypotension,
by other drugs such as praziquantel. tachycardia, oedema, lymphadenopathy, gastrointesti-
N nal symptoms, sore throat, cough, and headache. The
NH CH3 effects tend to be transient and if treatment is required
F N O they respond to analgesics and antihistamines.
H Hygromycin B
O
Higromicina B. O-6-Amino-6-deoxy-L-glycero-D-galacto-hepto- Ivermectin may cause mild ocular irritation. Somno-
pyranosylidene-(1→2-3)-O-β-D-talopyranosyl-(1→5)-2-deoxy- lence, transient eosinophilia, and raised liver enzyme
Pharmacopoeias. In Eur. (see p.vii).
N3-methyl-D-streptamine.
Ph. Eur. 6.2 (Flubendazole). A white or almost white powder. It values have also been reported.
exhibits polymorphism. Practically insoluble in water, in alco- Гигромицин Б
hol, and in dichloromethane. Protect from light. Ivermectin is not recommended during pregnancy.
C 20 H 37 N 3 O 13 = 527.5.
Profile Mass treatment is generally withheld from pregnant
Flubendazole, a benzimidazole carbamate anthelmintic, is an an- women (see Pregnancy, below), children under 15 kg,
alogue of mebendazole (p.148) and has similar actions and uses. CH3 and the seriously ill.
For the treatment of enterobiasis in adults and children, fluben- HN
dazole 100 mg is given as a single oral dose, repeated after 2 to 3
weeks. For ascariasis, hookworm infections, and trichuriasis OH Incidence of adverse effects. Some studies have shown quite
100 mg is given twice daily for 3 days. For discussions of these a high incidence of adverse effects with ivermectin and have as-
OH sociated the effects with the severity of infection.1-3 However, in
infections and their treatment, see under Choice of Anthelmintic,
p.134. HO none of these studies were the reactions considered to be life-
H 2N O OH
H H threatening and only symptomatic treatment was required. The
Preparations HO O severity, incidence, and duration of adverse reactions was report-
Proprietary Preparations (details are given in Part 3) O ed to be reduced after repeated annual administration.4 When
Arg.: Flumoxal; Fr.: Fluvermal; Port.: Fluvermal; Teniverme; Spain: Flicum; O OH larger groups of patients were considered in the Onchocerciasis
Venez.: Fluvermox. HO O H Control Programme (OCP) in West Africa, a much lower inci-
NH2
H dence of adverse reactions was seen in patients given ivermectin
OH for the first time5 and when treatment was repeated a year later
Haloxon (BAN, rINN) that incidence was reduced even further. The results from several
studies in this programme6 showed 93 severe reactions in 50 929
Haloxón; Haloxone; Haloxonum. Bis(2-chloroethyl) 3-chloro-4- Profile patients (1.83%), most of the reactions being orthostatic hypo-
methylcoumarin-7-yl phosphate. Hygromycin B is an anthelmintic used in veterinary medicine for tension or dizziness (53). In a 3-year randomised, double-blind,
Галоксон nematode infections. controlled study of ivermectin for onchocerciasis control in 572
C 14 H 14Cl 3 O 6 P = 415.6. patients,7 3-monthly treatment with the standard dose of
C AS — 321-55-1. 150 micrograms/kg was associated with a reduced risk of ad-
ATC Vet — QP52AB04. verse reactions, especially oedema, pruritus, and back pain,
Ivermectin (BAN, USAN, rINN) when compared with the same dose given annually. Higher doses
of 400 then 800 micrograms/kg, given either 3-monthly or annu-
Cl Ivermectina; Ivermectine; Ivermectinum; Ivermektiini; Ivermektin; ally, were associated with subjective ocular problems. Another
O Ivermektinas. study8 found 22 severe reactions in 17 877 patients treated for
O O O onchocerciasis in an area also endemic for Loa loa infection, and
O Ивермектин demonstrated a relationship to heavy L. loa microfilaraemia. The
Cl P
C AS — 70288-86-7 (ivermectin); 70161-11-4 (compo- Mectizan® Expert Committee and the Technical Consultative
O nent B 1a ); 70209-81-3 (component B 1b). Committee have reported the incidence of encephalopathy after
Cl
ivermectin treatment of onchocerciasis in Loa loa endemic areas
ATC — P02CF01. to be less than 1 case in 10 000 treatments9 and have implement-
CH3
ATC Vet — QP54AA01; QS02QA03. ed recommendations for ivermectin mass treatment programmes
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
146 Anthelmintics
of onchocerciasis in areas co-endemic for loiasis to reduce the treatment schedules with ivermectin. However, women not yet 2. Whitworth JAG, et al. A field study of the effect of ivermectin on
risk of serious adverse events, especially in areas where the pop- diagnosed as pregnant or unwilling to admit their pregnancy intestinal helminths in man. Trans R Soc Trop Med Hyg 1991;
ulation is ivermectin naive. have been treated. An assessment1 of 203 pregnancy outcomes 85: 232–4.
3. Whitworth JAG, et al. Community-based treatment with iver-
Some supervision is considered necessary after doses of iver- to women who had taken ivermectin during pregnancy, mostly mectin. Lancet 1988; ii: 97–8.
mectin;2,6 the OCP recommendation6 is for resident nurses to during the first 12 weeks, found that the rates of major congenital 4. Naquira C, et al. Ivermectin for human strongyloidiasis and oth-
monitor patients for a period of 36 hours after treatment, whatev- malformation, miscarriage, and still-birth associated with iver- er intestinal helminths. Am J Trop Med Hyg 1989; 40: 304–9.
er the level of endemicity. However, the incidence of adverse re- mectin were similar to those in untreated mothers. In another
Loiasis. There is evidence of reduced microfilaraemia after iver-
actions reported after repeated doses appears to be lower than study, 110 women also inadvertently given ivermectin during
mectin treatment1-5 in patients with loiasis (p.137), but concern
after the first dose and the need for supervision on re-treatment pregnancy experienced a similar lack of adverse effect on preg-
exists over its potential for neurotoxicity in patients with a high
has been questioned.10 nancy outcome;2 it was considered that the precaution of avoid-
microfilarial burden. 6 , 7 Low-dose regimens (about
Neurotoxicity seen in some breeds of dogs has not been seen in ing the use of ivermectin in women notifying a pregnancy should
25 micrograms/kg) have been investigated8 but did not seem to
cattle or horses11 and nor was it reported in man in the above be adequate.
offer much advantage in reducing neurotoxicity.
studies. Another potential concern was the prolongation of pro- 1. Pacqué M, et al. Pregnancy outcome after inadvertent ivermectin 1. Martin-Prevel Y, et al. Reduction of microfilaraemia with single
thrombin times observed in 28 patients given ivermectin,12 but treatment during community-based distribution. Lancet 1990; high-dose of ivermectin in loiasis. Lancet 1993; 342: 442.
others have not confirmed this effect13 or observed any bleeding 336: 1486–9.
2. Ranque S, et al. Decreased prevalence and intensity of Loa loa
disorders.14 2. Chippaux J-P, et al. Absence of any adverse effect of inadvertent infection in a community treated with ivermectin every three
ivermectin treatment during pregnancy. Trans R Soc Trop Med months for two years. Trans R Soc Trop Med Hyg 1996; 90:
There has been some concern over the use of ivermectin to treat Hyg 1993; 87: 318. 429–30.
scabies in elderly patients after a report suggesting a possible link 3. Duong TH, et al. Reduced Loa loa microfilaria count ten to
to an increased incidence of death among a cohort of 47 pa- twelve months after a single dose of ivermectin. Trans R Soc
tients.15 It has, however, been argued that no such association has
Pharmacokinetics Trop Med Hyg 1997; 91: 592–3.
been seen in other populations of elderly patients and that the Ivermectin is absorbed after oral doses, with peak plas- 4. Gardon J, et al. Marked decrease in Loa loa microfilaraemia six
statistical methods used by the original authors were defi- ma concentrations being obtained after about 4 hours. and twelve months after a single dose of ivermectin. Trans R Soc
cient.16-18 There was no evidence of an increase in death rate as- Trop Med Hyg 1997; 91: 593–4.
Ivermectin is reported to be about 93% bound to plas- 5. Chippaux J-P, et al. Impact of repeated large scale ivermectin
sociated with ivermectin in a community-based trial in Papua ma proteins and has a plasma elimination half-life of treatments on the transmission of Loa loa. Trans R Soc Trop Med
New Guinea of diethylcarbamazine with or without ivermectin Hyg 1998; 92: 454–8.
for lymphatic filariasis.19 about 12 hours. It undergoes metabolism and is excret- 6. Anonymous. Encephalitis following treatment of loiasis. WHO
1. Kumaraswami V, et al. Ivermectin for the treatment of ed largely as metabolites over a period of about 2 Drug Inf 1991; 5: 113–14.
Wuchereria bancrofti filariasis: efficacy and adverse reactions. weeks, chiefly in the faeces, with less than 1% appear- 7. Gardon J, et al. Serious reactions after mass treatment of on-
JAMA 1988; 259: 3150–3. chocerciasis with ivermectin in an area endemic for Loa loa in-
2. Rothova A, et al. Side-effects of ivermectin in treatment of on- ing in the urine and less than 2% in breast milk (see fection. Lancet 1997; 350: 18–22.
chocerciasis. Lancet 1989; i: 1439–41. also Breast Feeding, above). 8. Kamgno J, et al. Randomized, controlled, double-blind trial with
3. Zea-Flores R, et al. Adverse reactions after community treat- ivermectin on Loa loa microfilaraemia: efficacy of a low dose
ment of onchocerciasis with ivermectin in Guatemala. Trans R (~25 μg/kg) versus current standard dose (150 μg/kg). Trans R
Soc Trop Med Hyg 1992; 86: 663–6. Uses and Administration Soc Trop Med Hyg 2007; 101: 777–85.
4. Burnham GM. Adverse reactions to ivermectin treatment for
onchocerciasis: results of a placebo-controlled, double-blind tri- Ivermectin is a semisynthetic derivative of one of the Lymphatic filariasis. Ivermectin is used in the management of
al in Malawi. Trans R Soc Trop Med Hyg 1993; 87: 313–17. avermectins, a group of macrocyclic lactones produced lymphatic filariasis (p.137). In endemic areas mass treatment of
5. De Sole G, et al. Lack of adverse reactions in ivermectin treat- the entire population (excluding neonates, pregnant women, and
ment of onchocerciasis. Lancet 1990; 335: 1106–7. by Streptomyces avermitilis.
6. De Sole G, et al. Adverse reactions after large-scale treatment of
debilitated individuals) can reduce the intensity of transmission
onchocerciasis with ivermectin: combined results from eight
It has a microfilaricidal action in onchocerciasis and re- and the incidence of disease. In countries where there is co-en-
community trials. Bull WHO 1989; 67: 707–19. duces the microfilarial load without the toxicity seen demic loiasis or onchocerciasis, the Global Programme to Elim-
7. Kamgno J,et al. Adverse systemic reactions to treatment of on- with diethylcarbamazine. Ivermectin also has a micro- inate Lymphatic Filariasis launched by WHO, with other interna-
chocerciasis with ivermectin at normal and high doses given an- tional agencies, advocates a single oral dose of ivermectin 150 to
nually or three-monthly. Trans R Soc Trop Med Hyg 2004; 98: filaricidal action in lymphatic filariasis and is used in
496–504. 200 micrograms/kg with a single oral dose of albendazole
8. Gardon J, et al. Serious reactions after mass treatment of on-
its management. Ivermectin is active in some other 400 mg given once each year for at least 5 years.
chocerciasis with ivermectin in an area endemic for Loa loa in- worm infections. It is used in the treatment of strongy-
fection. Lancet 1997; 350: 18–22. Mansonella infections. The response of Mansonella infec-
loidiasis and has been tried in some Mansonella infec- tions (p.137) to ivermectin depends on the species. It may be ef-
9. The Mectizan Expert Committee and The Technical Consulta-
tive Committee. Recommendations for the treatment of on- tions. For details of these infections and their treat- fective against Mansonella ozzardi, but studies in M. perstans
chocerciasis with Mectizan in areas co-endemic for onchocer- ment, see under Choice of Anthelmintic, p.134, and infection have not shown ivermectin to produce a substantial re-
ciasis and loiasis. 2004. Available at: http://www.mectizan.org/ duction in microfilaraemia.1,2 A good response to ivermectin has
library/EnglishMECTCCLoaRecs-June04.pdf (accessed under the individual headings below.
20/09/05) been reported in infections with M. streptocerca.3,4
10. Whitworth JAG, et al. A community trial of ivermectin for on- In the treatment of onchocerciasis, a single oral dose of 1. Van den Enden E, et al. Treatment failure of a single high dose
chocerciasis in Sierra Leone: adverse reactions after the first 3 to 12 mg of ivermectin, based roughly on of ivermectin for Mansonella perstans filariasis. Trans R Soc
five treatment rounds. Trans R Soc Trop Med Hyg 1991; 85: Trop Med Hyg 1993; 87: 90.
501–5. 150 micrograms/kg for patients weighing more than 2. Schulz-Key H, et al. Efficacy of ivermectin in the treatment of
11. WHO. WHO expert committee on onchocerciasis: third report. 15 kg and over 5 years of age, is given annually or eve- concomitant Mansonella perstans infections in onchocerciasis
WHO Tech Rep Ser 752 1987. Available at: http://libdoc.who.int/ patients. Trans R Soc Trop Med Hyg 1993; 87: 227–9.
trs/WHO_TRS_752_(part1).pdf and http://libdoc.who.int/trs/ ry 6 months. This schedule has been adopted for mass
3. Fischer P, et al. Treatment of human Mansonella streptocerca in-
WHO_TRS_752_(part2).pdf (accessed 16/07/08) treatment in infected areas. No food should be taken fection with ivermectin. Trop Med Int Health 1997; 2: 191–9.
12. Homeida MMA, et al. Prolongation of prothrombin time with
ivermectin. Lancet 1988; i: 1346–7. for 2 hours before or after the dose. 4. Fischer P, et al. Long-term suppression of Mansonella strep-
tocerca microfilariae after treatment with ivermectin. J Infect
13. Richards FO, et al. Ivermectin and prothrombin time. Lancet Ivermectin 200 micrograms/kg as a single dose, or Dis 1999; 180: 1403–5.
1989; i; 1139–40.
14. Pacque MC, et al. Ivermectin and prothrombin time. Lancet daily on two consecutive days, is used for the treatment Onchocerciasis. Ivermectin has a microfilaricidal action
1989; i: 1140. of strongyloidiasis. against Onchocerca volvulus and is the main drug used in the
15. Barkwell R, Shields S. Deaths associated with ivermectin treat-
control of onchocerciasis (p.137). A single oral dose rapidly
ment of scabies. Lancet 1997; 349: 1144–5. ◊ Reviews. eliminates microfilariae from the skin, with maximum effect af-
16. Diazgranados JA, Costa JL. Deaths after ivermectin treatment.
Lancet 1997; 349: 1698. 1. Ottesen EA, Campbell WC. Ivermectin in human medicine. J ter 1 to 2 months,1 and gradually eliminates them from the cornea
17. Reintjes R, Hoek C. Deaths associated with ivermectin for sca- Antimicrob Chemother 1994; 34: 195–203. and anterior chamber of the eye.2 Ivermectin has little effect on
bies. Lancet 1997; 350: 215. 2. Õmura S. Ivermectin: 25 years and still going strong. Int J Anti- the adult worms but does suppress the release of microfilariae
18. Coyne PE, Addiss DG. Deaths associated with ivermectin for microb Agents 2008; 31: 91–8.
scabies. Lancet 1997; 350: 215–16. from the adult worm for several cycles which accounts for its
19. Alexander NDE, et al. Absence of ivermectin-associated excess Cutaneous larva migrans. There are some reports1,2 of iver- prolonged activity. Ivermectin therefore only controls the dis-
deaths. Trans R Soc Trop Med Hyg 1998; 92: 342. mectin being effective in the treatment of cutaneous larva mi- ease; it does not cure or eradicate it. Its action against O. volvulus
Breast feeding. Mean ivermectin concentrations in the breast grans (p.135). An oral dose of 200 micrograms/kg daily for 1 to has been attributed to a GABA-agonist effect. Studies have also
milk of 4 healthy women who had been given a standard dose of 2 days has been recommended.3 indicated that ivermectin inhibits the transmission of microfilar-
ivermectin were 14.13 nanograms/mL.1 It was felt that in view 1. Caumes E, et al. Efficacy of ivermectin in the therapy of cutane-
iae by reducing their uptake from man by the insect vector.3-6
of this low concentration the precaution of excluding lactating ous larva migrans. Arch Dermatol 1992; 128: 994–5. Ivermectin is donated by Merck through the Mectizan Expert
mothers from ivermectin mass treatment programmes should be 2. Caumes E, et al. A randomized trial of ivermectin versus alben- Committee (MEC) for human use in community-wide mass
reconsidered. Some authorities have recommended that iver- dazole for the treatment of cutaneous larva migrans. Am J Trop treatment programmes in all countries in which onchocerciasis is
mectin should not be given to mothers who are breast feeding Med Hyg 1993; 49: 641–4. endem ic, where it is gi ven at a standard do se of
until the infant is at least one week old. The American Academy 3. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New 150 micrograms/kg once or twice a year to all but pregnant
Rochelle NY: The Medical Letter, 2007. women, breast-feeding mothers of recently born babies, children
of Pediatrics states that, since no adverse effects have been seen
in breast-fed infants whose mothers were receiving ivermectin, it Intestinal nematode infections. Ivermectin activity has weighing less than 15 kg, and those unable to walk or otherwise
may be considered to be usually compatible with breast feeding.2 been seen in man against Ascaris lumbricoides, Strongyloides seriously ill.7 The adult worms live for about 15 years, therefore
1. Ogbuokiri JE, et al. Ivermectin levels in human breast milk. Eur stercoralis, and Trichuris trichiura;1 although some have failed treatment will need to be continued for many years. Several stud-
J Clin Pharmacol 1994; 46: 89–90. to detect activity against Trichuris,2 ivermectin given with alben- ies have confirmed the long-term safety and efficacy of such pro-
2. American Academy of Pediatrics. The transfer of drugs and oth- dazole has been studied for the treatment of trichuriasis (p.139) grammes.8-12 Studies have reported that increasing the frequency
er chemicals into human milk. Pediatrics 2001; 108: 776–89. of the standard doses of ivermectin to every 3 or 6 months ap-
Correction. ibid.; 1029. Also available at: and may prove useful. Roundworm expulsion has been reported
as a ‘side-effect’ of ivermectin when used in community-based pears to increase efficacy compared with annual treatments13,14
http://aappolicy.a ap public ations.org/cgi/c ontent/full/
pediatrics%3b108/3/776 (accessed 02/06/04) treatment of onchocerciasis.3 In a controlled study,4 single doses and that 3-monthly regimens may also reduce risk of adverse ef-
of ivermectin 150 or 200 micrograms/kg produced cure rates of fects.14,15 No additional benefit was noted by increasing the dose
Encephalopathy. For information on encephalopathy follow- of ivermectin to 400 or 800 micrograms/kg given either 3-
ing Ivermectin treatment of onchocerciasis in Loa loa endemic 94% in strongyloidiasis (see below) and above 67% in ascariasis,
trichuriasis, and enterobiasis. Although some activity has been monthly or annually.
areas, see Incidence of Adverse Effects, above.
observed against Necator americanus,1 cure rates for hookworm In non-endemic areas, repeated doses may be necessary to re-
Pregnancy. Ivermectin is teratogenic in animals and there are were considered unsatisfactory.4 duce recurrence; a study in the UK found that patients given
no adequate and well controlled studies in human pregnancy. 1. Freedman DO, et al. The efficacy of ivermectin in the chemo- three doses at monthly intervals had fewer relapses at 6 months
Ivermectin treatment is therefore usually contra-indicated during therapy of gastrointestinal helminthiasis in humans. J Infect Dis than patients who received a single dose, but relapses were nev-
pregnancy and pregnant women should be excluded from mass 1989; 159: 1151–3. ertheless seen in 50% of patients at 12 months.16
 Ivermectin/Levamisole 147
The ocular microfilarial load can be safely reduced by 3. Leppard B, Naburi AE. The use of ivermectin in controlling an When levamisole is used as an immunostimulant and
ivermectin2,17 and early lesions of the anterior segment of the eye outbreak of scabies in a prison. Br J Dermatol 2000; 143: 520–3.
4. Marlière V, et al. Crusted (Norwegian) scabies induced by use of given for longer periods, adverse effects are more fre-
have improved. 17 A reduction in the incidence 18 and
progression19 of optic nerve damage has also been reported, but
topical corticosteroids and treated successfully with ivermectin. quent and diverse and, in common with other immu-
J Pediatr 1999; 135: 122–4.
the effect on posterior segment disease is less certain.20 A sys- 5. Foucault C, et al. Oral ivermectin in the treatment of body lice.
nomodulators, may sometimes result from exacerba-
tematic review of 5 placebo-controlled studies, with data from J Infect Dis 2006; 193: 474–6. tion of the primary underlying disease. Adverse effects
3810 individuals, found no statistically significant difference be- 6. Mumcuoglu KY, et al. Systemic activity of ivermectin on the hu- associated especially with the more prolonged use of
tween ivermectin and placebo groups for preventing visual acui- man body louse (Anoplura: Pediculidae). J Med Entomol 1990;
27: 72–5. levamisole have included: hypersensitivity reactions
ty loss.21 Improvements in skin lesions have been reported.22
1. Basáñez MG, et al. Effect of single-dose ivermectin on On- Strongyloidiasis. Ivermectin is effective in the treatment of such as fever, a flu-like syndrome, arthralgia, muscle
chocerca volvulus: a systematic review and meta-analysis. Lan- strongyloidiasis (p.138) and is considered by some authorities to pain, skin rashes, and cutaneous vasculitis; CNS ef-
cet Infect Dis 2008; 8: 310–22. be the drug of choice. fects including headache, insomnia, dizziness, and
2. Newland HS, et al. Effect of single-dose ivermectin therapy on
human Onchocerca volvulus infection with onchocercal ocular References. convulsions; haematological abnormalities such as
involvement. Br J Ophthalmol 1988; 72: 561–9. 1. Naquira C, et al. Ivermectin for human strongyloidiasis and oth- agranulocytosis, leucopenia, and thrombocytopenia;
3. Taylor HR, et al. Impact of mass treatment of onchocerciasis er intestinal helminths. Am J Trop Med Hyg 1989; 40: 304–9.
with ivermectin on the transmission of infection. Science 1990; 2. Wijesundera M de S, Sanmuganathan PS. Ivermectin therapy in and gastrointestinal disturbances, including an abnor-
250: 116–18. chronic strongyloidiasis. Trans R Soc Trop Med Hyg 1992; 86: mal taste in the mouth.
4. Trpis M, et al. Effect of mass treatment of a human population 291.
with ivermectin on transmission of Onchocerca volvulus by 3. Lyagoubi M, et al. Chronic persistent strongyloidiasis cured by Incidence of adverse effects. In a review1 (by the manufac-
Simulium yahense in Liberia, West Africa. Am J Trop Med Hyg ivermectin. Trans R Soc Trop Med Hyg 1992; 86: 541.
1990; 42: 148–56. turers) of 46 controlled studies in which 2635 cancer patients re-
4. Datry A, et al. Treatment of Strongyloides stercoralis infection ceived adjuvant levamisole treatment, most patients received le-
5. Chavasse DC, et al. Low level ivermectin coverage and the
transmission of onchocerciasis. Trans R Soc Trop Med Hyg with ivermectin compared with albendazole: results of an open vamisole on 3 consecutive days every 2 weeks (1102 patients) or
1995; 89: 534–7. study of 60 cases. Trans R Soc Trop Med Hyg 1994; 88: 344–5.
5. Gann PH, et al. A randomized trial of single- and two-dose iver- on 2 consecutive days every week (1156 patients), usually in a
6. Boussinesq M, et al. Onchocerca volvulus: striking decrease in daily dose of 150 mg. Levamisole caused several adverse effects,
transmission in the Vina valley (Cameroon) after eight annual mectin versus thiabendazole for treatment of strongyloidiasis. J
large scale ivermectin treatments. Trans R Soc Trop Med Hyg Infect Dis 1994; 169: 1076–9. such as skin rash, nausea, vomiting, and a metallic or bitter taste
1997; 91: 82–6. 6. Marti H, et al. A comparative trial of a single-dose ivermectin in the mouth, which although troublesome were relatively trivial
7. Pond B. Distribution of ivermectin by health workers. Lancet versus three days of albendazole for treatment of Strongyloides and often regressed during therapy or disappeared on cessation
1990; 335: 1539. stercoralis and other soil-transmitted helminth infections in chil- of therapy. A total of 38 patients developed agranulocytosis and
8. De Sole G, et al. Adverse reactions after large-scale treatment of dren. Am J Trop Med Hyg 1996; 55: 477–81.
onchocerciasis with ivermectin: combined results from eight 7. Igual-Adell R, et al. Efficacy and safety of ivermectin and thia- of these 36 had received weekly treatment. Several contracted
community trials. Bull WHO 1989; 67: 707–19. bendazole in the treatment of strongyloidiasis. Expert Opin possible life-threatening infections and 2 died of septic shock.
9. Pacqué M, et al. Safety of and compliance with community- Pharmacother 2004; 5: 2615–9. 1. Amery WK, Butterworth BS. Review/commentary: the dosage
based ivermectin therapy. Lancet 1990; 335: 1377–80. regimen of levamisole in cancer: is it related to efficacy and safe-
10. Pacqué M, et al. Community-based treatment of onchocerciasis Trichostrongyliasis. For mention of the use of ivermectin in ty? Int J Immunopharmacol 1983; 5: 1–9.
with ivermectin: safety, efficacy, and acceptability of yearly Trichostrongylus infections, see p.139.
treatment. J Infect Dis 1991; 163: 381–5. Effects on the endocrine system. Rechallenge confirmed
11. Steel C, et al. Immunologic responses to repeated ivermectin Preparations that levamisole was responsible for inappropriate antidiuretic
treatment in patients with onchocerciasis. J Infect Dis 1991; USP 31: Ivermectin Tablets. hormone syndrome in a patient receiving levamisole with fluor-
164: 581–7. ouracil.1
12. Whitworth JAG, et al. A community trial of ivermectin for on- Proprietary Preparations (details are given in Part 3)
chocerciasis in Sierra Leone: clinical and parasitological re- Arg.: Dermopero; Securo; Austral.: Stromectol; Braz.: Ivermec†; Leverc- 1. Tweedy CR, et al. Levamisole-induced syndrome of inappropri-
sponses to four doses given at six-monthly interval. Trans R Soc tin; Revectina; Vermectil; Fr.: Mectizan; Stromectol; Jpn: Stromectol; Mex.: ate antidiuretic hormone. N Engl J Med 1992; 326: 1164.
Trop Med Hyg 1992; 86: 277–80. Ivexterm; Neth.: Stromectol; NZ: Stromectol; USA: Mectizan; Stromectol.
13. Greene BM, et al. A comparison of 6-, 12-, and 24-monthly dos- Effects on the liver. Elevated aspartate aminotransferase con-
ing with ivermectin for treatment of onchocerciasis. J Infect Dis centrations in 2 of 11 patients given levamisole for recurrent py-
1991; 163: 376–80. oderma suggested liver toxicity, a very rarely occurring adverse
14. Gardon J,et al. Effects of standard and high doses of ivermectin
Levamisole (BAN, rINN) effect.1 In a later report, liver enzyme concentrations were raised
on adult worms of Onchocerca volvulus: a randomised control-
led trial. Lancet 2002; 360: 203–10. in a 14-year-old boy treated with levamisole for minimal change
15. Kamgno J, et al. Adverse systemic reactions to treatment of on- Levamisol; Lévamisole; Levamisoli; Levamisolum; Levamizol. (S)- nephrotic syndrome.2
chocerciasis with ivermectin at normal and high doses given an- 2,3,5,6-Tetrahydro-6-phenylimidazo[2,1-b][1,3]thiazole. 1. Papageorgiou P, et al. Levamisole in chronic pyoderma. J Clin
nually or three-monthly. Trans R Soc Trop Med Hyg 2004; 98: Левамизол Lab Immunol 1982; 8: 121–7.
496–504. 2. Bulugahapitiya DTD. Liver toxicity in a nephrotic patient treated
16. Churchill DR, et al. A trial of a three-dose regimen of ivermec- C 11 H 12 N 2 S = 204.3. with levamisole. Arch Dis Child 1997; 76: 289.
tin for the treatment of patients with onchocerciasis in the UK. C AS — 14769-73-4.
Trans R Soc Trop Med Hyg 1994; 88: 242. Effects on the nervous system. Reports1,2 of inflammatory
17. Dadzie KY, et al. Changes in ocular onchocerciasis after two ATC — P02CE01.
leukoencephalopathy were associated with the use of fluorour-
rounds of community-based ivermectin treatment in a holo-en- ATC Vet — QP52AE01. acil and levamisole in 4 patients being treated for adenocarcino-
demic onchocerciasis focus. Trans R Soc Trop Med Hyg 1991;
85: 267–71. ma of the colon. Active demyelination was demonstrated in 2
18. Abiose A, et al. Reduction in incidence of optic nerve disease patients.1 Clinical improvement occurred when chemotherapy
with annual ivermectin to control onchocerciasis. Lancet 1993; H N S was stopped; 3 patients were treated with corticosteroids.1 A
341: 130–4. similar syndrome has been reported in a patient with a history of
19. Cousens SN, et al. Impact of annual dosing with ivermectin on
progression of onchocercal visual field loss. Bull WHO 1997; N hepatitis C given levamisole alone.3
75: 229–36. 1. Hook CC, et al. Multifocal inflammatory leukoencephalopathy
20. Whitworth JAG, et al. Effects of repeated doses of ivermectin on Pharmacopoeias. In Eur. (see p.vii) for veterinary use only. with 5-fluorouracil and levamisole. Ann Neurol 1992; 31: 262–7.
ocular onchocerciasis: community-based trial in Sierra Lione. 2. Kimmel DW, Schutt AJ. Multifocal leukoencephalopathy: oc-
Lancet 1991; 338: 1100–1103. Ph. Eur. 6.2 (Levamisole for Veterinary Use; Levamisole BP(Vet) currence during 5-fluorouracil and levamisole therapy and reso-
21. Ejere H, et al. Ivermectin for onchocercal eye disease (river 2008). A white or almost white powder. It exhibits polymor- lution after discontinuation of chemotherapy. Mayo Clin Proc
blindness). Available in The Cochrane Database of Systematic phism. Slightly soluble in water; freely soluble in alcohol and in 1993; 68: 363–5.
Reviews; Issue 2. Chichester: John Wiley; 2001 (accessed methyl alcohol. Store in airtight containers. Protect from light. 3. Lucia P, et al. Multifocal leucoencephalopathy induced by le-
29/07/07). vamisole. Lancet 1996; 348: 1450.
22. Pacqué M, et al. Improvements in severe onchocercal skin dis-
ease after a single dose of ivermectin. Am J Med 1991; 90: Levamisole Hydrochloride (BANM, USAN, rINNM)
590–4.
Cloridrato de Levamizol; Hidrocloruro de levamisol; ICI-59623;
Precautions
Scabies and pediculosis. Scabies (p.2035) is usually treated Lévamisole, chlorhydrate de; Levamisol-hydrochlorid; Levamisol- The use of levamisole should be avoided in patients
with a topically applied acaricide. However, a single oral dose of hydroklorid; Levamisoli hydrochloridum; Levamisolihydrokloridi; with pre-existing blood disorders. Patients given lev-
ivermectin has been reported to be effective.1,2 In a study of 11 Levamizol-hidroklorid; Levamizolio hidrochloridas; Lewamizolu amisole with fluorouracil should undergo appropriate
patients with uncomplicated scabies, a single oral dose of iver-
mectin 200 micrograms/kg was effective in curing infection after
chlorowodorek; NSC-177023; R-12564; RP-20605; l-Tetrami- monitoring of haematological and hepatic function.
4 weeks. In a group of 11 patients, also infected with HIV, scabies sole Hydrochloride; l-Tetramisole Hydrochloride.
Rheumatoid arthritis. The presence of HLA B27 in seropos-
was cured in 8 after 2 weeks.1 Two of the remaining 3 patients Левамизола Гидрохлорид itive rheumatoid arthritis is an important predisposing factor to
received a second dose of ivermectin which cured the scabies C 11 H 12 N 2 S,HCl = 240.8. the development of agranulocytosis with levamisole; it is recom-
infection by the fourth week. A single oral dose of ivermectin C AS — 16595-80-5. mended that the use of levamisole in this group should be avoid-
150 micrograms/kg was partially effective in an outbreak of sca- ATC — P02CE01. ed.1
bies in 1153 Tanzanian patients.3 Crusted (Norwegian) scabies Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet. 1. Mielants H, Veys EM. A study of the hematological side effects
has also been reported to be effectively treated by a single oral Ph. Eur. 6.2 (Levamisole Hydrochloride). A white to almost of levamisole in rheumatoid arthritis with recommendations. J
dose of 12 mg of ivermectin in addition to topical application of white crystalline powder. Freely soluble in water; soluble in al- Rheumatol 1978; 5 (suppl 4): 77–83.
3% salicylic acid ointment in 2 patients; the treatment was effec- cohol; slightly soluble in dichloromethane. A 5% solution in wa- Sjögren’s syndrome. The appearance of adverse effects in 9 of
tive in under one week.2 A single oral dose of ivermectin ter has a pH of 3.0 to 4.5. Protect from light. 10 patients with rheumatoid arthritis and Sjögren’s syndrome
200 micrograms/kg was effective for crusted scabies in a 2-year- USP 31 (Levamisole Hydrochloride). A white or almost white while being treated with levamisole led to abandonment of the
old infant who had contracted the disease following long-term crystalline powder. Freely soluble in water; soluble in alcohol; study.1 Levamisole should be given with caution, if at all, to pa-
corticosteroid use.4 slightly soluble in dichloromethane; practically insoluble in tients with Sjögren’s syndrome.
Ivermectin has also been investigated5 as a possible treatment for ether. pH of a 5% solution in water is between 3.0 and 4.5. Pro- 1. Balint G, et al. Sjögren’s syndrome: a contraindication to levam-
pediculosis (p.2034) although, again, topically applied insecti- tect from light. isole treatment? BMJ 1977; 2: 1386–7.
cides are the usual method of control. A study in vitro and in
animals showed that ivermectin killed nymphs and females of Adverse Effects
the human body louse (Pediculus humanus humanus). Ivermec-
Interactions
tin was known to be effective against other louse species that in- When given in single doses for the treatment of as- Alcohol. US licensed product information states that levamisole
fect a range of animals.6 cariasis or other worm infections, levamisole is gener- can produce a disulfiram-like reaction with alcohol.
1. Meinking TL, et al. The treatment of scabies with ivermectin. N ally well tolerated and adverse effects are usually lim- Anticoagulants. For an increase in the activity of warfarin
Engl J Med 1995; 333: 26–30.
2. Aubin F, Humbert P. Ivermectin for crusted (Norwegian) sca-
ited to nausea, vomiting, diarrhoea, abdominal pain, when given with levamisole and fluorouracil, see Interactions,
bies. N Engl J Med 1995; 332: 612. dizziness, and headache. Levamisole, under Warfarin, p.1431.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
148 Anthelmintics
Antiepileptics. For increased phenytoin concentrations when 3. Laurie JA, et al. Surgical adjuvant therapy of large-bowel carci- Male Fern
given with levamisole and fluorouracil, see Interactions, Antine- noma: an evaluation of levamisole and the combination of le-
vamisole and fluorouracil: the North Central Cancer Treatment Aspidium; Farnwurzel; Felce Maschio; Feto Macho; Filix Mas;
oplastics, under Phenytoin, p.499. Group and the Mayo Clinic. J Clin Oncol 1989; 7: 1447–56. Fougère Mâle; Helecho macho; Rhizoma Filicis Maris.
4. Moertel CG, et al. Levamisole and fluorouracil for adjuvant ther- Щитовник Мужской
Pharmacokinetics apy of resected colon carcinoma. N Engl J Med 1990; 322:
352–8. Pharmacopoeias. In Chin.
Levamisole is rapidly absorbed from the gastrointesti- 5. Moertel CG, et al. Fluorouracil plus levamisole as effective ad-
nal tract. Maximum plasma concentrations are attained juvant therapy after resection of stage III colon carcinoma: a fi- Profile
nal report. Ann Intern Med 1995; 122: 321–6. Male fern consists of the rhizome, frond-bases, and apical bud of
within 1.5 to 2 hours. It is extensively metabolised in 6. Chlebowski RT, et al. Long-term survival following levamisole Dryopteris filix-mas agg. (Polypodiaceae), collected late in the
the liver. The plasma half-life for levamisole is 3 to 4 or placebo adjuvant treatment of colorectal cancer: a Western autumn, divested of the roots and dead portions and carefully
hours and for the metabolites is 16 hours. It is excreted Cancer Study Group trial. Oncology 1988; 45: 141–3. dried, retaining the internal green colour. It contains not less than
7. QUASAR Collaborative Group. Comparison of fluorouracil 1.5% of filicin. During storage the green colour of the interior
mainly in the urine as metabolites and a small propor- with additional levamisole, higher-dose folinic acid, or both, as
tion in the faeces. About 70% of a dose is excreted in adjuvant chemotherapy for colorectal cancer: a randomised trial. gradually disappears, often after a lapse of 6 months, and such
Lancet 2000; 355: 1588–96. material is unfit for medicinal use.
the urine over 3 days, with about 5% as unchanged le- 8. Wolmark N, et al. Clinical trial to assess the relative efficacy of Filicin is the mixture of ether-soluble substances obtained from
vamisole. fluorouracil and leucovorin, fluorouracil and levamisole, and male fern. Its activity is chiefly due to flavaspidic acid, a phloro-
fluorouracil, leucovorin, and levamisole in patients with Dukes’
◊ References. B and C carcinoma of the colon: results from National Surgical
glucinol derivative.
Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999; 17: Male fern has anthelmintic properties and was formerly used as
1. Luyckx M, et al. Pharmacokinetics of levamisole in healthy sub-
jects and cancer patients. Eur J Drug Metab Pharmacokinet 3553–9. male fern extract (aspidium oleoresin) for the expulsion of tape-
1982; 7: 247–54. Mansonella infections. Levamisole is one of the drugs that has worms. However, male fern is highly toxic and has been super-
2. Kouassi E, et al. Novel assay and pharmacokinetics of levami- been suggested for the treatment of Mansonella infections seded by other drugs.
sole and p-hydroxylevamisole in human plasma and urine. Biop- (p.137). There have been reports1,2 of response when given with Adverse effects include headache, nausea and vomiting, severe
harm Drug Dispos 1986; 7: 71–89. abdominal cramp, diarrhoea, dyspnoea, albuminuria, hyperbi-
mebendazole.
1. Maertens K, Wery M. Effect of mebendazole and levamisole on lirubinaemia, dizziness, tremors, convulsions, visual disturbanc-
Uses and Administration Onchocerca volvulus and Dipetalonema perstans. Trans R Soc es including blindness (possibly permanent), stimulation of uter-
Levamisole hydrochloride is the active laevo-isomer Trop Med Hyg 1975; 69: 359–60. ine muscle, coma, respiratory failure, bradycardia, and cardiac
2. Bernberg HC, et al. The combined treatment with levamisole and failure. Fatalities have occurred.
of tetramisole hydrochloride. It is used as an an- mebendazole for a perstans-like filarial infection in Rhodesia.
thelmintic and as an adjuvant in malignant disease. It Trans R Soc Trop Med Hyg 1979; 73: 233–4. Preparations
Proprietary Preparations (details are given in Part 3)
has also been tried in several conditions where its stim- Mouth ulceration. Levamisole might be beneficial in severe
mouth ulceration (p.1700) but is limited by its adverse effects. A Multi-ingredient: Austria: Digestodoron; Ger.: Digestodoron; S.Afr.:
ulant effect on the depressed immune response might Digestodoron.
be useful. review1 of its use in recurrent aphthous stomatitis indicated that
beneficial results have been reported with levamisole in open
Levamisole is active against intestinal nematode studies, but results of double-blind studies have been conflicting.
Nevertheless, there have been patients with severe recurrent aph-
worms and appears to act by paralysing susceptible
thous stomatitis refractory to all other modes of treatment who
Mebendazole (BAN, USAN, rINN)
worms which are subsequently eliminated from the in- have responded to levamisole. Dosage has been with 150 mg Mebendatsoli; Mebendazol; Mebendazolas; Mébendazole; Me-
testines. In particular, levamisole is effective in the daily in divided doses given for 3 days at the first sign of ulcera- bendazolum; R-17635. Methyl 5-benzoyl-1H-benzimidazol-2-yl-
treatment of ascariasis (p.134). It is also used in hook- tion, followed by 11 days without treatment, repeated as neces- carbamate.
worm infections (p.136). sary. Мебендазол
1. Miller MF. Use of levamisole in recurrent aphthous stomatitis.
Doses of levamisole hydrochloride are expressed in Drugs 1980; 20: 131–6.
C 16 H 13N 3 O 3 = 295.3.
terms of the equivalent amount of levamisole. Levam- C AS — 31431-39-7.
Renal disorders. In a randomised double-blind study, children ATC — P02C A01.
isole hydrochloride 1.18 g is equivalent to about 1 g of with frequently relapsing corticosteroid-sensitive and corticos-
levamisole. The usual adult dose in ascariasis is teroid-dependent nephrotic syndrome were given placebo or le- ATC Vet — QP52AC09.
150 mg of levamisole orally as a single dose; children vamisole 2.5 mg/kg on alternate days and steroid therapy was
have been given 3 mg/kg as a single dose. For the gradually withdrawn.1 Of 31 children being treated with levami-
sole, 14 were still in remission 112 days after the start of the study O
H
hookworm infection ancylostomiasis or for mixed as- compared with 4 of 30 receiving placebo. There have been sub- N OCH3
cariasis-hookworm infections, both adults and children sequent reports of adjunctive use in children with nephrotic syn-
drome,2-6 but its place in therapy remains to be established. For a NH
may be given 2.5 mg/kg as a single dose, repeated after
7 days in cases of severe hookworm infection. discussion of the treatment of glomerular kidney disorders, in- N
cluding the nephrotic syndrome, see p.1504.
Levamisole influences host defences by modulating 1. British Association for Paediatric Nephrology. Levamisole for O
cell-mediated immune responses; it restores depressed corticosteroid-dependent nephrotic syndrome in childhood. Lan-
cet 1991; 337: 1555–7.
T-cell functions and has been described as an immu- 2. Donia AF, et al. Levamisole: adjunctive therapy in steroid de-
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet.
nostimulant, although stimulation above normal levels pendent minimal change nephrotic children. Pediatr Nephrol Ph. Eur. 6.2 (Mebendazole). A white or almost white powder. It
2002; 17: 355–8. shows polymorphism. Practically insoluble in water, in alcohol,
does not seem to occur. It has been tried in many disor- 3. Fu LS, et al. Levamisole in steroid-sensitive nephrotic syndrome and in dichloromethane. Protect from light.
ders, including bacterial and viral infections and rheu- children with frequent relapses and/or steroid dependency: com- USP 31 (Mebendazole). A white to slightly yellow, almost
matic disorders, although in these conditions results parison of daily and every-other-day usage. Nephron Clin Pract odourless, powder. Practically insoluble in water, in alcohol, in
2004; 97: c137–c141.
have not been encouraging. 4. Sümegi V, et al. Long-term effects of levamisole treatment in
chloroform, in ether, and in dilute mineral acids; freely soluble in
childhood nephrotic syndrome. Pediatr Nephrol 2004; 19: formic acid.
Levamisole has also been used as an adjunct in patients 1354–60.
with malignant disease, although it is not clear that any 5. Al-Saran K, et al. Experience with levamisole in frequently re- Adverse Effects
response is due to its action on the immune system. lapsing, steroid-dependent nephrotic syndrome. Pediatr Nephrol
2006; 21: 201–5. Since mebendazole is poorly absorbed from the gas-
Adjuvant treatment with levamisole and fluorouracil 6. Boyer O, et al. Short- and long-term efficacy of levamisole as trointestinal tract at the usual therapeutic doses, ad-
has been given to reduce recurrence after resection of adjunctive therapy in childhood nephrotic syndrome. Pediatr
verse effects have generally been restricted to gastroin-
Nephrol 2008; 23: 575–80.
adenocarcinoma of the colon with regional lymph testinal disturbances, such as transient abdominal pain
node involvement (but see Malignant Neoplasms, be- Vitiligo. In a study1 involving 36 patients with limited slow-
spreading vitiligo, response to levamisole treatment occurred in and diarrhoea, and have tended to occur in patients be-
low). 34 within 2 to 4 months. Patients received 150 mg of oral levam- ing treated for heavy intestinal infection. Headache and
◊ Reviews. isole daily on 2 consecutive days each week. Patients who were dizziness have been reported. Adverse effects have
additionally treated with topical fluocinolone or clobetasol had been reported more frequently with the high doses tried
1. Amery WKP, Bruynseels JPJM. Levamisole, the story and the
higher rates of repigmentation. A later controlled study2 involv-
lessons. Int J Immunopharmacol 1992; 14: 481–6.
ing 43 patients reported less benefit.
in echinococcosis and have included allergic reactions,
2. Scheinfeld N, et al. Levamisole in dermatology : a review. Am J raised liver enzyme values, alopecia, and bone marrow
Clin Dermatol 2004; 5: 97–104. The usual treatment of vitiligo is discussed under Pigmentation
Disorders, p.1582. depression.
Malignant neoplasms. Levamisole has been tried in the adju-
vant treatment of various malignant neoplasms1,2 with conflict-
1. Pasricha JS, Khera V. Effect of prolonged treatment with levam- Incidence of adverse effects. In the first phase1 of WHO-co-
isole on vitiligo with limited and slow-spreading disease. Int J ordinated multicentre studies on the treatment of echinococcosis
ing results. Based on the results of early adjuvant trials,3-5 levam- Dermatol 1994; 33: 584–7.
isole was used as standard therapy to modulate fluorouracil in 2. Agarwal S, et al. A randomized placebo-controlled double-blind
(hydatid disease) involving Echinococcus granulosus or E. mul-
patients with colorectal cancer (p.665), particularly in the USA. study of levamisole in the treatment of limited and slowly tilocularis, the most frequent adverse effects in the 139 patients
However, whether levamisole actually added to the beneficial ef- spreading vitiligo. Br J Dermatol 2005; 153: 163–6. given high-dose mebendazole, generally for 3 months, were re-
fect of adjuvant fluorouracil was unclear. Adjuvant levamisole Preparations duced leucocyte count (25 patients), gastrointestinal symptoms
alone was no more effective than placebo in 1 study,6 and more (22), and raised serum-transaminase values (22). Other adverse
USP 31: Levamisole Hydrochloride Tablets. effects were allergic conditions such as fever and skin reactions
recent trials have indicated that levamisole is no more effective
Proprietary Preparations (details are given in Part 3) (4), CNS symptoms including headache (6), and loss of hair (7).
than placebo when added to fluorouracil,7 or to fluorouracil plus Arg.: Levam; Meglum; Austral.: Ergamisol†; Belg.: Ergamisol†; Braz.: As-
folinic acid.8 Seven patients stopped treatment because of adverse effects.
caridil; Canad.: Ergamisol†; Cz.: Decaris†; Ger.: Ergamisol†; Gr.: Ergami-
1. Spreafico F. Use of levamisole in cancer patients. Drugs 1980; sol; Hong Kong: Decaris; Hung.: Decaris; India: Levomol; Vermisol; Vi- The second phase of studies2 compared albendazole with me-
20: 105–16. zole; Indon.: Askamex; Irl.: Ketrax†; Israel: Ergamisol; Mex.: Decaris; bendazole in more prolonged high-dosage schedules for cystic E.
Neth.: Ergamisol†; Rus.: Decaris (Декарис); S.Afr.: Ergamisol; Turk.: Par- granulosus infection. Adverse effects were similar to those re-
2. Amery WK, Butterworth BS. Review/commentary: the dosage aks; Sitraks; UK: Ketrax†; USA: Ergamisol†; Venez.: Decaris†.
regimen of levamisole in cancer: is it related to efficacy and safe- ported with the first phase. However, in the first phase the aller-
ty? Int J Immunopharmacol 1983; 5: 1–9. gic consequences of the 14 ruptured lung cysts and the 4 ruptured
 Male Fern/Melarsomine 149
liver cysts that occurred with mebendazole were not reported. In intestinal or absorptive cells. Inhibition of glucose up- 3. Bregani ER, et al. Comparison of different anthelmintic drug
the second phase, 2 patients suffered anaphylactic shock as a re- regimens against Mansonella perstans filariasis. Trans R Soc
take and depletion of glycogen stores follow as do oth- Trop Med Hyg 2006; 100: 458–63.
sult of rupture of a lung cyst and a cyst in the abdominal cavity.
These 2 patients were withdrawn from mebendazole treatment, er inhibitory effects leading to death of the worm with- 4. Wahlgren M, Frolov I. Treatment of Dipetalonema perstans in-
in several days. fections with mebendazole. Trans R Soc Trop Med Hyg 1983; 77:
as were another 4 patients as a consequence of their adverse re- 422–3.
actions, although in 3 the withdrawal was only temporary. Mebendazole, being poorly absorbed from the gas- Strongyloidiasis. Mebendazole has been used for the treatment
Although albendazole is preferred to mebendazole in the treat- trointestinal tract, is used principally in the treatment of of strongyloidiasis (p.138), but needs to be given for longer peri-
ment of echinococcosis, if either drug is used there should be the intestinal nematode infections ascariasis (round- ods than albendazole to control auto-infection, so that, of the two,
constant medical supervision with regular monitoring of serum- albendazole is preferred.1-3
transaminase concentrations and of leucocyte and platelet
worm infection), enterobiasis (pinworm or thread-
worm infections), hookworm (ancylostomiasis and ne- 1. Wilson KH, Kauffman CA. Persistent Strongyloides stercoralis
counts. Patients with liver damage should be treated with re- in a blind loop of the bowel: successful treatment with mebenda-
duced doses of benzimidazole carbamates, if at all.2 catoriasis), and trichuriasis (whipworm infection); it is zole. Arch Intern Med 1983; 143: 357–8.
1. Davis A, et al. Multicentre clinical trials of benzimidazolecar- useful in mixed infections. During treatment with me- 2. Mravak S, et al. Treatment of strongyloidiasis with mebenda-
bamates in human echinococcosis. Bull WHO 1986; 64: 383–8. bendazole, migration of worms with expulsion through zole. Acta Trop (Basel) 1983; 40: 93–4.
3. Pelletier LL, Baker CB. Treatment failures following mebenda-
2. Davis A, et al. Multicentre clinical trials of benzimidazolecar- the mouth and nose has occurred in some patients zole therapy for chronic strongyloidiasis. J Infect Dis 1987; 156:
bamates in human cystic echinococcosis (phase 2). Bull WHO
1989; 67: 503–8. heavily infected with Ascaris. Mebendazole is also 532–3.
used in the treatment of capillariasis and trichostrong- Syngamosis. Mebendazole has been used successfully1 to treat
Overdosage. Respiratory arrest and tachyarrhythmia associat- yliasis and has been used in strongyloidiasis. Other syngamosis (p.138).
ed with continuous convulsions were reported1 in an 8-week-old
infant after accidental poisoning with mebendazole. Treatment
nematode infections which may respond to mebenda- 1. Timmons RF, et al. Infection of the respiratory tract with Mam-
momanogamus (Syngamus) laryngeus: a new case in Largo,
by exchange transfusion and anticonvulsants was successful. zole are infection with the filarial nematode Mansonel- Florida, and a summary of previously reported cases. Am Rev
1. el Kalla S, Menon NS. Mebendazole poisoning in infancy. Ann
la perstans, and the tissue infections toxocariasis and Respir Dis 1983; 128: 566–9.
Trop Paediatr 1990; 10: 313–14. trichinosis. Mebendazole has also been tried in high Toxocariasis. Mebendazole has been used in the treatment of
doses in the treatment of echinococcosis (hydatid dis- toxocariasis (p.139). In comparative studies, mebendazole has
Precautions ease). For discussions of these infections and their been reported to produce similar improvements to those obtained
treatment, see under Choice of Anthelmintic, p.134, with tiabendazole1 and with diethylcarbamazine,2 in each case
Patients given high doses of mebendazole, such as with a lower incidence of adverse effects.
those with echinococcosis, should be supervised close- and under the individual headings below.
1. Magnaval JF, Charlet JP. Efficacité comparée du thiabendazole
ly with blood counts and liver function being moni- Mebendazole is given orally. The usual dose for adults et du mébendazole dans le traitement de la toxocarose. Therapie
tored; such high-dose therapy may be inappropriate in 1987; 42: 541–4.
and children aged over 2 years with enterobiasis is 2. Magnaval J-F. Comparative efficacy of diethylcarbamazine and
those with hepatic impairment (see under Incidence of 100 mg as a single dose, repeated if necessary after 2 to mebendazole for the treatment of human toxocariasis. Parasitol-
Adverse Effects, above). 3 weeks; for ascariasis, hookworm infections, and tri- ogy 1995; 110: 529–33.

Monitoring drug concentrations. In a retrospective analysis

churiasis the usual dose in adults and children over 1 Trichinosis. Mebendazole is used for the treatment of trichino-
of patients given high doses of mebendazole for echinococcosis,1 year is 100 mg twice daily for 3 days, although a single sis (p.139) in some countries.
no relationship was found between dose and plasma concentra- dose of 500 mg may be effective. References.
tion of mebendazole and considerable intra- and interindividual 1. Levin ML. Treatment of trichinosis with mebendazole. Am J
variation in plasma concentrations was observed, emphasising Angiostrongyliasis. Mebendazole was formerly used for the Trop Med Hyg 1983; 32: 980–3.
the need for repeated monitoring. Several patients appeared to treatment of angiostrongyliasis (p.134) but current opinion is that
have what were considered to be subtherapeutic plasma concen- there is no convincing evidence to support its use. Preparations
trations. Capillariasis. Mebendazole in a dose of 200 mg twice daily for USP 31: Mebendazole Tablets.
1. Luder PJ, et al. Treatment of hydatid disease with high oral doses 20 days has been used1 for the treatment of capillariasis (p.135). Proprietary Preparations (details are given in Part 3)
of mebendazole: long-term follow-up of plasma mebendazole Arg.: Dazomet; Helmint; Mebutar; Nemasole; Tesical; Austral.: Chemists
1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New Own De Worm; Combantrin-1 with Mebendazole; Vermox; Austria: Pan-
levels and drug interactions. Eur J Clin Pharmacol 1986; 31: Rochelle NY: The Medical Letter, 2007.
443–8. telmin; Belg.: Docmebenda; Vermox; Braz.: Ascariobel†; Averpan†; Ben-
drax†; Crisdazol†; Divermil†; Ductelmin; Eraverm†; Feller†; Geophagol;
Echinococcosis. Mebendazole has been used1-9 in echinococ- Gran-Verm†; Ibdazol†; Kindelmin; Mebental†; Mebiozol†; Medazol; Menbel;
Pregnancy. Mebendazole is teratogenic in rats and there are no cosis (p.136), but albendazole is generally preferred. The usual Moben; Multielmin†; Multizol; Necamin; Neo Mebend; Novelmin; Panfugan;
adequate and well controlled studies in human pregnancy. Me- dose of mebendazole in cystic echinococcosis is 40 to 50 mg/kg Pantelmin; Panverm†; Paraverm†; Pentazole†; Pluriverm; Plurivermil†; Poli-
bendazole is therefore usually contra-indicated during pregnan- daily for at least 3 to 6 months.8 A similar dose is used as an dazol†; Probendazol; Quintelmin†; Sifbem†; Sirben; Tetrahelmin†; Trotil†;
cy. However, it was noted that in a survey of a limited number of adjuvant to surgery. For alveolar echinococcosis, the dose is ad- Vermiben; Verminon†; Vermirax†; Vermoplex; Vermoral; Verzol; Zolda-
pregnant women who had inadvertently taken mebendazole dur- ben†; Canad.: Vermox; Chile: Diacor; Cz.: Vermox; Denm.: Vermox;
justed after 4 weeks to produce a plasma concentration of at least Ger.: Surfont; Vermox; Gr.: Vermox; Hong Kong: Elmetin†; Vermox;
ing the first trimester, the incidence of malformation and sponta- 250 nanomoles/litre (74 nanograms/mL), although adults should Hung.: Vermox; India: Mebex; Wormin; Indon.: Gavox; Vermox; Irl.:
neous abortion was no greater than that observed in the general not be given more than 6 g daily. Treatment is continued for at Vermox; Israel: Vermox; Ital.: Vermox; Malaysia: Quemox; Thelmox;
population. least 2 years after radical surgery, or indefinitely in inoperable Vermox; Mex.: Amatol; Bensolmin; Bestelar; Carbatil†; Daben; Diazolen;
Exaverm†; Exbenzol; Exteny; Fanciadazol; Hedazol; Helminzole†; L-Ombrix;
cases. Lumbicid; M-Bentabs†; Meb-Overoid; Mebelmin; Mebendicin; Mebensole;
Interactions 1. Ammann RW, et al. Recurrence rate after discontinuation of Mebentiasis; Mebentral; Nemapres; Panvermin; Paranzol†; Prodazol†; Pro-
long-term mebendazole therapy in alveolar echinococcosis (pre- fenzol; Revapol; Soltric†; Vermicol; Vermidil; Vermin-Dazol; Vermox; Ver-
Antiepileptics. Phenytoin or carbamazepine have been report- liminary results). Am J Trop Med Hyg 1990; 43: 506–15. tex†; Vertizole; Neth.: Anti-Worm; Kruidvat Anti-worm; Madicure; Trek-
pleister Anti-Worm†; Vermox; Norw.: Vermox; NZ: Combantrin-1;
ed to lower plasma-mebendazole concentrations in patients re- 2. Messaritakis J, et al. High mebendazole doses in pulmonary and Mindol†; Vermox; Philipp.: Antiox; Pol.: Vermox; Port.: Pantelmin;
ceiving high doses for echinococcosis, presumably as a result of hepatic hydatid disease. Arch Dis Child 1991; 66: 532–3. Toloxim; Rus.: Vermox (Вермокс); Wormin (Вормин); S.Afr.: Adco-
enzyme induction; valproate had no such effect.1 3. Teggi A, et al. Therapy of human hydatid disease with mebenda- Wormex; Cipex; D-Worm; Rioworm; Rolab-Anthex; Vermox; Wormgo;
zole and albendazole. Antimicrob Agents Chemother 1993; 37: Wormstop; Spain: Bantenol†; Lomper; Mebendan; Oxitover†; Sufil;
1. Luder PJ, et al. Treatment of hydatid disease with high oral doses 1679–84. Swed.: Vermox; Switz.: Vermox; Thai.: Benda†; Big-Ben; Drivermide; Fu-
of mebendazole: long-term follow-up of plasma mebendazole 4. Göçmen A, et al. Treatment of hydatid disease in childhood with gacar; Masaworm-1; Meba†; Meben; Mebenda-P†; Medazole; Noxworm†;
levels and drug interactions. Eur J Clin Pharmacol 1986; 31: Vagaka†; Warca; Turk.: Vermazol; Versid; UAE: Mebzol; UK: Boots
mebendazole. Eur Respir J 1993; 6: 253–7. Threadworm Tablets 2 Years Plus; Ovex; Pripsen; Vermox; USA: Vermox;
443–8.
5. Ammann RW, et al. Effect of chemotherapy on the larval mass Venez.: Bendacor; Bendamen; Eprofil; Flemdazole†; Pantelmin†; Pival†;
Histamine H2-antagonists. Plasma concentrations of meben- and the long-term course of alveolar echinococcosis. Hepatology Tamixan†; Vermalon.
dazole have been raised when the enzyme inhibitor cimetidine 1994; 19: 735–42.
Multi-ingredient: Arg.: Aduar; Helmint Compuesto; Mebutar Com-
was also given, and this has resulted in the resolution of previ- 6. Erdinçler P, et al. The role of mebendazole in the surgical treat- puesto; Tru Compuesto; Braz.: Eraverm-T†; Exelmin†; Forverm; Helmi-
ment of central nervous system hydatid disease. Br J Neurosurg Ped†; Helmib†; Helmiben; Helmidrax†; Josverm†; Metiaben†; Neovermin;
ously unresponsive hepatic hydatid cysts.1 1997; 11: 116–20. Octelmin†; Poliben†; Profium; Prohelmin†; Vermol†; Zoles†; India: Mebex
1. Bekhti A, Pirotte J. Cimetidine increases serum mebendazole 7. Vutova K, et al. Effect of mebendazole on human cystic echino- Plus; Mex.: Amibriz†; Amoebriz; Mebeciclol; Vermox-Plus.
concentrations: implications for treatment of hepatic hydatid coccosis: the role of dosage and treatment duration. Ann Trop
cysts. Br J Clin Pharmacol 1987; 24: 390–2. Med Parasitol 1999; 93: 357–65.
8. WHO Informal Working Group on Echinococcosis. Guidelines
for treatment of cystic and alveolar echinococcosis in humans. Melarsomine (rINN)
Pharmacokinetics Bull WHO 1996; 74: 231–42.
Mebendazole is poorly absorbed from the gastrointes- Melarsomina; Mélarsomine; Melarsominum. Bis(2-aminoethyl) p-
9. Smego RA, et al. Percutaneous aspiration-injection-reaspiration
[(4,6-diamino-s-triazin-2-yl)amino]dithiobenzenearsonite.
tinal tract and undergoes extensive first-pass elimina- drainage plus albendazole or mebendazole for hepatic cystic
echinococcosis: a meta-analysis. Clin Infect Dis 2003; 37: Меларсомин
tion, being metabolised in the liver, eliminated in the 1073–83.
bile as unchanged drug and metabolites, and excreted C 13 H 21 AsN 8 S 2 = 428.4.
Giardiasis. For mention of the use of mebendazole for the treat- C AS — 128470-15-5.
in the faeces. Only about 2% of a dose is excreted un- ment of giardiasis, see p.824. ATC Vet — QP51AD06.
changed or as metabolites in the urine.
Mansonella infections. Mebendazole is one of the drugs that
Mebendazole is highly protein bound. has been suggested for the treatment of infections with Man-
sonella perstans (p.137). Some patients have responded to me- H
bendazole with levamisole,1,2 diethylcarbamazine,3 or to meben- H 2N N N
Uses and Administration dazole alone.3,4
Mebendazole, a benzimidazole carbamate derivative, 1. Maertens K, Wery M. Effect of mebendazole and levamisole on N N S
is an anthelmintic with activity against most nema- Onchocerca volvulus and Dipetalonema perstans. Trans R Soc As NH2
todes and some other worms; activity against some lar- Trop Med Hyg 1975; 69: 359–60.
2. Bernberg HC, et al. The combined treatment with levamisole and NH2 S
val stages and ova has also been demonstrated. It inhib- mebendazole for a perstans-like filarial infection in Rhodesia. NH2
its or destroys cytoplasmic microtubules in the worm’s Trans R Soc Trop Med Hyg 1979; 73: 233–4.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
150 Anthelmintics
Profile Interactions Morantel Citrate (BANM, pINNM)
Melarsomine is a trivalent arsenical derivative used in veterinary Patients treated with metrifonate should not be given Citrato de morantel; Morantel, Citrate de; Moranteli Citras. (E)-
practice for the control of canine heartworm (dirofilariasis).
depolarising neuromuscular blockers such as suxame- 1,4,5,6-Tetrahydro-1-methyl-2-[2-(3-methyl-2-thienyl)vinyl]pyri-
thonium for at least 48 hours.The use of metrifonate midine citrate monohydrate.
should be avoided in those recently exposed to insecti- Морантела Цитрат
cides or other agricultural chemicals with anti- C 12 H 16N 2 S,C 6 H 8 O 7 ,H 2 O = 430.5.
Metrifonate (BAN, rINN) C AS — 20574-50-9 (morantel); 69525-81-1 (morantel ci-
cholinesterase activity.
Bayer-L-1359; DETF; Metrifonaatti; Metrifonát; Metrifonat; Met- trate).
rifonatas; Métrifonate; Metrifonato; Metrifonatum; Metriphonate;
Trichlorfon (USAN); Trichlorphon. Dimethyl 2,2,2-trichloro-1-hy- Pharmacokinetics
Metrifonate is absorbed after oral doses and some is H3C
droxyethylphosphonate.
Метрифонат converted to dichlorvos which is considered to be the
C 4 H 8 Cl 3 O 4 P = 257.4.
active moiety. Plasma concentrations of dichlorvos are N
about 1% of those of metrifonate with peak concentra- S
C AS — 52-68-6.
tions of both substances occurring within 2 hours. Ex- N
ATC — P02BB01.
cretion is via the kidney, mainly as glucuronides. CH3
ATC Vet — QP52AB01; QP53AF02.
◊ References. (morantel)
1. Nordgren I, et al. Plasma levels of metrifonate and dichlorvos
O during treatment of schistosomiasis with Bilarcil. Am J Trop Med
Hyg 1980; 29: 426–30.
Morantel Tartrate (BANM, USAN, pINNM)
P CCl3 2. Nordgren I, et al. Levels of metrifonate and dichlorvos in plasma
H3CO and erythrocytes during treatment of schistosomiasis with Bilar- CP-12009-18; Moranteelivetytartraatti; Morantel, hydrogéno-
H3CO cil. Acta Pharmacol Toxicol (Copenh) 1981; 49 (suppl V): tartrate de; Morantel, Tartrate de; Morantel-hidrogén-tartarát;
OH 79–86. Morantel-hydrogen-tartarát; Moranteli hydrogenotartras; Mor-
3. Pettigrew LC, et al. Pharmacokinetics, pharmacodynamics, and anteli Tartras; Morantelvätetartrat; Tartrato de morantel; UK-
safety of metrifonate in patients with Alzheimer’s disease. J Clin
Pharmacopoeias. In Eur. (see p.vii), Int., and US. Pharmacol 1998; 38: 236–45.
2964-18.
Ph. Eur. 6.2 (Metrifonate). A white or almost white, crystalline Морантела Тартрат
powder. M.p. is between 76° and 81°. Freely soluble in water, in C 12 H 16N 2 S,C 4 H 6 O 6 = 370.4.
alcohol, and in acetone; very soluble in dichloromethane. Protect Uses and Administration C AS — 20574-50-9 (morantel); 26155-31-7 (morantel
from light. Metrifonate is an organophosphorus compound and is tartrate).
USP 31 (Metrifonate). A white crystalline powder. M.p. about converted in the body to the active metabolite dichlor- Pharmacopoeias. In Eur. (see p.vii) and US for veterinary use
78° with decomposition. Freely soluble in water, in alcohol, in vos (p.2040), an anticholinesterase. only.
acetone, in chloroform, in ether, and in benzene; very soluble in
Ph. Eur. 6.2 (Morantel Hydrogen Tartrate for Veterinary Use;
dichloromethane; very slightly soluble in hexane and in pentane. Metrifonate has anthelmintic activity against Schisto- Morantel Tartrate BP(Vet) 2008). A white or pale yellow, crystal-
Decomposed by alkali. Store at a temperature not exceeding 25°. soma haematobium and has been given orally as an al- line powder. Very soluble in water and in alcohol; practically in-
ternative to praziquantel in the treatment of schisto- soluble in ethyl acetate. A 1% solution in water has a pH of 3.3
Adverse Effects, Treatment, and Precau- somiasis due to S. haematobium. It has usually been to 3.9. Protect from light.
tions given in three doses of 7.5 to 10 mg/kg at intervals of USP 31 (Morantel Tartrate). A white or pale yellow, crystalline
Metrifonate is generally well tolerated, but may cause powder. Very soluble in water and in alcohol; practically insolu-
2 weeks. ble in ethyl acetate. pH of a 1% solution in water is between 2.8
nausea, vomiting, abdominal pain, diarrhoea, head-
Metrifonate has also been used as an insecticide and as and 3.9. Store at a temperature of 25°, excursions permitted be-
ache, dizziness, and weakness. tween 15° and 30°. Protect from light.
a parasiticide in fish and domestic animals.
It is an organophosphorus compound and because of its Profile
anticholinesterase properties depresses plasma- Alzheimer’s disease. Metrifonate, like a number of other Morantel is an analogue of pyrantel. The citrate and the tartrate
cholinesterase concentrations. For a description of the cholinesterase inhibitors, has been tried in the treatment of are used as anthelmintics in veterinary medicine for the treatment
Alzheimer’s disease (see Dementia, p.362). Clinical studies1,2 of gastrointestinal roundworms.
toxic effects of organophosphorus compounds and the produced modest benefits but research was stopped after reports
treatment of acute poisoning, see Organophosphorus of muscle weakness, sometimes requiring respiratory support.
Insecticides, p.2047. Atropine has been used to relieve 1. Becker RE, et al. Effects of metrifonate on cognitive decline in
cholinergic adverse effects without affecting metri- Alzheimer disease: a double-blind, placebo-controlled, 6-month Moxidectin (BAN, USAN, rINN)
study. Alzheimer Dis Assoc Disord 1998; 12: 54–7.
fonate’s activity against Schistosoma haematobium. CL-301423; Moksidektiini; Moxidectina; Moxidectine; Moxidecti-
2. Morris JC, et al. Metrifonate benefits cognitive, behavioral, and num; Moxidektin. (6R,15S)-5-O-Demethyl-28-deoxy-25-[(E)-
Anticholinesterase effects. Metrifonate depresses global function in patients with Alzheimer’s disease. Neurology
1998; 50: 1222–30. 1,3-dimethylbut-1-enyl]-6,28-epoxy-23-oxomilbemycin B (E)-
cholinesterase activity and there has been the occasional report 23-O-methyloxime.
of severe cholinergic adverse effects.1 However, it does not usu- Schistosomiasis. While praziquantel is now the main treat-
ally give rise to troublesome effects at doses normally used, even Моксидектин
ment for schistosomiasis (p.138), metrifonate is an alternative for
though there may temporarily be almost complete inhibition of C 37 H 53NO 8 = 639.8.
infection due to Schistosoma haematobium. Cure rates with
plasma cholinesterase and considerable inhibition of erythrocyte C AS — 113507-06-5.
standard doses in schistosomiasis control programmes range
cholinesterase2 (but see also under Alzheimer’s Disease, below). from 40 to more than 80%, with a reduction of more than 80% in ATC Vet — QP54AB02.
The environmental aspects of metrifonate usage have been con- egg counts among those not cured, but a comparison with prazi-
sidered by WHO.3 quantel has shown praziquantel to be the more effective drug.1 In
O
1. Jamnadas VP, Thomas JEP. Metriphonate and organophosphate addition, metrifonate’s dosage schedule of 3 doses at intervals of N CH3
poisoning. Cent Afr J Med 1979; 25: 130. 2 weeks has caused problems of patient compliance;2 giving
2. Pleština R, et al. Effect of metrifonate on blood cholinesterases 5 mg/kg three times in one day has produced similar results to a CH3 CH3
H H
in children during the treatment of schistosomiasis. Bull WHO standard dosage schedule.3 O H
1972; 46: 747–59. CH3
1. Squires N. Interventions for treating schistosomiasis haemato- H O
3. WHO. Trichlorfon. Environmental Health Criteria 132. Geneva:
bium. Available in The Cochrane Database of Systematic Re-
WHO, 1992. Available at: http://www.inchem.org/documents/ H 3C CH3 CH3
views; Issue 3. Chichester: John Wiley; 1997 (accessed
ehc/ehc/ehc132.htm (accessed 16/07/08) H
16/05/05).
O O
Handling. Bulk metrifonate is very toxic when inhaled, swal- 2. Aden Abdi Y, Gustafsson LL. Poor patient compliance reduces
lowed, or spilled on the skin. It can be removed from the skin by the efficacy of metrifonate treatment of Schistosoma haemato- OH H
washing with soap and water. Contaminated material should be bium in Somalia. Eur J Clin Pharmacol 1989; 36: 161–4.
immersed in a 2% aqueous solution of sodium hydroxide for sev- 3. Aden Abdi Y, Gustafsson LL. Field trial of the efficacy of a sim-
eral hours. plified and standard metrifonate treatments of Schistosoma hae- O
matobium. Eur J Clin Pharmacol 1989; 37: 371–4. CH3
H
Pregnancy. WHO reported1 that metrifonate had not shown H OH
embryotoxicity or teratogenicity, but did not recommend the use
of metrifonate in pregnant patients unless immediate interven- Pharmacopoeias. In Eur. (see p.vii) for veterinary use.
tion was essential. There has been a report of an infant born with Milbemycin Oxime Ph. Eur. 6.2 (Moxidectin for Veterinary Use). A white or pale
massive hydrocephalus and a large meningomyelocele whose yellow, amorphous powder. Practically insoluble in water; very
mother had been treated twice with metrifonate during the sec- CGA-179246; Milbemicina oxima. A mixture of milbemycin A4
5-oxime and milbemycin A3 5-oxime. soluble in alcohol; slightly soluble in hexane.
ond month of pregnancy.2 A possible link between congenital
abnormalities and the use of metrifonate to eradicate fish para- Мильбемицин Оксим
Profile
sites has also been postulated.3 Moxidectin is an anthelmintic used in veterinary medicine. It is
C AS — 129496-10-2. also used as a systemic veterinary ectoparasiticide and is under
1. WHO. The control of schistosomiasis: second report of the
WHO expert committee. WHO Tech Rep Ser 830 1993. Available ATC Vet — QP54AB01. investigation for the treatment of human onchocerciasis.
at: http://libdoc.who.int/trs/WHO_TRS_830.pdf (accessed
16/07/08) Profile ◊ References.
2. Monson MH, Alexander K. Metrifonate in pregnancy. Trans R Milbemycin oxime is an anthelmintic used in veterinary medi- 1. Cotreau MM, et al. The antiparasitic moxidectin: safety, tolera-
Soc Trop Med Hyg 1984; 78: 565. cine. bility, and pharmacokinetics in humans. J Clin Pharmacol 2003;
43: 1108–15.
3. Czeizel AE, et al. Environmental trichlorfon and cluster of con-
genital abnormalities. Lancet 1993; 341: 539–42.
 Metrifonate/Oxamniquine 151
Naftalofos (BAN, USAN, rINN) Niclosamide Monohydrate (BANM)
Bay-9002; E-9002; ENT-25567; Naftalofós; Naftalofosum; Naph- Niclosamida Mono-hidratada; Niclosamida monohidrato;
O
thalophos; Phthalophos; S-940. Diethyl naphthalimido-oxyphos- Niclosamide monohydraté; Niclosamidum monohydricum; Nik-
phonate. losamid monohydrát; Niklosamidimonohydraatti; Niklosamid-
monohydrat; Niklozamidas monohidratas; Niklozamid-mono-
Нафталофос O2N N S
hidrát.
C 16 H 16NO 6 P = 349.3. Никлозамид Моногидрат
C 13 H 8 Cl 2 N 2O 4 ,H 2 O = 345.1. Profile
C AS — 1491-41-4. Nitroscanate is an isothiocyanate anthelmintic used in veterinary
ATC — P02DA01.
ATC Vet — QP52AB06. medicine.
Pharmacopoeias. In Eur. (see p.vii).
Int. permits the monohydrate or the anhydrous substance under
the title Niclosamide.
O Ph. Eur. 6.2 (Niclosamide Monohydrate). Yellowish, fine crys- Nitroxinil (BAN, rINN)
O CH3 tals. Practically insoluble in water; slightly soluble in dehydrated Nitroxinilo; Nitroxinilum; Nitroxynil. 4-Hydroxy-3-iodo-5-ni-
alcohol; sparingly soluble in acetone. Protect from light. trobenzonitrile.
N O P O
Нитроксинил
O CH3 Adverse Effects C 7 H 3 IN 2 O 3 = 290.0.
O Gastrointestinal disturbances may occur occasionally C AS — 1689-89-0 (nitroxinil); 27917-82-4 (nitroxinil eg-
with niclosamide. Lightheadedness and pruritus have lumine).
been reported less frequently. ATC Vet — QP52AG08.
Profile
Naftalofos is an organophosphorus compound (see Organophos-
phorus Insecticides, p.2047) used as an anthelmintic in veteri- Pharmacokinetics OH
nary medicine. Niclosamide is not significantly absorbed from the
gastrointestinal tract. I NO2

Uses and Administration

Netobimin (BAN, USAN, rINN)
Niclosamide is an anthelmintic which is active against
Netobimina; Nétobimine; Netobiminum; Sch-32481. 2-{3-Meth- most tapeworms, including the beef tapeworm (Taenia CN
oxycarbonyl-2-[2-nitro-5-(propylthio)phenyl]guanidi- saginata), the pork tapeworm (T. solium), the fish tape-
no}ethanesulphonic acid. worm (Diphyllobothrium latum) and the dog tape- Pharmacopoeias. In BP(Vet). Also in Fr. for veterinary use
only.
Нетобимин worm (Dipylidium caninum); it has also been given for BP(Vet) 2008 (Nitroxinil). A yellow to yellowish brown pow-
C 14 H 20N 4 O 7 S 2 = 420.5. infections with the dwarf tapeworm, Hymenolepis der. Practically insoluble in water; slightly soluble in alcohol;
C AS — 88255-01-0. nana. For discussions of the treatment of tapeworm in- sparingly soluble in ether; it dissolves in solutions of alkali hy-
fections, see Diphyllobothriasis, p.136, Hymenolepia- droxides. Protect from light.
ATC Vet — QP52AC06.
sis, p.136, and Taeniasis, p.139. The activity of niclosa- Profile
mide against these worms appears to be due to Nitroxinil is an anthelmintic used in veterinary medicine for the
inhibition of mitochondrial oxidative phosphorylation; treatment of fascioliasis and some gastrointestinal roundworms
HO O CH3 in cattle and sheep.
O anaerobic ATP production is also affected.
S O
O Niclosamide is given as tablets, which must be chewed
NH S
thoroughly before swallowing and washed down with
HN CH3 water. Oxamniquine (BAN, USAN, rINN)
N For infections with pork tapeworm a single 2-g dose is Oxamniquina; Oxamniquinum; UK-4271. 1,2,3,4-Tetrahydro-2-
given after a light breakfast. Niclosamide is not active isopropylaminomethyl-7-nitro-6-quinolylmethanol.
-O against the larval form (cysticerci) and, although the Оксамнихин
N+
risk of inducing cysticercosis appears to be theoretical, C 14 H 21 N 3 O 3 = 279.3.
O C AS — 21738-42-1.
a laxative is given about 2 hours after the dose to expel
ATC — P02BA02.
the killed worms and minimise the possibility of the
Profile ATC Vet — QP52AA02.
Netobimin is an anthelmintic used in veterinary medicine.
migration of ova of T. solium into the stomach; an an-
tiemetic may also be given before treatment.
For infections with beef or fish tapeworms the 2-g dose O CH3
of niclosamide may be divided, with 1 g taken after H
N+ N
breakfast and 1 g an hour later. -
Niclosamide (BAN, USAN, rINN) O N
H
CH3
In dwarf-tapeworm infections an initial dose of 2 g has HO
Anhydrous Niclosamide; Bay-2353; Niclosamida; Niclosamida been given on the first day followed by 1 g daily for 6
Anidra; Niclosamide anhydre; Niclosamidum; Niclosamidum an- days.
hydricum; Niklosamid; Niklosamid, vattenfri; Niklosamidi; Niklos- Pharmacopoeias. In Fr. and Int.
amidi, vedetön; Niklozamid; Niklozamid bezwodny; Niklozami- Children aged 2 to 6 years are given half the above dos-
das, bevandenis; Phenasale; Vízmentes niklozamid. 2′,5-Dichloro- es and those under 2 years of age are given one-quarter Adverse Effects
4′-nitrosalicylanilide; 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hy- the above doses. Oxamniquine causes severe pain at the injection site
droxybenzamide. Unless expulsion of the worm is aided by a laxative, when given intramuscularly and is no longer given by
Никлозамид portions are voided in a partially digested form after this route.
C 13 H 8Cl 2 N 2 O 4 = 327.1. treatment with niclosamide; the scolex is rarely identi- It is generally well tolerated after oral doses, although
fiable. dizziness with or without drowsiness occurs in at least
C AS — 50-65-7.
In schistosomiasis (p.138), niclosamide is used as a a third of patients, beginning up to 3 hours after a dose
ATC — P02DA01. molluscicide in water-treatment control programmes. and usually lasting for up to 6 hours. Headache and
ATC Vet — QP52AG03. Preparations gastrointestinal effects such as nausea, vomiting, and
BP 2008: Niclosamide Tablets. diarrhoea are also common.
Proprietary Preparations (details are given in Part 3) Allergic-type reactions including urticaria, pruritic
OH Belg.: Yomesan; Braz.: Atenase†; Cz.: Yomesan†; Denm.: Yomesan†;
Cl Fin.: Kontal; Fr.: Tredemine; Ger.: Yomesan; Gr.: Tredemine; Yomesan; In- skin rashes, and fever may occur. Liver enzyme values
H dia: Niclosan; Israel: Yomesan; Ital.: Yomesan; Mex.: Overoid; Neth.: have been raised transiently in some patients. Epilepti-
N Yomesan; S.Afr.: Yomesan; Swed.: Yomesan; Thai.: Manozide; Niclosan†;
Cl Telmitin; Unicide; Yomesan; Turk.: Yomesan; UK: Yomesan. form convulsions have been reported, especially in pa-
Multi-ingredient: Thai.: Zenda†. tients with a history of convulsive disorders. Hallucina-
O tions and excitement have occurred rarely.
NO2
A reddish discoloration of urine, probably due to a me-
Nitroscanate (BAN, USAN, rINN) tabolite of oxamniquine, has been reported.
Pharmacopoeias. In Chin. and Eur. (see p.vii).
Int. permits the anhydrous substance or the monohydrate under CGA-23654; Nitroscanato; Nitroscanatum; Nitroskanaatti; Ni- Effects on body temperature. A review1 in 1987 noted that
the title Niclosamide. troskanat. 4-(4-Nitrophenoxy)phenyl isothiocyanate. although a modest post-treatment rise in temperature had been
Ph. Eur. 6.2 (Niclosamide, Anhydrous). Yellowish-white to yel- Нитросканат reported occasionally, fever was not a common adverse effect of
lowish, fine crystals. Practically insoluble in water; slightly solu- C 13 H 8 N 2 O 3 S = 272.3. oxamniquine, except in Egypt where it appeared to be character-
ble in dehydrated alcohol; sparingly soluble in acetone. Store in C AS — 19881-18-6. istic. The cause was not known. Increased immune complexes
airtight containers. Protect from light. ATC Vet — QP52AX01. and excretion of antigens occurred in only half the cases, there
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
152 Anthelmintics
was no evidence that Egyptian patients metabolised the drug dif- 2. Ferrari ML, et al. Efficacy of oxamniquine and praziquantel in Profile
ferently to produce a pyrogenic metabolite, and the effect had not the treatment of Schistosoma mansoni infection: a controlled tri- Oxibendazole is a benzimidazole carbamate anthelmintic struc-
been seen in other areas where a similar high-dose regimen was al. Bull WHO 2003; 81: 190–6. turally related to mebendazole (p.148). It is used in veterinary
3. WHO. The control of schistosomiasis: report of a WHO expert
used.1 committee. WHO Tech Rep Ser 728 1985. Available at: http:// medicine.
1. Foster R. A review of clinical experience with oxamniquine. libdoc.who.int/trs/WHO_TRS_728.pdf (accessed 16/07/08)
Trans R Soc Trop Med Hyg 1987; 81: 55–9.
Preparations
Effects on the nervous system. In 37 patients with Schisto- Proprietary Preparations (details are given in Part 3) Oxyclozanide (BAN, rINN)
soma mansoni infection treated successfully with oxamniquine,1 Braz.: Mansil; Gr.: Vansil†.
dizziness and drowsiness were most common, but the most sig- ICI-46683; Oxiclozanida; Oxyclozanidum. 3,3′,5,5′,6-Pentachlo-
nificant adverse effect was the development of EEG abnormali- ro-2′-hydroxysalicylanilide.
ties in 6 of 34 patients whose pre-treatment EEG was normal. Of Оксиклозанид
the 3 patients with pre-existing EEG abnormalities, 1 suffered a Oxantel Embonate (BANM, rINNM) C 13 H 6 Cl 5 NO 3 = 401.5.
tonic-clonic seizure during therapy as previously reported,2 1 did CP-14445-16; Embonato de oxantel; Oxantel, Embonate d’; Ox- C AS — 2277-92-1.
not suffer seizures, and the third received phenytoin prophylaxis antel Pamoate (USAN); Oxanteli Embonas. (E)-3-[2-(1,4,5,6-Tet- ATC Vet — QP52AG06.
during oxamniquine therapy. It was considered prudent to give rahydro-1-methylpyrimidin-2-yl)vinyl]phenol 4,4′-methyleneb-
antiepileptics before starting oxamniquine in patients with a his- is(3-hydroxy-2-naphthoate).
tory of seizure disorder. After completion of this study, a patient Cl
with no history of seizures suffered a tonic-clonic seizure 2 hours Оксантела Эмбонат
after each of the second and third doses of oxamniquine. C 13 H 16N 2 O,C 23 H 16O 6 = 604.6. HO
C AS — 36531-26-7 (oxantel); 68813-55-8 (oxantel em- OH O
The main neuropsychiatric adverse effects seen in 180 Brazilian bonate); 42408-84-4 (oxantel embonate).
patients with Schistosoma mansoni infection treated with single ATC — P02CC02. Cl
oral doses of oxamniquine were: drowsiness (50.6%), dizziness N Cl
(41.1%), headache (16.1%), temporary amnesia (2.2%), behav- H
ioural disturbances (1.7%), chills (1.1%), and seizures (1.1%).3 N
An EEG was performed before and after treatment in 20 patients; Cl
there were alterations in 3 but they were not associated with neu- Cl
ropsychiatric changes. N
1. Krajden S, et al. Safety and toxicity of oxamniquine in the treat- Pharmacopoeias. In BP(Vet).
ment of Schistosoma mansoni infections, with particular refer- CH3
ence to electroencephalographic abnormalities. Am J Trop Med BP(Vet) 2008 (Oxyclozanide). A pale cream or cream-coloured
Hyg 1983; 32: 1344–6. OH powder. Very slightly soluble in water; soluble in alcohol; freely
2. Keystone JS. Seizures and electroencephalograph changes asso- soluble in acetone; slightly soluble in chloroform.
ciated with oxamniquine therapy. Am J Trop Med Hyg 1978; 27: (oxantel)
360–2. Profile
3. de Carvalho SA, et al. Neurotoxicidade do oxamniquine no trata- Profile Oxyclozanide is an anthelmintic used in veterinary medicine for
mento da infeçáo humana pelo Schistosoma mansoni. Rev Inst Oxantel is an analogue of pyrantel that has been used as the em- the control of fascioliasis in cattle and sheep.
Med Trop Sao Paulo 1985; 27: 132–42.
bonate in the treatment of trichuriasis. It is used with pyrantel for
various intestinal nematode infections.
Precautions Preparations
Oxamniquine should be used with caution in patients Proprietary Preparations (details are given in Part 3)
Piperazine
with epilepsy or a history of convulsive disorders. Pa- Multi-ingredient: Indon.: Quantrel; Philipp.: Quantrel; Venez.: Dualid; Piperatsiini; Piperazin; Piperazina; Piperazinum.
tients should be warned that oxamniquine can cause Quantrel. Пиперазин
dizziness or drowsiness and if affected they should not C 4 H 10 N 2 = 86.14.
drive or operate machinery. C AS — 110-85-0.
Oxfendazole (BAN, USAN, rINN) ATC — P02CB01.
Pharmacokinetics Oksfendatsoli; Oxfendazol; Oxfendazolum; RS-8858. Methyl 5- ATC Vet — QP52AH01.
Oxamniquine is readily absorbed after oral doses. Peak phenylsulphinyl-1H-benzimidazol-2-ylcarbamate.
plasma concentrations are achieved 1 to 3 hours after a Оксфендазол
dose and the plasma half-life is 1 to 2.5 hours. C 15 H 13N 3 O 3 S = 315.3. H
C AS — 53716-50-0. N
It is extensively metabolised to inactive metabolites, ATC Vet — QP52AC02.
principally the 6-carboxy derivative, which are excret-
ed in the urine. About 70% of a dose of oxamniquine is N
excreted as the 6-carboxy metabolite within 12 hours O H
of a dose; traces of the 2-carboxy metabolite have also S N
been detected in the urine. Pharmacopoeias. In US.
NH CH3 USP 31 (Piperazine). White to off-white lumps or flakes having
N an ammoniacal odour. Soluble in water and in alcohol; insoluble
Uses and Administration O
H in ether. Store in airtight containers. Protect from light.
Oxamniquine is an anthelmintic used in the treatment O
of schistosomiasis caused by Schistosoma mansoni, Piperazine Adipate
but not by other Schistosoma spp. It causes worms to Pharmacopoeias. In Eur. (see p.vii) and US for veterinary use
only. Piperatsiiniadipaatti; Piperaz. Adip.; Piperazina, adipato de; Piper-
shift from the mesenteric veins to the liver where the Ph. Eur. 6.2 (Oxfendazole for Veterinary Use; Oxfendazole azinadipat; Piperazin-adipát; Pipérazine, adipate de; Piperazini ad-
male worms are retained; the female worms return to BP(Vet) 2008). A white or almost white powder. It shows poly- ipas; Piperazino adipatas; Piperazinum Adipicum.
the mesentery, but can no longer release eggs. Resist- morphism. Practically insoluble in water; slightly soluble in al- Пиперазина Адипат
ance may occur. cohol and in dichloromethane. Protect from light. C 4 H 10 N 2 ,C 6 H 10 O 4 = 232.3.
USP 31 (Oxfendazole). A white or almost white powder. Prac- C AS — 142-88-1.
Oxamniquine is given orally, preferably after food. tically insoluble in water; slightly soluble in alcohol and in ATC — P02CB01.
Dosage depends on the geographical origin of the in- dichloromethane. Protect from light.
Pharmacopoeias. In Eur. (see p.vii), Int., Jpn, and Viet.
fection and total doses range from 15 mg/kg as a single Profile Ph. Eur. 6.2 (Piperazine Adipate). A white or almost white, crys-
dose to 60 mg/kg given over 2 to 3 days. A single dose Oxfendazole is a benzimidazole carbamate anthelmintic struc- talline powder. Soluble in water; practically insoluble in alcohol.
should not exceed 20 mg/kg. turally related to mebendazole (p.148). It is used in veterinary
medicine. Piperazine Citrate
Schistosomiasis. Oxamniquine is an alternative to praziquan-
tel for the treatment of schistosomiasis (p.138) due to Schisto- Hydrous Tripiperazine Dicitrate; Piperatsiinisitraatti; Piperazina,
soma mansoni, although resistance has occurred, particularly in citrato de; Piperazincitrat; Piperazin-citrát; Piperazin-citrát hydrát;
South America,1 and it is somewhat less effective than praziqu- Oxibendazole (BAN, USAN, rINN) Pipérazine, citrate de; Piperazini citras; Piperazini Citras Hydricus;
antel.2 Oxibendazol; Oxibendazolum; SKF-30310. Methyl 5-propoxy- Piperazino citratas.
The dose ranges between a single dose of 15 mg/kg and 1H-benzimidazol-2-ylcarbamate. Пиперазина Цитрат
60 mg/kg given over 2 or 3 days.1,3 Doses in the low range have Оксибендазол
been used effectively in South America, the Caribbean, and West (C 4 H 10 N 2 ) 3 ,2C 6 H 8 O 7 ,xH 2 O = 642.7 (anhydrous sub-
C 12 H 15N 3 O 3 = 249.3. stance).
Africa while patients in Egypt, South Africa, and Zimbabwe re- C AS — 20559-55-1.
quire doses at the top end of the range; intermediate doses may C AS — 144-29-6 (anhydrous piperazine citrate); 41372-
ATC Vet — QP52AC07. 10-5 (piperazine citrate hydrate).
be effective in other parts of Africa.3
ATC — P02CB01.
After the appropriate therapeutic dose of oxamniquine, cure rates
of at least 60%, and often more than 90%, can be expected. Egg Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet.
O N Ph. Eur. 6.2 (Piperazine Citrate). A white or almost white gran-
excretion in those not cured will be reduced by over 80%, and
usually by over 90%, one year after treatment.3 NH CH3 ular powder. It contains a variable amount of water. Freely solu-
ble in water; practically insoluble in alcohol.
1. WHO. The control of schistosomiasis: second report of the
H 3C N O USP 31 (Piperazine Citrate). A white, crystalline powder having
WHO expert committee. WHO Tech Rep Ser 830 1993. Available H
at: http://libdoc.who.int/trs/WHO_TRS_830.pdf (accessed O not more than a slight odour. Soluble in water; insoluble in alco-
16/07/08) hol and in ether. pH of a 10% solution in water is about 5.
 Oxantel Embonate/Praziquantel 153
Stability. A decrease in the content of piperazine [as citrate] in Effects on the liver. A reaction resembling viral hepatitis oc- Adults and children over 12 years of age are given the
syrups on storage was attributed to interaction with fructose and curred on 2 occasions in a 25-year-old woman after use of piper- equivalent of 2.25 g of the hydrate once daily, children
glucose formed by hydrolysis of sucrose.1 A syrup prepared with azine; it appeared to be a hypersensitivity reaction.1
sorbitol lost no potency when stored at 25° for 14 months. 1. Hamlyn AN, et al. Piperazine hepatitis. Gastroenterology 1976;
aged 7 to 12 years the equivalent of 1.5 g daily, those
1. Nielsen A, Reimer P. The stability of piperazine in syrup. Arch 70: 1144–7. aged 4 to 6 years the equivalent of 1.125 g daily, and
Pharm Chemi (Sci) 1975; 3: 73–8. Hypersensitivity. A patient experienced a serum-sickness-like those aged 1 to 3 years the equivalent of 750 mg daily.
illness associated with piperazine,1 which was followed by a de- Children under 1 year should receive piperazine on
Piperazine Hydrate layed hypersensitivity vasculitis. medical advice only; a dose equivalent to 45 to
Piperatsiinihydraatti; Piperazin Heksahidrat; Piperazin hexahy- See also Effects on the Blood and Effects on the Liver, above. 75 mg/kg has been suggested.
drát; Piperazina hexahidrato; Piperazinas hidratas; Pipérazine, hy- 1. Balzan M, Cacciottolo JM. Hypersensitivity vasculitis associat-
ed with piperazine therapy. Br J Dermatol 1994; 131: 133–4. Piperazine is also used as a preparation with senna in a
drate de; Piperazin-hidrát; Piperazinhydrat; Piperazini Hydras; single dose of 4 g of the phosphate for adults and chil-
Piperazinium Hexahydricum; Piperazinum hydricum; Piperazyna
Precautions dren over 6 years of age, repeated after 14 days for en-
uwodniona. Piperazine hexahydrate.
Piperazine is contra-indicated in patients with epilepsy terobiasis, or repeated monthly if necessary for up to 3
Пиперазина Гидрат
or severe renal impairment and should be given with months to treat and prevent ascariasis.
C 4 H 10N 2 ,6H 2 O = 194.2.
C AS — 142-63-2.
care to patients with neurological disturbances or mild Preparations
ATC — P02CB01. to moderate renal impairment. It should also be avoid- BP 2008: Piperazine Citrate Elixir; Piperazine Phosphate Tablets;
Pharmacopoeias. In Eur. (see p.vii) and Viet.
ed or given with extreme caution in patients with he- USP 31: Piperazine Citrate Syrup; Piperazine Citrate Tablets.
patic impairment. Proprietary Preparations (details are given in Part 3)
Ph. Eur. 6.2 (Piperazine Hydrate). Colourless deliquescent crys- Braz.: Ascarinase†; Ortovermim†; Vermifran†; Vermilen†; Canad.: Enta-
tals. M.p. about 43°. Freely soluble in water and in alcohol. A 5% Breast feeding. The UK licensed product information for cyl†; Fr.: Vermifuge†; Indon.: Combicitrine; Piperacyl; Upixon; Ital.: Citro-
solution in water has a pH of 10.5 to 12.0. Store in airtight con- Pripsen (piperazine and senna) states that piperazine is distribut- piperazina; Mex.: Desparasil†; Helmifar†; Lu-Peracina; Overpon; Piperawitt
tainers. Protect from light. DS†; Piperazil; Pipergress; Pipermed†; Pirzinol; Verfid; Vermin; Port.: Lom-
ed into breast milk. Mothers should be advised to take a dose brimade†; Pipermel; Pipertox; S.Afr.: Padax; Pipralen; Piprine; SB Tox
after breast feeding then not to breast feed for 8 hours during Worm; Spain: Mimedran; Vermi; Thai.: Vermex; Turk.: Asepar; Askari-
Piperazine Phosphate which period milk should be expressed and discarded at the reg- par; Helmicide; Helmipar; Oksiaskaril; Siropar; UK: Pripsen†; Venez.: Cipe-
ular feeding times. rina; Inquiper†; Jetsan†; Oxine†; Piperato; Piperazil; Piperdin; Piperzan; Ver-
Piperazina, fosfato de; Piperazini Phosphas. pirol.
Pregnancy. It has been reported that piperazine is teratogenic in Multi-ingredient: Braz.: Vermilen Composto†; India: Helmazan†; Irl.:
Пиперазина Фосфат
rabbits and that there have been isolated reports of fetal malfor- Pripsen†; Port.: Biureol; UK: Pripsen.
C 4 H 10N 2 ,H 3 PO 4 ,H 2 O = 202.1. mations after clinical use, though no causal relationship has been
C AS — 14538-56-8 (anhydrous piperazine phosphate); established. Two infants with malformations have been de-
18534-18-4 (piperazine phosphate monohydrate). scribed briefly:1 one had bilateral hare lip, cleft palate, and ano-
ATC — P02CB01. phthalmia; the other had an abnormality of one foot. Both moth-
Pomegranate Bark
Pharmacopoeias. In Br., Chin., Jpn, and Viet. ers had taken Pripsen (piperazine and senna). UK licensed Granado; Granati Cortex; Granatrinde; Granatum; Grenadier;
BP 2008 (Piperazine Phosphate). A white odourless or almost product information for Pripsen advises against use in pregnan- Melograno; Pomegranate; Pomegranate Root Bark; Romeira.
odourless crystalline powder. Sparingly soluble in water; practi- cy, especially during the first trimester, unless immediate treat- Кора Гранатового Дерева
cally insoluble in alcohol. A 1% solution in water has a pH of 6.0 ment with piperazine is essential.
Profile
to 6.5. 1. Leach FN. Management of threadworm infestation during preg-
nancy. Arch Dis Child 1990; 65: 399–400. Pomegranate bark, the dried bark of the stem and root of Punica
granatum (Punicaceae) containing about 0.4 to 0.9% of alka-
Adverse Effects Interactions loids,, has been used for the expulsion of tapeworms.
Serious adverse effects are rare with piperazine and The anthelmintic effects of piperazine and pyrantel Preparations
generally indicate overdosage or impaired excretion. may be antagonised when the two compounds are used Proprietary Preparations (details are given in Part 3)
Nausea, vomiting, diarrhoea, abdominal pain, head- Fr.: Hexaporine.
together. The possibility that piperazine may enhance
ache, skin rashes, and urticaria occasionally occur. Se- the adverse effects of phenothiazines such as chlorpro-
vere neurotoxicity and EEG abnormalities have been mazine is discussed on p.975.
reported with symptoms including somnolence, dizzi- Praziquantel (BAN, USAN, rINN)
ness, nystagmus, muscular incoordination and weak- Pharmacokinetics EMBAY-8440; Pratsikvanteli; Prazicuantel; Prazikvantel; Prazikvan-
ness, ataxia, paraesthesia, myoclonic contractions, Piperazine is readily absorbed from the gastrointestinal telis; Praziquantelum. 2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hex-
choreiform movements, tremor, convulsions, and loss tract and is excreted in the urine within 24 hours, partly ahydropyrazino[2,1-a]isoquinolin-4-one.
of reflexes. as metabolites. The rate at which different individuals Празиквантел
Transient visual disturbances such as blurred vision C 19 H 24 N 2 O 2 = 312.4.
excrete piperazine has been reported to vary widely. It
have occurred occasionally and there were reports of C AS — 55268-74-1.
is distributed into breast milk. ATC — P02BA01.
cataract formation after treatment with piperazine al- ATC Vet — QP52AA01.
though they do not appear to have been substantiated. Uses and Administration
Hypersensitivity reactions such as bronchospasm, Ste- Piperazine is an anthelmintic effective against the in-
vens-Johnson syndrome, and angioedema have oc- testinal nematodes Ascaris lumbricoides (roundworm) O
curred in some individuals. and Enterobius vermicularis (pinworm, threadworm), N
although other anthelmintics are usually preferred (see
◊ Piperazine has been taken off the market in some European
countries because of general concern about its safety.1 A study
the discussions on the treatment of ascariasis and enter-
obiasis on p.134 and p.136). In roundworms piperazine N
carried out in Sweden on 2 healthy subjects had indicated that
mononitrosation of piperazine can occur in the stomach to pro- produces a neuromuscular block leading to a flaccid
duce the potential carcinogen N-mononitrosopiperazine; the muscle paralysis in susceptible worms, which are then O
more potent N,N-dinitrosopiperazine was not found.2 However, easily dislodged by the movement of the gut and ex-
the disease risk to man from such N-nitroso compounds has been Pharmacopoeias. In Chin., Eur. (see p.vii), Int., and US.
questioned3 and certainly reports of tumours associated with the pelled in the faeces.
Ph. Eur. 6.2 (Praziquantel). White or almost white crystalline
use of piperazine have not been traced. Also, in the UK the CSM Piperazine is usually given as the citrate or phosphate, powder. It exhibits polymorphism. Very slightly soluble in water;
concluded that the incidence of serious adverse effects associated but the adipate may also be used. The dosage of the freely soluble in alcohol and in dichloromethane. Protect from
with piperazine was low and that, with appropriate pack warn- salts of piperazine is usually expressed in terms of pip- light.
ings, piperazine products could remain as medicines available to
erazine hydrate; 100 mg of piperazine hydrate is equiv- USP 31 (Praziquantel). A white or practically white crystalline
the public through pharmacies.1
alent to about 44.4 mg of piperazine, 120 mg of piper- powder; odourless or with a faint characteristic odour. Very
1. Anonymous. Data sheet changes for piperazine in pregnancy. slightly soluble in water; freely soluble in alcohol and in chloro-
Pharm J 1988; 240: 367. azine adipate, 125 mg of piperazine citrate (110 mg of form. Protect from light.
2. Bellander BTD, et al. Nitrosation of piperazine in the stomach. anhydrous piperazine citrate), and to 104 mg of piper-
Lancet 1981; ii: 372.
3. Tannenbaum SR. N-nitroso compounds: a perspective on human azine phosphate. Adverse Effects
exposure. Lancet 1983; i: 629–32. For the treatment of ascariasis, a single dose, repeated Adverse effects with praziquantel may be common but
Abuse. Derivatives of piperazine have been developed and once after 14 days, has been used. In adults and chil- are usually mild and transient. Headache, diarrhoea,
abused as ‘designer drugs’—see Benzylpiperazine (p.2152). dren over 12 years of age, a dose equivalent to 4.5 g of dizziness, drowsiness, malaise, abdominal discomfort,
Effects on the blood. A 4-year-old African boy with G6PD piperazine hydrate is given orally. Children aged 9 to nausea, and vomiting have been reported most fre-
deficiency developed haemolytic anaemia; no cause for the 12 years may be given the equivalent of 3.75 g, those quently. Hypersensitivity reactions such as fever, urti-
haemolysis was found except that 2 days previously he had taken aged 6 to 8 years the equivalent of 3 g, those aged 4 to caria, pruritic skin rashes, and eosinophilia can occur;
Pripsen (piperazine and senna).1 Severe thrombocytopenia with
epistaxis and haemoptysis, which developed in a 61-year-old
5 years the equivalent of 2.25 g, and those aged 1 to 3 they may be due to death of the infecting parasites.
man after piperazine self-medication, was probably the result of years the equivalent of 1.5 g. Children under 1 year Raised liver enzyme values have been reported rarely.
sensitisation to piperazine 15 years earlier.2 should receive piperazine on medical advice only; a Most patients with neurocysticercosis who are given
1. Buchanan N, et al. G-6-PD deficiency and piperazine. BMJ dose equivalent to 120 mg/kg has been suggested. praziquantel suffer CNS effects, including headache,
1971; 2: 110.
2. Cork MJ, et al. Pruritus ani, piperazine, and thrombocytopenia.
For enterobiasis, piperazine has been given for 7 days. hyperthermia, seizures, and intracranial hypertension,
BMJ 1990; 301: 1398. A second course after a 7-day interval may be required. which are thought to result from an inflammatory re-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
154 Anthelmintics
sponse to dead and dying parasites in the CNS. Use Pharmacokinetics the small cysts; 2 large cysts were removed surgically, one before
with corticosteroids is advised in such patients. Praziquantel is rapidly absorbed after oral doses; more praziquantel was started. However, activity in 9 other patients
given praziquantel was disappointing.3 A combination of prazi-
Effects on the gastrointestinal tract. Colicky abdominal than 80% of a dose is reported to be absorbed. Peak quantel with albendazole may be effective.4
pain and bloody diarrhoea occurred in a small community in Za- plasma concentrations occur 1 to 3 hours after a dose, 1. Morris DL, et al. Protoscolicidal effect of praziquantel— in vitro
ire shortly after treatment for Schistosoma mansoni infection but there is a pronounced first-pass effect and praziqu- and electron microscopical studies on Echinococcus granulosus.
with single oral doses of praziquantel 40 mg/kg.1 A similar syn- antel undergoes rapid and extensive metabolism in the J Antimicrob Chemother 1986; 18: 687–91.
drome has been reported in some patients with Schistosoma 2. Henriksen T-H, et al. Treatment of disseminated peritoneal hy-
japonicum infection given praziquantel.2 The abdominal pain liver, being hydroxylated to metabolites that are datid disease with praziquantel. Lancet 1989; i: 272.
thought to be inactive. It is distributed into the CSF. 3. Piens MA, et al. Praziquantel dans l’hydatidose humaine: évalu-
occurring in these patients was very different from the mild ab- ation par traitement médical pré-opératoire. Bull Soc Pathol Exot
dominal discomfort much more commonly reported with prazi- The plasma elimination half-life of praziquantel is Filiales 1989; 82: 503–12.
quantel therapy. about 1 to 1.5 hours and that of the metabolites about 4 4. Ayles HM, et al. A combined medical and surgical approach to
1. Polderman AM, et al. Side effects of praziquantel in the treat- hydatid disease: 12 years’ experience at the Hospital for Tropical
ment of Schistosoma mansoni in Maniema, Zaire. Trans R Soc
hours. Diseases, London. Ann R Coll Surg Engl 2002; 84: 100–105.
Trop Med Hyg 1984; 78: 752–4. It is excreted in the urine, mainly as metabolites, about Intestinal fluke infections. Praziquantel is used in the treat-
2. Watt G, et al. Bloody diarrhoea after praziquantel therapy. Trans
R Soc Trop Med Hyg 1986; 80: 345–6. 80% of the dose being eliminated within 4 days and ment of intestinal fluke infections (p.136). In the treatment of fas-
more than 90% of this in the first 24 hours. ciolopsiasis, heterophyiasis, and metagonimiasis, the usual rec-
Effects on the nervous system. Adverse nervous system ef- ommended dose is 25 mg/kg three times daily for one day.1
fects are common in patients with neurocysticercosis given Praziquantel is distributed into breast milk. However, a single dose of 25 mg/kg has also been recommend-
praziquantel. Neurological symptoms have also been reported1 ed.2 Single doses of 15 mg/kg, 25 mg/kg, or 40 mg/kg all yielded
with the much lower doses of praziquantel used in the treatment ◊ References. a cure rate of 100% in a study in 72 primary-school children in
of taeniasis in a patient with undiagnosed neurocysticercosis. 1. Leopold G, et al. Clinical pharmacology in normal volunteers of Thailand who were harbouring Fasciolopsis buski, suggesting
1. Flisser A, et al. Neurological symptoms in occult neurocysticer- praziquantel, a new drug against schistosomes and cestodes: an that a single dose of 15 mg/kg at bedtime might be tried.3 In an-
cosis after single taenicidal dose of praziquantel. Lancet 1993; example of a complex study covering both tolerance and phar-
342: 748. macokinetics. Eur J Clin Pharmacol 1978; 14: 281–91. other study, 9 patients infected with the trematode Nanophyetus
2. Bühring KU, et al. Metabolism of praziquantel in man. Eur J salmincola were treated with praziquantel 20 mg/kg three times
Drug Metab Pharmacokinet 1978; 3: 179–90. daily for one day and were negative for eggs in their stools 2 to
Precautions 12 weeks later,4 and this has become the usual recommended
3. Patzschke K, et al. Serum concentrations and renal excretion in
Praziquantel should not be used in patients with ocular humans after oral administration of praziquantel—results of dose.1
cysticercosis because of the risk of severe eye damage three determination methods. Eur J Drug Metab Pharmacokinet 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
1979; 3: 149–56. Rochelle NY: The Medical Letter, 2007.
resulting from destruction of the parasite.
4. Mandour M El M, et al. Pharmacokinetics of praziquantel in 2. WHO. WHO model formulary. Geneva: WHO, 2004.
Patients should be warned that praziquantel may cause healthy volunteers and patients with schistosomiasis. Trans R 3. Harinasuta T, et al. Efficacy of praziquantel on fasciolopsiasis.
dizziness or drowsiness and if affected they should not Soc Trop Med Hyg 1990; 84: 389–93. Arzneimittelforschung 1984; 34: 1214–15.
4. Fritsche TR, et al. Praziquantel for treatment of human Nano-
drive or operate machinery during or for 24 hours after phyetus salmincola (Troglotrema salmincola) infection. J Infect
treatment. Uses and Administration Dis 1989; 160: 896–9.
Praziquantel is an anthelmintic with a broad spectrum Liver fluke infections. Praziquantel is used in the treatment of
Breast feeding. Praziquantel is distributed into breast milk and
mothers should not breast feed during treatment or for 72 hours of activity against trematodes (flukes) including all clonorchiasis and opisthorchiasis, and has also been used in the
thereafter. species of Schistosoma pathogenic to man, and against treatment of fascioliasis (p.137) although in this latter infection
cestodes (tapeworms). It is used in the treatment of bithionol or triclabendazole are preferred.
Pregnancy. In a review of 637 women given praziquantel in a Various studies have shown praziquantel to be effective in
mass distribution programme, 88 had had a single oral dose dur- cysticercosis, diphyllobothriasis, hymenolepiasis,
clonorchiasis1-4 and opisthorchiasis,5,6 although one study in
ing pregnancy, including 37 in their first trimester. All pregnan- schistosomiasis, taeniasis, and intestinal, liver, and opisthorchiasis7 showed that re-infection was common despite
cies ended in full-term babies and there was no evidence of clin- lung fluke infections. For discussions of these infec- praziquantel therapy, particularly in those with heavy initial in-
ical abnormality. No difference was found in the rates of preterm tions and their treatment, see under Choice of An- fection. A study in Thailand8 confirmed that mass treatment for
delivery or abortion compared with a control group.1 opisthorchiasis with a single dose of praziquantel was beneficial,
1. Adam I,et al. Is praziquantel therapy safe during pregnancy?
thelmintic, p.134, and under the individual headings
below. although it was suggested that ideally treatment should be given
Trans R Soc Trop Med Hyg 2004; 98: 540–3.
twice a year.
Praziquantel is given orally with food. While praziquantel is not the drug of choice for fascioliasis, there
Interactions has been a report9 of successful treatment of a patient with severe
In the treatment of schistosomiasis in adults and chil-
Anthelmintics. For reference to plasma concentrations of the infection. Subsequent studies10-12 have, however, shown prazi-
active metabolite of albendazole being increased by praziquan- dren over 4 years it is given on one day as three doses quantel to be of little benefit.
tel, see p.139. of 20 mg/kg at intervals of 4 to 6 hours or it is given as 1. Soh C-J. Clonorchis sinensis: experimental and clinical studies
a single dose of 40 to 60 mg/kg (but see below). with praziquantel in Korea. Arzneimittelforschung 1984; 34:
Antibacterials. A study1 in healthy subjects found that oral 1156–9.
rifampicin decreased plasma concentrations after single and mul- Doses in adults and children over 4 years in the liver 2. Chen C-Y, Hsieh W-C. Clonorchis sinensis: epidemiology in
tiple doses of oral praziquantel to subtherapeutic levels. Taiwan and clinical experience with praziquantel. Arzneimittel-
fluke infections clonorchiasis and opisthorchiasis are forschung 1984; 34: 1160–2.
1. Ridtitid W, et al. Rifampin markedly decreases plasma concen-
trations of praziquantel in healthy volunteers. Clin Pharmacol 25 mg/kg three times daily for one or two days or a 3. Kuang Q-H, et al. Clonorchiasis: treatment with praziquantel in
50 cases. Arzneimittelforschung 1984; 34: 1162–3.
Ther 2002; 72: 505–13. single dose of 40 mg/kg. Similar doses may be used in 4. Lee S-H. Large scale treatment of clonorchis sinensis infections
Antiepileptics. Carbamazepine and phenytoin have been re- intestinal fluke and lung fluke infections (see below). with praziquantel under field conditions. Arzneimittelforschung
ported to reduce the bioavailability of praziquantel.1 1984; 34: 1227–8.
1. Quinn DI, Day RO. Drug interactions of clinical importance: an
Single doses of 5 to 25 mg/kg are used in adults and 5. Bunnag D, et al. Opisthorchis viverrini: clinical experience with
children over 4 years in tapeworm infections. praziquantel in hospital for tropical diseases. Arzneimittelforsc-
updated guide. Drug Safety 1995; 12: 393–452. hung 1984; 34: 1173–4.
Antimalarials. Chloroquine has been reported to reduce the bi- Praziquantel is used in adults and children over 4 years 6. Ambroise-Thomas P, et al. Therapeutic results in opisthorchia-
sis with praziquantel in a reinfection-free environment in
oavailability of praziquantel.1 in the treatment of neurocysticercosis in a dose of France. Arzneimittelforschung 1984; 34: 1177–9.
1. Masimirembwa CM, et al. The effect of chloroquine on the phar- 7. Upatham ES, et al. Rate of re-infection by Opisthorchis viver-
macokinetics and metabolism of praziquantel in rats and in hu- 50 mg/kg daily in 3 divided doses for 14 days. An al- rini in an endemic northeast Thai community after chemothera-
mans. Biopharm Drug Dispos 1994; 15: 33–43. ternative regimen of 3 doses of 25 mg/kg every 2 hours py. Int J Parasitol 1988; 18: 643–9.
Corticosteroids. Corticosteroids may be used to reduce the in- has been proposed. 8. Pungpak S, et al. Opisthorchis viverrini infection in Thailand:
studies on the morbidity of the infection and resolution follow-
flammatory reactions that often occur within 2 to 3 days of start-
ing cysticidal therapy. However, use is complicated by the fact ◊ Reviews. ing praziquantel treatment. Am J Trop Med Hyg 1997; 56:
311–14.
that dexamethasone roughly halves the plasma concentration of 1. Pearson RD, Guerrant RL. Praziquantel: a major advance in an- 9. Schiappacasse RH, et al. Successful treatment of severe infec-
praziquantel. It has therefore been suggested that when praziqu- thelmintic therapy. Ann Intern Med 1983; 99: 195–8. Correction. tion with Fasciola hepatica with praziquantel. J Infect Dis 1985;
ibid.; 574. 152: 1339–40.
antel is given in the 2-week treatment regimen, corticosteroids 10. Farag HF, et al. A short note on praziquantel in human fascio-
2. King CH, Mahmoud AAF. Drugs five years later: praziquantel.
should not be given prophylactically but only if an inflammatory Ann Intern Med 1989; 110: 290–6. liasis. J Trop Med Hyg 1986; 89: 79–80.
reaction develops. Dexamethasone is then given daily for 2 or 3 3. Cioli D, Pica-Mattocia L. Praziquantel. Parasitol Res 2003; 90
11. Farid Z, et al. Unsuccessful use of praziquantel to treat acute
days and most of the treatment period will be free of pharmaco- fascioliasis in children. J Infect Dis 1986; 154: 920–1.
(suppl 1): S3–S9. 12. Farid Z, et al. Treatment of acute toxaemic fascioliasis. Trans R
kinetic interaction. When the short course praziquantel regimen Soc Trop Med Hyg 1988; 82: 299.
is used (3 doses given 2 hours apart), the corticosteroid may be Cysticercosis. Praziquantel is used in the treatment of neuro-
given prophylactically. The first dose of dexamethasone is given cysticercosis (p.135) although albendazole is also considered to Lung fluke infections. Praziquantel is used in the treatment of
4 hours after the last dose of praziquantel (when the concentra- be the drug of choice. the lung fluke infection paragonimiasis (p.137).
tion of praziquantel is starting to decrease and the pharmacolog- References. References.
ical action is assumed to have been accomplished) and then daily 1. Sotelo J, Jung H. Pharmacokinetic optimisation of the treatment 1. Vanijanonta S, et al. Paragonimus heterotremus and other Para-
for 2 to 3 days. No pharmacokinetic interaction would be expect- of neurocysticercosis. Clin Pharmacokinet 1998; 34: 503–15. gonimus spp. in Thailand: pathogenesis clinic and treatment.
ed at this point.1 Arzneimittelforschung 1984; 34: 1186–8.
2. Del Brutto OH, et al. Single-day praziquantel versus 1-week al- 2. Pachucki CT, et al. American paragonimiasis treated with prazi-
1. Sotelo J, Jung H. Pharmacokinetic optimisation of the treatment bendazole for neurocysticercosis. Neurology 1999; 52: 1079–81. quantel. N Engl J Med 1984; 311: 582–3.
of neurocysticercosis. Clin Pharmacokinet 1998; 34: 503–15. 3. OH Del Brutto, et al. Meta-analysis: cysticidal drugs for neuro- 3. De NV, et al. Epidemiology, symptoms and treatment of parag-
Histamine H2-antagonists. Cimetidine has been reported to cysticercosis: albendazole and praziquantel. Ann Intern Med onimiasis in Sin Ho district, Lai Chau province, Vietnam. South-
2006; 145: 43–51. east Asian J Trop Med Public Health 2000; 31 (suppl 1): 26–30.
increase praziquantel bioavailability.1,2
1. Metwally A, et al. Effect of cimetidine, bicarbonate and glucose Echinococcosis. Praziquantel may be used as an adjunct to sur- Schistosomiasis. Praziquantel is the main drug1,2 used in the
on the bioavailability of different formulations of praziquantel. gery in echinococcosis (p.136). Praziquantel has been reported to treatment of schistosomiasis (p.138). It is effective against all
Arzneimittelforschung 1995; 45: 516–18. possess a scolicidal effect in vitro against Echinococcus species of schistosomes.1 Doses are either 20 mg/kg given three
2. Jung H, et al. Pharmacokinetic study of praziquantel adminis-
tered alone and in combination with cimetidine in a single-day granulosus1 and there has been a report of the successful treat- times in one day or a single dose of 40 mg/kg. WHO considers1
therapeutic regimen. Antimicrob Agents Chemother 1997; 41: ment of disseminated peritoneal hydatid disease with praziquan- that in the field such a single-dose treatment will produce a cure
1256–9. tel and surgery.2 In this case praziquantel was effective against rate of 60 to 90% with a reduction in egg count in those not cured
 Praziquantel/Rafoxanide 155
of 90 to 95%. Good as such results are, a single dose or one day’s Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US. Pyrvinium Embonate (rINNM)
sole treatment should not be considered to be all that is required Ph. Eur. 6.2 (Pyrantel Embonate). A pale yellow or yellow pow-
to achieve a permanent cure or prevent re-infection, and any Embonato de pirvinio; Pirvinyum Pamoat; Pyrvinii Embonas; Pyr-
der. Practically insoluble in water and in methyl alcohol; soluble
treatment plan should be reassessed after 6 or 12 months.3,4 Such in dimethyl sulfoxide. Protect from light. vinium, Embonate de; Pyrvinium Pamoate (BAN); Viprynium Em-
an approach with annual screening and targeted chemotherapy USP 31 (Pyrantel Pamoate). A yellow to tan solid. Practically bonate; Viprynium Pamoate. Bis{6-dimethylamino-2-[2-(2,5-
can provide, at least in some endemic areas, successful protec- insoluble in water and in methyl alcohol; soluble in dimethyl sul- dimethyl-1-phenylpyrrol-3-yl)vinyl]-1-methylquinolinium} 4,4′-
tion for children against intense infection and consequent hepatic foxide; slightly soluble in dimethylformamide. Protect from methylenebis(3-hydroxy-2-naphthoate).
disease.4 light. Пирвиния Эмбонат
Several studies indicate that doses lower than those recommend- C 52 H 56 N 6 ,C 23 H 14 O 6 = 1151.4.
ed above might be effective and in some control programmes Adverse Effects and Precautions C AS — 3546-41-6.
20 mg/kg might be enough for S. haematobium5-7 or 30 mg/kg ATC — P02CX01.
for S. mansoni.5 The extent to which low doses contribute to re- The adverse effects of pyrantel embonate are generally
sistance, as has been suggested with oxamniquine,8 is unclear, mild and transient. The most frequent are gastrointesti-
but refractory infections have been reported. A 4-day treatment nal effects such as nausea and vomiting, anorexia, ab- CH3
course was needed to produce a complete cure in a patient who CH3
dominal pain, and diarrhoea. Other adverse effects re-
relapsed twice following standard one-day treatment regimens.9 N+
Hepatic impairment, specifically hepatic fibrosis, is a feature of
ported include headache, dizziness, drowsiness,
N
some schistosomal infections and patients with such liver in- insomnia, skin rashes, and raised liver enzyme values.
H3C
volvement have benefited from treatment with praziquantel.4,10 N H3C
Pyrantel embonate should be used with caution in pa-
1. WHO. The control of schistosomiasis: second report of the
WHO expert committee. WHO Tech Rep Ser 830 1993. tients with hepatic impairment. CH3 2
2. Doenhoff MJ, Pica-Mattocia L. Praziquantel for the treatment
of schistosomiasis: its use for control in areas with endemic dis-
ease and prospects for drug resistance. Expert Rev Anti Infect Interactions COO−
Ther 2006; 4: 199–210. The anthelmintic effects of both pyrantel and pipera-
3. Anonymous. The chemotherapy of schistosomiasis control. Bull zine may be antagonised when the two drugs are used
WHO 1986; 64: 23–5. OH
4. Anonymous. Mass treatment of schistosomiasis with praziquan-
together.
tel. WHO Drug Inf 1988; 2: 184–5.
OH
5. Taylor P, et al. Efficacy of low doses of praziquantel for Schis- Pharmacokinetics
tosoma mansoni and S. haematobium. J Trop Med Hyg 1988;
91: 13–17. Only a small proportion of a dose of pyrantel embonate
COO−
6. King CH, et al. Dose-finding study for praziquantel therapy of is absorbed from the gastrointestinal tract. Up to about
Schistosoma haematobium in Coast Province, Kenya. Am J
Trop Med Hyg 1989; 40: 507–13. 7% is excreted as unchanged drug and metabolites in Pharmacopoeias. In US.
7. Hatz C, et al. Ultrasound scanning for detecting morbidity due the urine but over half of the dose is excreted un- USP 31 (Pyrvinium Pamoate). A bright orange or orange-red to
to Schistosoma haematobium and its resolution following treat- changed in the faeces. practically black crystalline powder. Practically insoluble in wa-
ment with different doses of praziquantel. Trans R Soc Trop Med ter and in ether; slightly soluble in chloroform and in methox-
Hyg 1990; 84: 84–8.
yethanol; freely soluble in glacial acetic acid; very slightly solu-
8. Coles GC, et al. Tolerance of Kenyan Schistosoma mansoni to Uses and Administration ble in methyl alcohol. Store in airtight containers. Protect from
oxamniquine. Trans R Soc Trop Med Hyg 1987; 81: 782–5.
9. Murray-Smith SQ, et al. A case of refractory schistosomiasis.
Pyrantel embonate is an anthelmintic effective against light.
Med J Aust 1996; 165: 458. intestinal nematodes including roundworms (Ascaris Adverse Effects
10. Zwingenberger K, et al. Praziquantel in the treatment of hepat- lumbricoides), threadworms (Enterobius vermicula- Pyrvinium occasionally causes nausea, vomiting, abdominal
osplenic schistosomiasis: biochemical disease markers indicate ris), and Trichostrongylus spp., the tissue nematode pain, and diarrhoea. Hypersensitivity reactions and photosensi-
deceleration of fibrogenesis and diminution of portal flow ob-
struction. Trans R Soc Trop Med Hyg 1990; 84: 252–6. Trichinella spiralis, and hookworms, although it is tivity have been reported. Headache may occur.
possibly less effective against Necator americanus Pyrvinium stains the stools bright red and may stain clothing if
Taeniasis. Praziquantel is used in the treatment of taeniasis vomiting occurs.
(p.139). It has been studied in the mass control of taeniasis when hookworms than against Ancylostoma duodenale. Pyr-
a single dose of 5 mg/kg was used.1 antel embonate is one of the anthelmintics that may be Pharmacokinetics
used in the treatment of infections with these worms, as Pyrvinium embonate is not significantly absorbed from the gas-
Praziquantel is also effective against the larval form of Taenia trointestinal tract.
solium and is used to treat neurocysticercosis (see above). discussed under Choice of Anthelmintic, p.134. It ap-
1. Cruz M, et al. Operational studies on the control of Taenia so- pears to act by paralysing susceptible worms which are Uses and Administration
lium taeniasis/cysticercosis in Ecuador. Bull WHO 1989; 67: then dislodged by peristaltic activity. Pyrvinium embonate is an effective anthelmintic in the treatment
401–7. of enterobiasis (p.136), but has generally been superseded by
Pyrantel is given orally as the embonate, but doses are other drugs.
Preparations Pyrvinium is given as the embonate but doses are described in
described in terms of the base. Pyrantel embonate 2.9 g
USP 31: Praziquantel Tablets. is equivalent to about 1 g of pyrantel. terms of the base. Pyrvinium embonate 7.5 mg is equivalent to
about 5 mg of pyrvinium.
Proprietary Preparations (details are given in Part 3)
Arg.: Prazitral; Austral.: Biltricide; Braz.: Cestox; Cisticid; Canad.: Biltri- Single or mixed infections due to susceptible worms in It has been given orally in a single dose equivalent to pyrvinium
cide; Chile: Cesol; Cisticid; Fr.: Biltricide; Ger.: Biltricide; Cesol; Cysticide; adults and children may be treated with the equivalent 5 mg/kg, repeated after 2 to 3 weeks.
Gr.: Biltricide; Hong Kong: Biltricide; Israel: Biltricide; Mex.: Bio-Cest†;
Cesol; Cisticid; Extiser-Q†; Prozitel†; Tecprazin; Teniken; Zifartel; Neth.: Bil- of pyrantel 10 mg/kg as a single oral dose. Ascariasis Preparations
tricide; Rus.: Biltricid (Бильтрицид); S.Afr.: Biltricide; Cysticide; Thai.: My- occurring alone may only require 5 mg/kg; a single USP 31: Pyrvinium Pamoate Oral Suspension; Pyrvinium Pamoate Tablets.
cotricide; Opticide; Praquantel; Prasikon; Prazite; Wormicide; USA: Biltri-
cide; Venez.: Cestox; Cisticid†. dose of 2.5 mg/kg given three or four times a year has Proprietary Preparations (details are given in Part 3)
been used in mass treatment programmes. In necatoria- Arg.: Tru; Austria: Molevac; Braz.: Enterocid†; Pyr-Pam†; Pyverm; Ca-
nad.: Vanquin†; Denm.: Vanquin; Fin.: Pyrvin; Fr.: Povanyl; Ger.: Molevac;
sis, 10 mg/kg daily for 3 or 4 days or 20 mg/kg daily Pyrcon; Norw.: Vanquin; Spain: Pamoxan; Swed.: Vanquin; Turk.: Pirok.
for 2 days may be necessary. The response in enterobi-
Pyrantel Embonate (BANM, rINNM) asis may be improved by repeating the 10 mg/kg dose
after 2 to 4 weeks. In trichinosis, a dose of 10 mg/kg Rafoxanide (BAN, USAN, rINN)
CP-10423-16; Embonato de pirantel; Pirantel Pamoat; Pirantel
daily for 5 days has been used.
Pamoate; Pirantelio embonatas; Pyranteeliembonaatti; Pyrantel, MK-990; Rafoxanida; Rafoxanidum. 3′-Chloro-4′-(4-chlorophe-
embonate de; Pyrantel Pamoate (USAN); Pyrantelembonat; Pyr- Pyrantel tartrate has been used as a veterinary an- noxy)-3,5-di-iodosalicylanilide.
antel-embonát; Pyranteli embonas; Pyrantelu embonian. 1,4,5,6- thelmintic. Рафоксанид
Tetrahydro-1-methyl-2-[(E)-2-(2-thienyl)vinyl]pyrimidine 4,4′-
C 19 H 11 Cl 2 I 2 NO 3 = 626.0.
methylenebis(3-hydroxy-2-naphthoate). Preparations C AS — 22662-39-1.
Пирантела Эмбонат ATC Vet — QP52AG05.
USP 31: Pyrantel Pamoate Oral Suspension.
C 11 H 14N 2 S,C 23H 16 O 6 = 594.7.
Proprietary Preparations (details are given in Part 3)
C AS — 15686-83-6 (pyrantel); 22204-24-6 (pyrantel em- O
bonate); 33401-94-4 (pyrantel tartrate). Arg.: Aut†; Austral.: Anthel; Combantrin; Early Bird; Austria: Combantrin;
Braz.: Ascarical; Canad.: Combantrin; Jaa Pyral; Chile: Combantrin; Fr.: O
ATC — P02CC01. Combantrin; Helmintox; Ger.: Helmex; Gr.: Combantrin†; Hong Kong:
Combantrin; Pyrantin; Pyrantrin†; India: Nemocid; Indon.: Combantrin; I
Konvermex; Medicomtrin; Piraska; Proworm; Israel: Combantrin†; Ital.: N CI CI
Combantrin; Mex.: Combantrin; Pirantrim; NZ: Combantrin; Philipp.: H
H 3C Combantrin; Gelminthic; Port.: Combantrin; Vertel†; Rus.: Helmintox
(Гельминтокс); Nemocid (Немоцид); S.Afr.: Combantrin; Singapore: OH
N Bearantel; Spain: Lombriareu; Trilombrin; Switz.: Cobantril; Thai.: Ban-
S tel†; Pyrapam; Turk.: Kontil; USA: Antiminth†; Pin-Rid; Pin-X; Reese’s Pin- I
worm; Venez.: Combantrin; Etimex†; Pamoval†; Pleosan†; Tamoa; Ten-
N echa†.
Profile
Multi-ingredient: India: Mebex Plus; Indon.: Quantrel; Philipp.: Rafoxanide is an anthelmintic used in veterinary medicine for the
Quantrel; Venez.: Dualid; Quantrel. treatment of fascioliasis in cattle and sheep.
(pyrantel)

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
156 Anthelmintics
Santonin Profile inal pain are common during treatment with tiabenda-
Tetramisole hydrochloride is an anthelmintic used in veterinary zole. Other adverse effects occurring occasionally in-
Santoniini; Santonina; Santoninum. (3S,3aS,5aS,9bS)-3a,5,5a,9b-
medicine for the control of nematode infections. It is a racemic
Tetrahydro-3,5a,9-trimethylnaphtho[1,2-b]furan-2,8(3H,4H)-di- mixture and the laevo-isomer, levamisole hydrochloride (p.147), clude pruritus, skin rashes, headache, fatigue,
one. accounts for most of its activity. drowsiness, drying of mucous membranes, hypergly-
Сантонин Preparations caemia, disturbance of vision including colour vision,
C 15 H 18 O 3 = 246.3. Proprietary Preparations (details are given in Part 3) leucopenia, tinnitus, effects on the liver including
C AS — 481-06-1. Braz.: Ascarizole†; Tetramizotil†. cholestasis and parenchymal damage (in some cases
Multi-ingredient: India: Jetomisol-P. severe and irreversible), enuresis, crystalluria, and
CH3 bradycardia and hypotension. There have also been re-
ports of erythema multiforme, fatal Stevens-Johnson
Thiacetarsamide (rINNM) syndrome, toxic epidermal necrolysis, convulsions,
Thiacétarsamide; Thiacetarsamidum; Tiacetarsamida. p-[Bis(car- and effects on mental state.
CH3 boxymethylmercapto)arsino]benzamide; 4-Carbamylphenyl
O Fever, chills, angioedema, and lymphadenopathy have
bis[carboxymethylthio]arsenite.
CH3 O been reported, but may represent allergic response to
Тиацетарсамид
O C 11 H 12AsNO 5 S 2 = 377.3.
dead parasites rather than to tiabendazole.
C AS — 531-72-6. The urine of some patients taking tiabendazole may
Pharmacopoeias. In Jpn. ATC Vet — QP52AX08. have a characteristic odour similar to that after eating
Profile asparagus; it is attributed to the presence of a tiabenda-
Santonin is a crystalline lactone obtained from the dried unex- O
zole metabolite.
panded flowerheads of Artemisia cina (santonica, wormwood) Effects on the salivary glands. Dry mouth with swollen pa-
and other species of Artemisia (Compositae). It was formerly OH
rotid and salivary glands suggestive of the sicca complex preced-
used as an anthelmintic in the treatment of roundworm (Ascaris) ed the development of cholestatic jaundice in a 17-year-old boy
infection, but has been superseded by other less toxic an- given tiabendazole.1
thelmintics. H 2N S
1. Davidson RN, et al. Intrahepatic cholestasis after thiabendazole.
It is used as a flavour in food. As Trans R Soc Trop Med Hyg 1988; 82: 620.
O S Hypersensitivity. Severe erythema multiforme developed in a
patient 16 days after a course of tiabendazole.1 Many of the le-
sions encircled pre-existing melanocytic naevi.
Selamectin (USAN, rINN)
OH 1. Humphreys F, Cox NH. Thiabendazole-induced erythema multi-
Selamectina; Sélamectine; Selamectinum; Selamektiini; Selamek- forme with lesions around melanocytic naevi. Br J Dermatol
tin; UK-124114. (2aE,4E,5′S,6S,6′S,7S,8E,11R,13R,15S,17aR,20aR, O 1988; 118: 855–6.
20bS)-6′-Cyclohexyl-7-[(2,6-dideoxy-3-O-methyl-α-L-arabino-
hexopyranosyl)oxy]-3′,4′,5′,6,6′,7,10,11,14,15,20a,20b-dodec- Profile Precautions
ahydro-20b-hydroxy-5′,6,8,19-tetramethylspiro(11,15-methano- Thiacetarsamide is an anthelmintic used in veterinary medicine. Tiabendazole should be used with caution in patients
2H,13H,17H-furo[4,3,2-p,q][2,6]benzodioxacyclooctadecin- with hepatic or renal impairment. Tiabendazole causes
13,2′-[2H]pyran)-17,20(17aH)-dione 20-oxime. drowsiness in some patients and those affected should
Селамектин Thiophanate (BAN) not drive or operate machinery.
C 43 H 63 NO 11 = 770.0. Tiofanato. 4,4′-o-Phenylenebis(ethyl 3-thioallophanate). Tiabendazole should not be used in mixed worm infec-
C AS — 165108-07-6. C 14 H 18N 4 O 4 S 2 = 370.4. tions involving Ascaris lumbricoides as it can cause
ATC Vet — QP54AA05. C AS — 23564-06-9.
ATC Vet — QP52AC04. these roundworms to migrate; live roundworms have
emerged through the mouth or nose.
CH3 CH3 Pregnancy. Tiabendazole is teratogenic in mice although there
O S
H 3C O O O are no adequate and well controlled studies in human pregnancy.
O H3C O N NH Renal impairment. Tiabendazole and its 5-hydroxy metabo-
HO H3C
H H H lite did not accumulate in an anephric patient on haemodialysis
N N O CH3 and haemoperfusion who was treated for severe strongyloidia-
O O O sis.1 However, the potentially toxic conjugated glucuronide and
CH3
OH S O sulfate metabolites did accumulate. The clearance of all 3 metab-
olites was poor by haemodialysis; haemoperfusion was much
more efficient, although for rapid removal the haemoperfusion
O Profile columns should be changed every hour.
CH3 Thiophanate is an anthelmintic used in veterinary medicine for
H 1. Bauer L, et al. The pharmacokinetics of thiabendazole and its
N
the control of nematode infections. metabolites in an anephric patient undergoing hemodialysis and
OH hemoperfusion. J Clin Pharmacol 1982; 22: 276–80.

Pharmacopoeias. In Eur. (see p.vii) for veterinary use only. Interactions

Ph. Eur. 6.2 (Selamectin for Veterinary Use). A semi-synthetic Tiabendazole (BAN, rINN) Xanthines. For the effect of tiabendazole on serum concentra-
product derived from a fermentation product. A white or almost
white, hygroscopic powder. Practically insoluble in water; solu- E233; MK-360; Thiabendazole (USAN); Tiabendatsoli; Tiabenda- tions of theophylline, see p.1145.
ble in acetone and in dichloromethane; freely soluble in isopro- zol; Tiabendazolas; Tiabendazolum. 2-(Thiazol-4-yl)-1H-benzim-
pyl alcohol; sparingly soluble in methyl alcohol. Store in airtight idazole. Pharmacokinetics
containers. Тиабендазол Tiabendazole is readily absorbed from the gastrointes-
C 10 H 7N 3 S = 201.2. tinal tract and reaches peak concentrations in the plas-
Profile
Selamectin is an avermectin anthelmintic and ectoparasiticide C AS — 148-79-8. ma after 1 to 2 hours. It is metabolised to 5-hydroxythi-
used in veterinary medicine. ATC — D01AC06; P02C A02. abendazole and excreted principally in the urine as
ATC Vet — QD01AC06; QP52AC10.
glucuronide or sulfate conjugates; about 90% is recov-
ered in the urine within 48 hours of ingestion, but only
Tetramisole Hydrochloride (BANM, USAN, rINNM) H 5% in the faeces. Absorption may occur from prepara-
Hidrocloruro de tetramisol; ICI-50627; McN-JR-8299-11; R- N tions applied to the skin or eyes.
S
8299; Tétramisole, Chlorhydrate de; Tetramisoli Hydrochlori- ◊ References.
dum. (±)-2,3,5,6-Tetrahydro-6-phenylimidazo[2,1-b]thiazole hy- N N 1. Tocco DJ, et al. Absorption, metabolism, and excretion of thia-
drochloride. bendazole in man and laboratory animals. Toxicol Appl Pharma-
col 1966; 9: 31–9.
Тетрамизола Гидрохлорид Pharmacopoeias. In Chin., Eur. (see p.vii), Int., and US.
C 11 H 12 N 2 S,HCl = 240.8. Ph. Eur. 6.2 (Tiabendazole). A white or almost white crystalline
powder. Practically insoluble in water; slightly soluble in alcohol Uses and Administration
C AS — 5036-02-2 (tetramisole); 5086-74-8 (tetramisole
hydrochloride). and in dichloromethane; it dissolves in dilute mineral acids. Pro- Tiabendazole, a benzimidazole derivative, is an an-
tect from light. thelmintic with activity against most nematode worms;
USP 31 (Thiabendazole ). A white to practically white, odour- activity against some larval stages and ova has also
H N S less or practically odourless, powder. Practically insoluble in wa- been demonstrated. The mode of action is not certain,
ter; slightly soluble in alcohol and in acetone; very slightly solu-
ble in chloroform and in ether. but tiabendazole may inhibit the fumarate-reductase
N system of worms thereby interfering with their source
(tetramisole) Adverse Effects of energy.
Dizziness and gastrointestinal disturbances, especially Tiabendazole is used in the treatment of cutaneous lar-
Pharmacopoeias. In Fr. for veterinary use only. anorexia, nausea and vomiting, diarrhoea, and abdom- va migrans, dracunculiasis (guinea worm infection),
 Santonin/Triclabendazole 157
and toxocariasis. It may also be used in the treatment of Strongyloidiasis. Tiabendazole may be used in the treatment of ingly being used in the treatment of human fascioliasis, and is
strongyloidiasis, and can provide symptomatic relief strongyloidiasis (p.138), but albendazole or ivermectin are gen- under investigation for the treatment of human paragonimiasis.
erally preferred.
during the larval invasion stage of trichinosis. Tiaben- Liver fluke infections. Although bithionol or praziquantel are
References.
dazole is also active against some intestinal nematodes, 1. Grove DI. Treatment of strongyloidiasis with thiabendazole: an used to treat fascioliasis (p.137), some consider triclabendazole
but should not be used as primary therapy; the treat- analysis of toxicity and effectiveness. Trans R Soc Trop Med Hyg to be the drug of choice.1 A suggested oral dose is 10 mg/kg,
ment of mixed infections including ascariasis is not 1982; 76: 114–18. given as a single dose after food; the dose may be repeated once.1
2. Barnish G, Barker J. An intervention study using thiabendazole Several studies2-7 have demonstrated the efficacy of triclabenda-
recommended since tiabendazole may cause the suspension against strongyloides fuelleborni-like infections in zole in fascioliasis.
worms to migrate to other body organs causing serious Papua New Guinea. Trans R Soc Trop Med Hyg 1987; 81: 60–3.
3. Boken DJ, et al. Treatment of Strongyloides stercoralis hyperin- 1. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
complications. For discussions of the treatment of the fection syndrome with thiabendazole administered per rectum. Rochelle NY: The Medical Letter, 2007.
above infections see under Choice of Anthelmintic, Clin Infect Dis 1993; 16: 123–6.
2. Apt W, et al. Treatment of human chronic fascioliasis with tricla-
4. Gann PH, et al. A randomized trial of single- and two-dose iver-
p.134, and under the individual headings below. mectin versus thiabendazole for treatment of strongyloidiasis. J bendazole: drug efficacy and serologic response. Am J Trop Med
Infect Dis 1994; 169: 1076–9. Hyg 1995; 52: 532–5.
Tiabendazole is given orally, with meals, usually in a 5. Pitisuttithum P, et al. A randomized comparative study of alben- 3. El-Karaksy H, et al. Human fascioliasis in Egyptian children:
dose of 25 mg/kg twice daily for 2 or more days, the dazole and thiabendazole in chronic strongyloidiasis. Southeast successful treatment with triclabendazole. J Trop Pediatr 1999;
duration depending on the type of infection; the daily Asian J Trop Med Public Health 1995; 26: 735–8. 45: 135–8.
6. Schaffel R, et al. Thiabendazole for the treatment of strongyloi-
dose should not exceed 3 g. For those unable to tolerate diasis in patients with hematologic malignancies. Clin Infect Dis 4. Millán JC, et al. The efficacy and tolerability of triclabendazole
2000; 31: 821–2. in Cuban patients with latent and chronic Fasciola hepatica in-
2 doses daily, 25 mg/kg may be given after the largest fection. Am J Trop Med Hyg 2000; 63: 264–9.
meal on day 1 and repeated 24 hours later after a simi- Syngamosis. Tiabendazole has been used successfully1,2 to
5. Graham CS, et al. Imported Fasciola hepatica infection in the
lar meal on day 2. For mass treatment, a single dose of treat syngamosis (p.138) when it has occurred in man. United States and treatment with triclabendazole. Clin Infect Dis
1. Grell GAC, et al. Syngamus in a West Indian. BMJ 1978; 2: 2001; 33: 1–5.
50 mg/kg after the evening meal is suggested although 1464.
the incidence of adverse effects may be higher than 2. Leers W-D, et al. Syngamosis, an unusual case of asthma: the 6. Talaie H, et al. Randomized trial of a single, double and triple
first reported case in Canada. Can Med Assoc J 1985; 132: dose of 10 mg/kg of a human formulation of triclabendazole in
with 2 doses of 25 mg/kg. 269–70. patients with fascioliasis. Clin Exp Pharmacol Physiol 2004; 31:
777–82.
In cutaneous larva migrans, 25 mg/kg may be given Preparations 7. Marcos LA, et al. Natural history, clinicoradiologic correlates,
twice daily for 2 days, repeated after 2 days if neces- BP 2008: Tiabendazole Tablets; and response to triclabendazole in acute massive fascioliasis. Am
sary; topical treatment with a 10 to 15% suspension in- USP 31: Thiabendazole Oral Suspension; Thiabendazole Tablets. J Trop Med Hyg 2008; 78: 222–7.
tended for oral use has also been advocated as an alter- Proprietary Preparations (details are given in Part 3)
Arg.: Foldan; Austral.: Mintezol; Braz.: Benzol†; Foldan; Thiaben†; Thi- Lung fluke infections. Encouraging results were reported
native or adjunct to oral treatment. anax; Tiabenzol†; Tiadol; Tiaplex; Chile: Soldrin; Gr.: Mintezol; Mex.: from a pilot study of triclabendazole1 in the treatment of para-
Eprofil; Spain: Triasox†; USA: Mintezol; Venez.: Drofen†. gonimiasis (p.137). In an open comparative study2 in 62 patients,
In dracunculiasis, 25 to 50 mg/kg may be given twice Multi-ingredient: Braz.: Derms; Eraverm-T†; Folderm Pomada; For- a more rapid parasitological response was obtained with tricla-
daily for one day; in massive infection a further verm; Helmi-Ped†; Helmib†; Helmiben; Helmidrax†; Josverm†; Metiaben†;
bendazole in oral doses of 5 mg/kg once daily for 3 days,
50 mg/kg may be given after 5 to 8 days. Micoplex; Neovermin; Octelmin†; Poliben†; Profium; Prohelmin†; Thiabe-
na†; Vermilen Composto†; Vermol†; Zoles†. 10 mg/kg twice on one day, or 10 mg/kg as a single dose, than
In strongyloidiasis, 25 mg/kg may be given twice daily with praziquantel. Clinical symptoms resolved at a comparable
rate in all groups. A later study compared the two one-day regi-
for 2 or 3 days or 50 mg/kg as a single dose; when the mens in 154 patients.3 After 3 months, the cure rates (assessed by
infection is disseminated treatment for at least 5 days Triclabendazole (BAN, rINN) clearance of eggs from sputum) were 84.4% in those given a
may be necessary. Triclabendazol; Triclabendazolum. 5-Chloro-6-(2,3-dichlorophe- single dose of 10 mg/kg, and 90.9% in those given two such dos-
noxy)-2-(methylthio)benzimidazole. es on the same day. In those who were still infected at 3 months,
In trichinosis, 25 mg/kg may be given twice daily for 2 Триклабендазол a second two-dose course resulted in complete parasitological
to 4 successive days. C 14 H 9 Cl 3 N 2OS = 359.7. clearance at 1 year.
In toxocariasis, 25 mg/kg may be given twice daily for C AS — 68786-66-3. 1. Ripert C, et al. Therapeutic effect of triclabendazole in patients
ATC — P02BX04. with paragonimiasis in Cameroon: a pilot study. Trans R Soc
5 to 7 days. ATC Vet — QP52AC01. Trop Med Hyg 1992; 86: 417.
Tiabendazole also has some antifungal activity. It is 2. Calvopiña M, et al. Treatment of human pulmonary paragonim-
iasis with triclabendazole: clinical tolerance and drug efficacy.
used as a fungicidal preservative for certain foods. Cl Trans R Soc Trop Med Hyg 1998; 92: 566–9.
Dracunculiasis. Tiabendazole1,2 may be used for symptomatic H O Cl
3. Calvopiña M, et al. Comparison of two single-day regimens of
treatment of dracunculiasis (p.136), although it has no direct an- H 3C N triclabendazole for the treatment of human pulmonary parag-
onimiasis. Trans R Soc Trop Med Hyg 2003; 97: 451–4.
thelmintic effect. It is used to facilitate removal of the worm from S
subcutaneous tissues. Preparations
N Cl
1. Muller R. Guinea worm disease: epidemiology, control, and
treatment. Bull WHO 1979; 57: 683–9. Proprietary Preparations (details are given in Part 3)
2. Kale OO, et al. Controlled comparative trial of thiabendazole Profile Fr.: Egaten.
and metronidazole in the treatment of dracontiasis. Ann Trop Triclabendazole is a benzimidazole anthelmintic used in veteri-
Med Parasitol 1983; 77: 151–7. nary medicine for the treatment of fascioliasis. It is also increas-

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
Antibacterials
Drug Groups, p.158 Escherichia coli enteritis, p.170 Pregnancy and the neonate, p.188
Aminoglycosides, p.158 Eye infections, p.171 Premature labour, p.188
Antimycobacterials, p.159 Gas gangrene, p.171 Proctitis, p.188
Cephalosporins and related beta lactams, p.159 Gastro-enteritis, p.171 Prostatitis, p.188
Chloramphenicols, p.159 Antibiotic-associated colitis, p.171 Psittacosis, p.188
Glycopeptides, p.160 Campylobacter enteritis, p.172 Q fever, p.188
Lincosamides, p.160 Cholera and other vibrio infections, p.172 Relapsing fever, p.189
Macrolides, p.160 Escherichia coli enteritis, p.173 Respiratory-tract infections, p.189
Penicillins, p.160 Necrotising enterocolitis, p.173 Rheumatic fever, p.189
Quinolones, p.161 Salmonella enteritis, p.173 Rickettsial infections, p.190
Sulfonamides and diaminopyrimidines, p.161 Shigellosis, p.173 Salmonella enteritis, p.190
Tetracyclines, p.162 Yersinia enteritis, p.174 Salpingitis, p.190
Miscellaneous Antibacterials, p.162 Gonorrhoea, p.174 Septicaemia, p.190
Choice of Antibacterial, p.162 Granuloma inguinale, p.174 Sexually transmitted diseases, p.191
Abscess, abdominal, p.162 Haemophilus influenzae infections, p.174 Chancroid, p.191
Abscess, brain, p.162 Helicobacter pylori infections, p.174 Gonorrhoea, p.191
Abscess, liver, p.162 Infections in immunocompromised patients, p.174 Granuloma inguinale, p.192
Abscess, lung, p.163 Intensive care, p.175 Lymphogranuloma venereum, p.192
Actinomycosis, p.163 Legionnaires’ disease, p.176 Syphilis, p.192
Anaerobic bacterial infections, p.163 Leprosy, p.176 Shigellosis, p.193
Anthrax, p.163 Leptospirosis, p.177 Sickle-cell disease, p.193
Antibiotic-associated colitis, p.164 Listeriosis, p.177 Sinusitis, p.193
Arthritis, bacterial, p.164 Lyme disease, p.177 Skin infections, p.194
Bacillary angiomatosis, p.164 Lymphogranuloma venereum, p.178 Spleen disorders, p.194
Bacterial vaginosis, p.164 Melioidosis, p.178 Spotted fevers, p.194
Biliary-tract infections, p.164 Meningitis, p.178 Staphylococcal infections, p.195
Bites and stings, p.164 Meningococcal infections, p.179 Surgical infection, p.195
Bone and joint infections, p.164 Mouth infections, p.180 Syphilis, p.196
Botulism, p.165 Mycetoma, p.180 Tetanus, p.196
Bronchitis, p.165 Necrotising enterocolitis, p.180 Tonsillitis, p.196
Brucellosis, p.165 Necrotising fasciitis, p.180 Toxic shock syndrome, p.196
Campylobacter enteritis, p.166 Neonatal conjunctivitis, p.180 Trachoma, p.196
Cat scratch disease, p.166 Nocardiosis, p.181 Trench fever, p.196
Cellulitis, p.166 Nontuberculous mycobacterial infections, p.181 Tuberculosis, p.196
Cervicitis, p.166 Obstetric disorders, p.182 Tularaemia, p.198
Chancroid, p.166 Osteomyelitis, p.182 Typhoid and paratyphoid fever, p.198
Chlamydial infections, p.166 Otitis externa, p.182 Typhus, p.198
Cholera and other vibrio infections, p.166 Otitis media, p.182 Urethritis, p.199
Cystic fibrosis, p.166 Pancreatitis, p.183 Urinary-tract infections, p.199
Diarrhoea, infective, p.168 Pelvic inflammatory disease, p.184 Catheter-related, p.199
Diphtheria, p.168 Peptic ulcer disease, p.184 The elderly, p.199
Ear infections, p.168 Perinatal streptococcal infections, p.184 Infants and children, p.199
Ehrlichiosis, p.168 Peritonitis, p.184 Men, p.199
Endocarditis, p.168 Pertussis, p.185 Pregnancy, p.199
Endometritis, p.170 Pharyngitis, p.185 Women, p.200
Enterococcal infections, p.170 Pinta, p.186 Whipple’s disease, p.200
Epididymitis, p.170 Plague, p.186 Yaws, p.200
Epiglottitis, p.170 Pneumonia, p.186 Yersinia enteritis, p.200

This chapter includes antimicrobial drugs whose main nerve and neomycin and kanamycin to be more toxic to the than neomycin and can be used systemically. Although it
use is the treatment and prophylaxis of bacterial infec- auditory branch. Other adverse effects common to the has been used in penicillin-resistant gonorrhoea, it is not
tions. In practice the term ‘antibiotics’ is often, and in group include nephrotoxicity, neuromuscular blockade, active against Pseudomonas aeruginosa and has generally
some instances erroneously, used to encompass all of and allergy, including cross-reactivity. been replaced by gentamicin and other newer aminoglyco-
these drugs. In Martindale the term antibacterial is pre- The pharmacokinetics of the aminoglycosides are very sides.
ferred for the drugs in this chapter. The groups into similar. Little is absorbed from the gastrointestinal tract
which these drugs may be categorised are described but they are generally well distributed in the body after Gentamicin was isolated from Micromonospora purpurea
below. Antibacterials described elsewhere in Martin- parenteral dosage although penetration into the CSF is in 1963 and, being active against Ps. aeruginosa and Ser-
dale include metronidazole (p.837), nitazoxanide poor. They are excreted unchanged in the urine by glomer- ratia marcescens, is widely used in the treatment of life-
(p.842), and tinidazole (p.848), which, as well as being ular filtration. threatening infections. Tobramycin is one of several com-
antiprotozoals, are used in the treatment of anaerobic ponents of the nebramycin complex of aminoglycosides
The aminoglycosides have a similar antimicrobial spec- produced by Streptomyces tenebrarius. It has an antimi-
bacterial infections. trum and appear to act by interfering with bacterial protein
crobial spectrum very similar to that of gentamicin and is
Immunological approaches to the treatment and proph- synthesis, possibly by binding irreversibly to the 30S and
to some extent the 50S portions of the bacterial ribosome. reported to be more active against Ps. aeruginosa. Ami-
ylaxis of bacterial infections are discussed under Vac- kacin, a semisynthetic derivative of kanamycin, has a side-
The manner in which they bring about cell death is not ful-
cines Immunoglobulins and Antisera, p.2201. ly understood. They are most active against Gram-nega- chain rendering it less susceptible to inactivating enzymes.
In addition, disinfectants and preservatives (p.1622) are tive rods. Staphylococcus aureus is susceptible to the It has a spectrum of activity like that of gentamicin but
used to kill or inhibit the growth of micro-organisms. aminoglycosides but otherwise most Gram-positive bacte- Gram-negative bacteria resistant to gentamicin, tobramy-
ria, and also anaerobic bacteria, are naturally resistant. cin, and kanamycin are often sensitive. Sisomicin is close-
Aminoglycosides show enhanced activity with penicillins ly related structurally to gentamicin. Netilmicin, the N-
Drug Groups against some enterococci and streptococci. Bacterial re-
Although antibacterials are very diverse compounds ethyl derivative of sisomicin, may be active against some
sistance to streptomycin may occur by mutation, whereas
they are often classified and discussed in groups. They with the other aminoglycosides it is usually associated gentamicin-resistant strains of bacteria although not to the
may be classified according to their mode of action or with the plasmid-mediated production of inactivating en- same extent as amikacin. Other aminoglycosides include
spectrum of antimicrobial activity, but generally those zymes which are capable of phosphorylation, acetylation, apramycin, arbekacin, astromicin, bekanamycin,
with similar chemical structures are grouped together. or adenylation. The aminoglycosides have a postantibiotic dibekacin, etimicin, isepamicin, and micronomicin.
effect, that is antibacterial activity persisting after concen-
trations have dropped below minimum inhibitory concen- Aminoglycosides should in general only be used for the
Aminoglycosides trations. treatment of serious infections because of their potential
The aminoglycosides are a closely related group of bacte- toxicity and antimicrobial spectrum. Doses must be care-
Streptomycin was the first aminoglycoside to become fully regulated to maintain plasma concentrations within
ricidal antibacterials derived from bacteria of the order Ac-
available commercially and was isolated from a strain of
tinomycetales or, more specifically, the genus Strepto- the therapeutic range but avoid accumulation, especially in
Streptomyces griseus in 1944. Its use is now restricted
myces (framycetin, kanamycin, neomycin, paromomycin, patients with renal impairment. Neomycin and framycetin,
mainly to the treatment of tuberculosis when it is always
streptomycin, and tobramycin) and the genus Micromono- which are considered too toxic to be given parenterally,
given with other antituberculous drugs because of the rap-
spora (gentamicin and sisomicin). They are polycationic have been given orally to suppress the intestinal flora. The
id development of resistance. Dihydrostreptomycin, a re-
compounds that contain an aminocyclitol, usually 2-de-
duction product of streptomycin, is only rarely used be- topical use of neomycin and gentamicin has been associat-
oxystreptamine, or streptidine in streptomycin and related
cause of its toxicity. The neomycin complex of ed with allergic reactions and the emergence of resistant
compounds, with cyclic amino-sugars attached by glyco-
antibacterials were the next to be isolated; neomycin itself bacteria. Gentamicin or tobramycin are the drugs of choice
sidic linkages. Therefore, they have also been termed
is mainly a mixture of the B and C isomers and neomycin in the treatment of life-threatening infections due to
aminoglycosidic aminocyclitols. The sulfate salts are gen-
B is considered to be identical with framycetin. Because of
erally used. aminoglycoside-sensitive organisms and are often used
their toxicity they are not given systemically. The related
The aminoglycosides have broadly similar toxicological compound paromomycin (p.843) also has antiprotozoal with other antibacterials. With the continuing emergence
features. Ototoxicity is a major limitation to their use; and anthelmintic properties and may be used in the treat- of resistant strains, amikacin and netilmicin should be re-
streptomycin and gentamicin are generally considered to ment of intestinal amoebiasis, cestode infections, crypto- served for severe infections resistant to gentamicin and the
be more toxic to the vestibular branch of the eighth cranial sporidiosis, and leishmaniasis. Kanamycin is less toxic other aminoglycosides.
158
 Antibacterials 159
Described in this chapter are Substitution at the 7-amino group tends to affect antibacte- the 7-aminocephalosporanic acid nucleus. Steric hin-
Amikacin, p.200 Gentamicin, p.282 rial action whereas at position 3 it may have more of an drance by this methoxy group is considered to be respon-
Apramycin, p.205 Isepamicin, p.288
Arbekacin, p.206 Kanamycin, p.291
effect on pharmacokinetic properties. sible for their greater stability to beta lactamases. For prac-
Astromicin, p.206 Micronomicin, p.300 tical purposes they are generally classified with the
The cephalosporins are bactericidal and, like the penicil- second-generation cephalosporins, but are more active
Bekanamycin, p.211 Neomycin, p.305
Dibekacin, p.265 Netilmicin, p.306 lins, they act by inhibiting synthesis of the bacterial cell against anaerobic bacteria, especially Bacteroides fragilis.
Dihydrostreptomycin, Sisomicin, p.332 wall. The most widely used system of classification of ce- Cefoxitin was one of the first cephamycins available; ce-
p.266 Streptomycin, p.333 phalosporins is by generations and is based on the general fmetazole and cefotetan have been introduced more re-
Etimicin, p.276 Tobramycin, p.354 features of their antibacterial activity, but may depend to cently. Another is cefminox. All these cephamycins must
Framycetin, p.279 some extent on when they were introduced. Succeeding be given parenterally.
generations generally have increasing activity against
Gram-negative bacteria. Cefalotin was one of the first ce- Imipenem was the first of the carbapenem group of anti-
Antimycobacterials phalosporins to become available and is representative of bacterials to become available; it is the N-formimidoyl de-
The antimycobacterials are a miscellaneous group of anti- the first-generation cephalosporins. It has good activity rivative of thienamycin which is produced by Streptomy-
bacterials whose spectrum of activity includes Mycobacte- against a wide spectrum of Gram-positive bacteria includ- ces cattleya. It is bactericidal, and, similarly to the
rium spp. and which are used in the treatment of tubercu- ing penicillinase-producing, but not meticillin-resistant, cephalosporins, acts by inhibiting synthesis of the bacterial
losis, leprosy, and other mycobacterial infections. They staphylococci; enterococci are, however, resistant. Its ac- cell wall. It has a very broad spectrum of antimicrobial ac-
include the rifamycins, also known as ansamycins or rifo- tivity against Gram-negative bacteria is modest. Cefalotin tivity including Gram-positive and Gram-negative aerobic
mycins, a group of antibacterials isolated from a strain of is not absorbed from the gastrointestinal tract and must be and anaerobic organisms; it has good activity against both
Amycolatopsis mediterranei (Nocardia mediterranei; given parenterally although intramuscular dosage is pain- Ps. aeruginosa and B. fragilis. Imipenem is given
Streptomyces mediterranei). The main antibacterial in this ful. Cefalotin has generally been replaced by cefazolin or parenterally with cilastatin, a dehydropeptidase I inhibitor
group, rifampicin, is a mainstay of regimens for the treat- cefradine. Cefaloridine is now rarely used because of its that inhibits the renal metabolism of imipenem. Similarly,
ment of tuberculosis and leprosy, and is increasingly being nephrotoxicity. Cefradine is absorbed from the gastroin- the carbapenem panipenem is given with the renal protect-
used for other infections. The related drug rifabutin is also testinal tract and can be given both orally and by injection. ant betamipron. Two other carbapenems, ertapenem and
used in mycobacterial disease, especially nontuberculous Cefadroxil, cefatrizine, and cefalexin are all given orally. meropenem, are relatively stable to renal dehydropepti-
mycobacterial infections due to Mycobacterium avium All of these drugs have a very similar spectrum of antimi- dase and can be used without such an inhibitor. Ertapenem
complex (MAC). Other rifamycins described in this chap- crobial activity to cefalotin. Cefaclor is also given orally. It has a narrower spectrum of activity than other carbapen-
ter include rifapentine, rifaximin which is poorly absorbed has similar activity to cefalotin against Gram-positive coc- ems, including no activity against Ps. aeruginosa. Dori-
and is mainly used for a local effect on the gastrointestinal ci, but because of its greater activity against Gram-nega- penem is a carbapenem claimed to have particular activity
tract, and rifamycin sodium, a rifamycin rarely used as it tive bacteria, particularly Haemophilus influenzae, it is of- against Ps. aeruginosa.
has been superseded by more effective drugs. ten classified as a second-generation drug. Cefprozil is an
oral cephalosporin with a longer half-life than cefaclor. The monobactams were first identified as monocyclic
Another antimycobacterial widely used for tuberculosis is beta lactams isolated from bacteria; they are now produced
isoniazid, a derivative of isonicotinic acid; it is invariably Cefamandole was the first available second-generation synthetically. Aztreonam was the first commercially avail-
used with other drugs to avoid or delay emergence of re- cephalosporin. It has similar or slightly less activity than able monobactam. It is bactericidal with a similar action on
sistance. Pyrazinamide, a nicotinamide derivative, is also cefalotin against Gram-positive bacteria, but greater stabil- bacterial cell-wall synthesis to the cephalosporins. Its anti-
an important component of regimens for tuberculosis, ity to hydrolysis by beta lactamases produced by Gram- microbial activity, however, differs from imipenem and
while ethambutol and the aminoglycoside streptomycin negative bacteria and enhanced activity against many of the newer cephalosporins in that it is restricted to Gram-
are added when resistance to first-line drugs is likely. The the Enterobacteriaceae and Haemophilus influenzae. It is negative aerobic organisms. It has good activity against
thiosemicarbazone derivative thioacetazone is now less given parenterally. Cefuroxime has a similar spectrum of Ps. aeruginosa. Aztreonam is given parenterally. Other
widely used in tuberculosis because of its toxicity and be- activity to cefamandole although it is even more resistant monobactams include carumonam.
cause more effective drugs are available, but is sometimes to hydrolysis by beta lactamases. It is given parenterally
used in developing countries. Other drugs that have been but, cefuroxime axetil, the acetoxyethyl ester of cefuroxi- Carbacephems are structurally related to the cepha-
used to treat tuberculosis including aminosalicylic acid me, is given orally. Other drugs classified as second-gen- losporins, but the sulfur atom of the 7-aminocephalospo-
and its salts, capreomycin, cycloserine, ethionamide, pro- eration cephalosporins and given parenterally include ce- ranic acid nucleus is replaced by a methylene group. Lora-
tionamide, and kanamycin are regarded as secondary fonicid, ceforanide, and cefotiam; these all have spectra of carbef is an oral carbacephem.
drugs and are reserved for patients in whom resistance or activity similar to cefamandole. Cephamycins (see below)
toxicity to first-line drugs is a problem. are also classified with second-generation cephalosporins. Described in this chapter are
Aztreonam, p.209 Cefotiam, p.230
The sulfones have been used since the 1940s in the treat- The third-generation cephalosporins, sometimes referred Betamipron, p.215 Cefovecin, p.230
ment of leprosy, but the only one widely used now is dap- Biapenem, p.215 Cefoxitin, p.230
to as extended-spectrum cephalosporins, are even more Carumonam, p.217 Cefozopran, p.231
sone, an important component of multidrug regimens. Its stable to hydrolysis by beta lactamases than cefamandole Cefaclor, p.217 Cefpiramide, p.231
action is thought to involve inhibition of folate metabo- and cefuroxime. Compared with the earlier generations of Cefadroxil, p.218 Cefpirome, p.231
lism, similarly to the sulfonamides, and dapsone is also cephalosporins they have a wider spectrum and greater po- Cefalexin, p.218 Cefpodoxime, p.232
used for the prophylaxis of malaria and for prophylaxis tency of activity against Gram-negative organisms, includ- Cefalonium, p.219 Cefprozil, p.232
and treatment of pneumocystis pneumonia. Also impor- ing most clinically important Enterobacteriaceae. Their Cefaloridine, p.219 Cefquinome, p.233
Cefalotin, p.219 Cefradine, p.233
tant in the treatment of leprosy is the phenazine dye clofaz- activity against Gram-positive organisms is said to be less Cefamandole, p.220 Cefsulodin, p.233
imine. Additionally, it has a role in the treatment of type 2 than that of the first-generation drugs, but they are very Cefapirin, p.221 Ceftazidime, p.234
lepra reactions and has been used in other mycobacterial active against streptococci. Cefotaxime was the first of this Cefatrizine, p.221 Cefteram, p.235
infections. The thioamides ethionamide and protionamide group to become available and it has relatively modest ac- Cefazolin, p.222 Ceftezole, p.235
have been used in the treatment of leprosy and tuberculo- tivity against Pseudomonas aeruginosa. Cefmenoxime, ce- Cefbuperazone, p.222 Ceftibuten, p.235
sis, but have generally been replaced by less toxic drugs, Cefcapene, p.223 Ceftiofur, p.236
fodizime, ceftizoxime, and ceftriaxone are all very similar Cefdinir, p.223 Ceftizoxime, p.236
for example clarithromycin, ofloxacin, minocycline, or pe- to cefotaxime in their antimicrobial activity. These drugs Cefditoren, p.223 Ceftobiprole, p.236
floxacin, in alternative antileprotic regimens. are all given parenterally and differ mainly in their phar- Cefepime, p.223 Ceftriaxone, p.237
macokinetic characteristics. Cefixime is a third-generation Cefetamet, p.224 Cefuroxime, p.238
Described in this chapter are cephalosporin given by mouth; others include cefdinir, Cefixime, p.224 Cilastatin, p.243
Aminosalicylic Acid, Methaniazide, p.298 cefetamet pivoxil, cefpodoxime proxetil, and ceftibuten. Cefmenoxime, p.225 Doripenem, p.266
p.201 Morinamide, p.302 Cefmetazole, p.225 Ertapenem, p.269
Capreomycin, p.215 Protionamide, p.320 Ceftazidime is typical of a group of parenteral third-gener- Cefminox, p.226 Faropenem, p.276
Clofazimine, p.254 Pyrazinamide, p.320 ation cephalosporins with enhanced activity against Ps. Cefodizime, p.226 Flomoxef, p.276
Cycloserine, p.260 Rifabutin, p.323 aeruginosa. Cefoperazone is similar in its activity to Cefonicid, p.226 Imipenem, p.286
Dapsone, p.261 Rifampicin, p.325 ceftazidime. Cefpiramide is structurally related to cefoper- Cefoperazone, p.227 Latamoxef, p.292
Ethambutol, p.274 Rifamycin, p.329 azone and has comparable activity. Although cefsulodin is Ceforanide, p.227 Loracarbef, p.295
Ethionamide, p.275 Rifapentine, p.329 Cefoselis, p.228 Meropenem, p.297
Ftivazide, p.279 Rifaximin, p.330 classified as a third-generation cephalosporin its activity Cefotaxime, p.228 Panipenem, p.313
Isoniazid, p.288 Thioacetazone, p.351 against Gram-negative bacteria is confined to Ps. aerugi- Cefotetan, p.229
nosa. Latamoxef is an oxacephalosporin which differs
from the true cephalosporins in that the sulfur atom of the
Cephalosporins and related beta lactams 7-aminocephalosporanic acid nucleus is replaced by an Chloramphenicols
The cephalosporins or cephem antibacterials are semisyn- oxygen atom. It differs from cefotaxime mainly in its en- Chloramphenicol is an antibacterial which was first isolat-
thetic antibacterials derived from cephalosporin C, a natu- hanced activity against Bacteroides fragilis. ed from cultures of Streptomyces venezuelae in 1947 but is
ral antibacterial produced by the mould Cephalosporium The newer cephalosporins cefepime and cefpirome are now produced synthetically. It has a relatively simple
acremonium. The active nucleus, 7-aminocephalosporanic generally considered to be fourth-generation because of structure and is a derivative of dichloroacetic acid with a
acid, is very closely related to the penicillin nucleus, 6- their broad spectrum of activity. Ceftobiprole is active nitrobenzene moiety. Chloramphenicol was the first
aminopenicillanic acid, and consists of a beta-lactam ring against meticillin-resistant staphylococci. broad-spectrum antibacterial to be discovered; it acts by
fused with a 6-membered dihydrothiazine ring and having interfering with bacterial protein synthesis and is mainly
an acetoxymethyl group at position 3. Cephalosporin C The semisynthetic cephamycins are chemical modifica- bacteriostatic. Its range of activity is similar to that of tet-
has a side-chain at position 7 derived from D-α-aminoadi- tions of cephamycin C, a beta-lactam antibacterial pro- racycline and includes Gram-positive and Gram-negative
pic acid. Chemical modification of positions 3 and 7 has duced naturally by Streptomyces spp. They differ from the bacteria, Rickettsia spp., and Chlamydiaceae. The sensi-
resulted in a series of drugs with different characteristics. cephalosporins by the addition of a 7-α-methoxy group to tivities of Salmonella typhi, Haemophilus influenzae, and
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
160 Antibacterials
Bacteroides fragilis to chloramphenicol have dictated the Although not related structurally to erythromycin and the Other macrolides include spiramycin, which has been
principal indications for its use. other macrolide antibacterials, the lincosamides have sim- used extensively in Europe and has also been used in the
Shortly after its introduction chloramphenicol was found ilar antimicrobial activity and act at the same site on the treatment and prophylaxis of toxoplasmosis. It may be
to have a serious and sometimes fatal depressant effect on bacterial ribosome to suppress protein synthesis. useful in the treatment of cryptosporidiosis.
the bone marrow. The ‘grey syndrome’, another potential- The lincosamides are bacteriostatic or bactericidal, de- Oleandomycin has been used orally and parenterally as the
ly fatal adverse effect, was reported later in neonates. As a pending on the concentration, and are active mainly phosphate. Its ester, troleandomycin, is better absorbed
result of this toxicity the systemic use of chloramphenicol against Gram-positive bacteria, and against Bacteroides from the gastrointestinal tract but, like erythromycin es-
has been restricted in many countries; it should only be spp. They also appear to have some antiprotozoal activity. tolate, has proved hepatotoxic and more effective antibac-
given when there is no suitable alternative and never for Clindamycin and lincomycin have qualitatively similar ac- terials are generally preferred. Josamycin, kitasamycin,
minor infections. tivity but clindamycin is more active than lincomycin in midecamycin, and rokitamycin have been used in Europe
Chloramphenicol is active when given orally and, unlike vitro. Cross-resistance occurs between the lincosamides, and/or Japan. Meleumycin has been used in China.
most other antibacterials, it diffuses into the CSF even macrolides, and streptogramins. Tilmicosin, tulathromycin, and tylosin are used in veteri-
when the meninges are not inflamed. The majority of a The lincosamides have been used, like erythromycin, as an nary practice.
dose is inactivated in the liver, only a small proportion ap- alternative to penicillin, but reports of severe and some- The streptogramin group of antibacterials are also de-
pearing unchanged in the urine. times fatal pseudomembranous colitis in association with rived from Streptomyces spp. and include pristinamycin
Chloramphenicol is widely used for typhoid fever, al- lincomycin and clindamycin have led to the recommenda- and virginiamycin. They consist of two components that
though resistance is a problem in some countries. For Haem- tion that they should only be used when there is no suitable act synergistically and are therefore also known as syner-
ophilus influenzae infections, especially meningitis, the alternative. gistins. One of the components is structurally related to the
emergence of ampicillin-resistant strains led to a reap- Both lincomycin and clindamycin can be given orally and macrolides, and they have a similar spectrum of antimicro-
praisal of the use of chloramphenicol, and suggestions that parenterally, but clindamycin is much better absorbed bial activity to erythromycin. Semisynthetic derivatives
ampicillin and chloramphenicol should both be given em- from the gastrointestinal tract and less affected by the pres- such as quinupristin/dalfopristin may be useful in the
pirically to patients with meningitis until the sensitivity of ence of food in the stomach. They both penetrate well into treatment of infections with multidrug-resistant organisms
the infecting organisms was known, but the newer third- bone and have been used successfully in osteomyelitis. including meticillin-resistant Staphylococcus aureus and
generation cephalosporins are increasingly preferred be- They have also been used topically in the treatment of acne vancomycin-resistant enterococci.
cause of resistance. For proven H. influenzae meningitis, vulgaris. Cross-resistance is often observed between the mac-
chloramphenicol is used as an alternative to the third-gen- rolides, lincosamides, and streptogramins. The ketolide
eration cephalosporins, which are now regarded as treat- The main indication for the use of lincosamides is now in
the treatment of severe anaerobic infections, although met- antibacterials telithromycin and cethromycin are semisyn-
ment of choice. Chloramphenicol is also effective against thetic derivatives of erythromycin A that have been devel-
many anaerobic bacteria and may be valuable in such con- ronidazole (p.839) or some beta lactams may be a more
suitable choice in such infections. Clindamycin also has a oped to overcome macrolide resistance in respiratory-tract
ditions as cerebral abscess where anaerobes such as pathogens.
Bacteroides fragilis are often involved, although metroni- role in the prophylaxis of endocarditis in penicillin-allergic
dazole may be preferred. patients and has been used, usually with other antiprotozo- Described in this chapter are
als, in babesiosis, chloroquine-resistant malaria, toxoplas- Azithromycin, p.207 Quinupristin/Dalfopristin,-
Chloramphenicol sodium succinate is used parenterally mosis, and pneumocystis pneumonia. Cethromycin, p.239 p.322
and the palmitate is given orally. Ophthalmic and other Clarithromycin, p.248 Rokitamycin, p.330
topical preparations of chloramphenicol are used widely in Described in this chapter are Dirithromycin, p.266 Roxithromycin, p.331
some countries. Clindamycin, p.251 Pirlimycin, p.316 Erythromycin, p.269 Spiramycin, p.333
Lincomycin, p.293 Flurithromycin, p.278 Telithromycin, p.345
Thiamphenicol is a semisynthetic derivative of chloram- Josamycin, p.291 Tilmicosin, p.354
phenicol in which the nitro group on the benzene ring has Kitasamycin, p.292 Troleandomycin, p.357
been replaced by a methylsulfonyl group, resulting, in gen- Macrolides Meleumycin, p.297 Tulathromycin, p.357
eral, in a loss of activity in vitro. It has been claimed that The macrolides are a large group of antibacterials mainly Midecamycin, p.300 Tylosin, p.357
thiamphenicol is less toxic than chloramphenicol and there derived from Streptomyces spp. and having a common Oleandomycin, p.311 Virginiamycin, p.361
have been fewer reports of aplastic anaemia but reversible Pristinamycin, p.319
macrocyclic lactone ring to which one or more sugars are
bone-marrow depression may occur more frequently. It is attached. They are all weak bases and only slightly soluble
also less likely to cause the ‘grey syndrome’. Unlike chlo- in water. Their properties are very similar and in general Penicillins
ramphenicol, thiamphenicol is not metabolised in the liver they have low toxicity and a similar spectrum of antimi- Penicillin was the first antibacterial to be used therapeuti-
to any extent and is excreted largely unchanged in the crobial activity with cross-resistance between individual cally and was originally obtained, as a mixture of penicil-
urine. It has been used similarly to chloramphenicol in members of the group. The macrolides are bacteriostatic or lins known as F, G, X, and K, from the mould Penicillium
some countries. bactericidal, depending on the concentration and the type notatum. Better yields were achieved using P. chrysoge-
Azidamfenicol is another analogue of chloramphenicol of micro-organism, and are thought to interfere with bac- num and benzylpenicillin (penicillin G) was selectively
that has been used topically in the treatment of eye infec- terial protein synthesis. Their antimicrobial spectrum is produced by adding the precursor phenylacetic acid to the
tions. similar to that of benzylpenicillin but they are also active fermentation medium. The term ‘penicillin’ is now used
against such organisms as Legionella pneumophila, Myco- generically for the entire group of natural and semisynthet-
Described in this chapter are
Azidamfenicol, p.206 Florfenicol, p.277 plasma pneumoniae, and some rickettsias, chlamydias, ic penicillins. Penicillins are still widely used; they are
Chloramphenicol, p.239 Thiamphenicol, p.351 and chlamydophilas. Macrolides and related drugs have a generally well tolerated, apart from hypersensitivity reac-
postantibiotic effect: that is, antibacterial activity persists tions, and are usually bactericidal by virtue of their inhibi-
after concentrations have dropped below the minimum in- tory action on the synthesis of the bacterial cell wall.
Glycopeptides hibitory concentration.
Vancomycin has a glycopeptide structure; it acts by inter- Penicillins all have the same ring structure and are mono-
fering with bacterial cell wall synthesis and is very active Erythromycin was discovered in 1952 and is the macrolide basic acids that readily form salts and esters; 6-aminopen-
against Gram-positive cocci. Intravenous vancomycin is used most widely. It is destroyed by gastric acid and must icillanic acid, the penicillin nucleus, consists of a fused thi-
reserved for the treatment of severe staphylococcal infec- therefore be given as enteric-coated formulations or as one azolidine ring and a beta-lactam ring with an amino group
tions and for the treatment and prophylaxis of endocarditis of its more stable salts or esters such as the stearate or ethyl at the 6-position.
when other antibacterials cannot be used, either because of succinate. Hepatotoxicity has been reported after the use The earlier or so-called ‘natural’ penicillins were produced
patient sensitivity or bacterial resistance. It is the treatment of erythromycin, most commonly as the estolate. Erythro- by adding different side-chain precursors to fermentations
of choice for infections caused by meticillin-resistant sta- mycin lactobionate or gluceptate may be given intrave- of the Penicillium mould; benzylpenicillin, with a phenyl-
phylococci. Vancomycin hydrochloride is poorly absorbed nously. Cardiac arrhythmias have been reported occasion- acetamido side-chain at the 6-position, and phenoxymeth-
when taken orally; it is used in the treatment of pseu- ally after intravenous use. Erythromycin is used as an ylpenicillin (penicillin V), with a phenoxyacetamido side-
domembranous colitis. Teicoplanin is a glycopeptide with alternative to penicillin in many infections, especially in chain, were 2 of the first and are still widely used. Ben-
similar properties to vancomycin, but a longer duration of patients who are allergic to penicillin. It has similar uses to zylpenicillin can be considered the parent compound of
action. It can be given intramuscularly as well as intrave- tetracycline in the treatment of infections due to Mycoplas- the penicillins and is active mainly against Gram-positive
nously. Ramoplanin is under investigation, especially for ma pneumoniae and Chlamydia trachomatis, and in acne bacteria and Neisseria spp. It is inactivated by penicilli-
the treatment of Clostridium difficile-associated diarrhoea. vulgaris. It is also used in the treatment of infections nase-producing bacteria and because of its instability in
It has also been investigated for the prevention of infection caused by Legionella pneumophila. gastric acid it is usually injected. Long-acting preparations
due to vancomycin-resistant enterococci. Also under in- More recently developed macrolides include azithromy- include procaine benzylpenicillin and benzathine ben-
vestigation are dalbavancin and oritavancin. cin, clarithromycin, dirithromycin, and roxithromycin. zylpenicillin, which slowly release benzylpenicillin after
Described in this chapter are
These drugs all appear to have similar properties to eryth- injection. Phenoxymethylpenicillin is acid-stable and is
Avoparcin, p.206 Ramoplanin, p.323 romycin although they may differ in their pharmacokinet- therefore given orally but it is also inactivated by penicilli-
Dalbavancin, p.261 Teicoplanin, p.344 ics. Clarithromycin and, to a lesser extent, azithromycin nase. It is generally used for relatively mild infections.
Norvancomycin, p.310 Vancomycin, p.358 are more active than erythromycin against opportunistic When no side-chain precursor is added to the fermentation
Oritavancin, p.311 mycobacteria such as Mycobacterium avium complex. medium, 6-aminopenicillanic acid itself is obtained. A
Clarithromycin is also used in the treatment of leprosy and range of penicillins has been synthesised from 6-ami-
Lincosamides in regimens for the eradication of Helicobacter pylori in nopenicillanic acid by substitution at the 6-amino position
Lincomycin is an antibacterial produced by a strain of peptic ulcer disease. Both azithromycin and clarithromy- in an effort to improve on the instability of benzylpenicil-
Streptomyces lincolnensis and was first described in 1962; cin have activity against protozoa including Toxoplasma lin to gastric acid and penicillinases, to widen its antimi-
clindamycin is the 7-chloro-7-deoxy derivative of linco- gondii. crobial spectrum, and to reduce its rapid rate of renal ex-
mycin. Flurithromycin is another newer macrolide in use. cretion. Phenoxypenicillins with an α -phenoxy-
 Antibacterials 161
propionamido (pheneticillin) or α-phenoxybutyramido cinoxacin, a cinnoline derivative, is a 2-aza-4-quinolone, medium- or intermediate-, long-, and ultra-long-acting.
(propicillin) side-chain are more stable to acid than ben- and pipemidic and piromidic acids, pyrido-pyrimidine de- The short-acting sulfonamides are excreted in the urine in
zylpenicillin but offer no advantage over phenoxymethyl- rivatives, are 6,8-diaza-4-quinolones. high concentrations and have therefore been of particular
penicillin. Nalidixic acid is active against Gram-negative bacteria but use in the treatment of urinary-tract infections. The solu-
Meticillin has a 2,6-dimethoxybenzamido group at the 6- has little activity against Pseudomonas and Gram-positive bility in urine of earlier short-acting sulfonamides, such as
position and was the first penicillin found to be resistant to organisms. Because bactericidal concentrations can only sulfapyridine, and their acetyl metabolites is low and
destruction by staphylococcal penicillinase. However, it is be achieved in urine its use has generally been limited to hence crystalluria has been reported frequently. Of the
not acid-resistant and has to be injected. The isoxazolyl the treatment of urinary-tract infections. short-acting sulfonamides most commonly used, sulfadi-
penicillins, cloxacillin, dicloxacillin, flucloxacillin, and Modification of the structure of nalidixic acid has pro- azine also has low solubility in urine whereas sulfadimi-
oxacillin, are resistant to penicillinase and gastric acid. duced related antibacterials such as oxolinic acid, dine and sulfafurazole and their acetyl conjugates are very
They have very similar chemical structures and differ cinoxacin, and rosoxacin. Although some of these have a soluble. Three short-acting sulfonamides (triple sulfona-
mainly in their absorption characteristics. Nafcillin is a greater activity in vitro against Gram-negative organisms mides) have been given together to reduce the risk of crys-
similar penicillinase-resistant antibacterial but is irregular- and activity against some Gram-positive organisms, none talluria, as the constituent sulfonamides can co-exist in so-
ly absorbed when taken orally. has been considered to represent a significant clinical ad- lution in urine without affecting each other’s solubility.
Ampicillin has a D(−)-α-aminophenylacetamido side- vance over nalidixic acid; rosoxacin is only used in the Preparations of mixed sulfonamides have, however, gen-
chain and a broader spectrum of activity than benzylpeni- treatment of gonorrhoea. Addition of a piperazinyl radical erally been replaced by the more soluble sulfonamides.
cillin; although generally less active against Gram-positive at position 7, as in pipemidic acid, appears to confer some The medium-acting sulfonamides such as sulfamethoxa-
bacteria, some Gram-negative organisms including Es- activity against Pseudomonas. Flumequine was the first zole, the long-acting sulfonamides such as sulfadimethox-
cherichia coli, Haemophilus influenzae, and Salmonella fluorinated 4-quinolone to be synthesised, but has no pip- ine, sulfamethoxypyridazine, and sulfametoxydiazine, and
spp. are sensitive although resistance is being reported in- erazinyl group. Addition of the 7-piperazinyl group and a the ultra-long-acting sulfonamides such as sulfadoxine
creasingly. Pseudomonas spp. are not sensitive. Ampicil- fluorine atom at position 6 has produced a group of fluori- and sulfametopyrazine do not attain such high concentra-
lin is acid-stable and can be given orally but is destroyed nated piperazinyl quinolones or fluoroquinolones with a tions in the urine and rarely cause crystalluria. Sulfona-
by penicillinase. A number of prodrugs including bacamp- broader spectrum of activity than nalidixic acid and phar- mides that are slowly excreted from the body do appear,
icillin, metampicillin, and pivampicillin are also said to be macokinetic properties more suitable for the treatment of however, to have been more commonly implicated in the
better absorbed and are hydrolysed to ampicillin in vivo. systemic infections. They include ciprofloxacin, enoxacin, development of reactions such as the Stevens-Johnson
Amoxicillin, with a D(−)-α-aminohydroxyphenylacetami- fleroxacin, gatifloxacin, gemifloxacin, levofloxacin, lome- syndrome.
do side-chain, only differs from ampicillin by the addition floxacin, moxifloxacin, nadifloxacin, norfloxacin, The sulfonamides are usually bacteriostatic, and interfere
of a hydroxyl group, but is better absorbed from the gas- ofloxacin, pazufloxacin, pefloxacin, rufloxacin, spar- with folic acid synthesis of susceptible organisms; their
trointestinal tract. floxacin, and trovafloxacin. Trovafloxacin and its prodrug, broad spectrum of antimicrobial activity has, however,
Carbenicillin, with an α-carboxyphenylacetamido side- alatrofloxacin, have been withdrawn worldwide after re- been limited by the development of resistance. The clinical
chain, has marked activity against Pseudomonas aerugi- ports of unpredictable hepatotoxicity, including some fa- use of sulfonamides has therefore been greatly reduced; in
nosa and some Proteus spp. but otherwise is generally less talities. Other fluoroquinolones withdrawn because of tox- general they are indicated only in the treatment of urinary-
active than ampicillin. It has to be given by injection and icity include: clinafloxacin, grepafloxacin, and tract infections and a few other disorders such as nocardi-
large doses are required. Carfecillin and carindacillin are temafloxacin. Danofloxacin, enrofloxacin, ibafloxacin, osis. Sulfonamides such as sulfaguanidine, succinylsul-
the phenyl and indanyl esters of carbenicillin respectively marbofloxacin, orbifloxacin, and sarafloxacin are used in fathiazole, phthalysulfacetamide, and phthalylsulfathia-
and are hydrolysed to carbenicillin in vivo when taken veterinary practice. Development of difloxacin for human zole are poorly absorbed from the gastrointestinal tract and
orally. Sulbenicillin has an α-phenylsulfoacetamido side- use was suspended because of the high incidence of ad- have been used for the treatment of gastrointestinal infec-
chain and ticarcillin an α-carboxythienylacetamido side- verse effects, but it is used in veterinary practice. tions although they are now rarely indicated. Sulfadiazine
chain and both have similar activity to carbenicillin; ticar- silver, sulfathiazole silver, and mafenide are applied topi-
The fluoroquinolones are very active against aerobic cally for their antibacterial action in patients with burns.
cillin is more active against Ps. aeruginosa. The ureido- Gram-negative bacilli and cocci including the Enterobac-
penicillins azlocillin and mezlocillin, and the closely relat- Sulfasalazine (p.1773), a conjugate of 5-aminosalicylic
teriaceae, Haemophilus influenzae, Moraxella catarrhalis acid (mesalazine) and sulfapyridine, is used in the treat-
ed drug piperacillin are more active than carbenicillin (Branhamella catarrhalis), and Neisseria gonorrhoeae
against Ps. aeruginosa and have a wider range of activity ment of inflammatory bowel diseases and in rheumatoid
and are also active against Pseudomonas aeruginosa. arthritis.
against Gram-negative bacteria. They are generally less active against Gram-positive or-
Temocillin, a 6-α-methoxy derivative of ticarcillin, is re- ganisms such as staphylococci and much less active Trimethoprim is a diaminopyrimidine that also inhibits fol-
sistant to many beta lactamases and is active against most against streptococci such as Streptococcus pneumoniae, ic acid synthesis but at a different stage in the metabolic
Gram-negative aerobic bacteria, but not Ps. aeruginosa. although some fluoroquinolones now developed have in- pathway to that inhibited by the sulfonamides. It has a sim-
creased activity against these organisms. They also have ilar spectrum of antimicrobial activity to sulfonamides and
Mecillinam is a penicillanic acid derivative with a substi-
activity against mycobacteria, mycoplasmas, and rickett- often shows synergy in vitro with these drugs. Trimetho-
tuted amidino group in the 6-position. Unlike the 6-ami-
sias. Some, for example ofloxacin, have useful activity prim was initially available only in combination with sul-
nopenicillanic acid derivatives it is active mainly against
against Chlamydia trachomatis. Activity against anaero- fonamides, most commonly with sulfamethoxazole as co-
Gram-negative bacteria, although Ps. aeruginosa, and
bic bacteria is generally poor. There is concern that the trimoxazole. It is now used alone particularly in the treat-
Bacteroides spp. are considered resistant. Mecillinam it-
emergence of resistant strains of organisms may limit the ment of infections of the urinary and respiratory tracts. An-
self is not active orally; it is given as pivmecillinam, which
usefulness of fluoroquinolones. alogues of trimethoprim include baquiloprim, brodimo-
is hydrolysed to mecillinam on absorption.
prim, ormetoprim, and tetroxoprim.
The beta-lactamase inhibitors clavulanic acid, sulbactam, One disadvantage of the quinolone antibacterials is that Co-trimoxazole generally replaced use of sulfonamides
and tazobactam are used to extend the antimicrobial range they are generally not recommended for use in children, alone in the treatment of systemic infections, although its
of certain beta-lactam antibacterials. adolescents, and pregnant or breast-feeding women be- use has also been restricted in some countries and trimeth-
Described in this chapter are cause of their propensity to cause joint erosions in imma- oprim may be preferred. Co-trimoxazole is however indi-
Amoxicillin, p.202 Flucloxacillin, p.277 ture animals. cated for pneumocystis pneumonia and nocardiosis and
Ampicillin, p.204 Mecillinam, p.297
Aspoxicillin, p.206 Metampicillin, p.298 Described in this chapter are may be useful in protozoal infections such as toxoplasmo-
Azidocillin, p.206 Meticillin, p.299 Alatrofloxacin, p.200 Nadifloxacin, p.303 sis. Other sulfonamides which have been combined with
Azlocillin, p.208 Mezlocillin, p.299 Balofloxacin, p.211 Nalidixic Acid, p.303 trimethoprim include sulfadiazine (see co-trimazine), sul-
Bacampicillin, p.210 Nafcillin, p.303 Cinoxacin, p.243 Norfloxacin, p.309
Ciprofloxacin, p.243 Ofloxacin, p.310 famethoxypyridazine, sulfametopyrazine, sulfametrole,
Benethamine Penicillin, Oxacillin, p.311 and sulfamoxole (see co-trifamole). Sulfadiazine has been
p.212 Penethamate, p.314 Danofloxacin, p.261 Orbifloxacin, p.311
Benzathine Benzylpenicillin, Pheneticillin, p.314 Difloxacin, p.265 Oxolinic Acid, p.312 used with tetroxoprim (see co-tetroxazine).
p.212 Phenoxymethylpenicillin, Enoxacin, p.268 Pazufloxacin, p.313 Sulfonamides have also been used with pyrimethamine
Benzathine Phenoxymethyl- p.314 Enrofloxacin, p.269 Pefloxacin, p.313 (p.610) in the treatment or prophylaxis of some protozoal
penicillin, p.212 Piperacillin, p.315 Fleroxacin, p.276 Pipemidic Acid, p.315
Flumequine, p.278 Piromidic Acid, p.316 infections. Common combinations are sulfadoxine and py-
Benzylpenicillin, p.213 Pivampicillin, p.316 rimethamine for malaria, and sulfadiazine and pyrimeth-
Carbenicillin, p.216 Pivmecillinam, p.317 Garenoxacin, p.281 Prulifloxacin, p.320
Carfecillin, p.217 Procaine Benzylpenicillin, Gatifloxacin, p.281 Rosoxacin, p.330 amine for the treatment of toxoplasmosis.
Carindacillin, p.217 p.319 Gemifloxacin, p.281 Rufloxacin, p.331
Described in this chapter are
Ciclacillin, p.243 Propicillin, p.319 Ibafloxacin, p.286 Sarafloxacin, p.331
Baquiloprim, p.211 Sulfadimidine, p.338
Clavulanic Acid, p.250 Sulbactam, p.335 Levofloxacin, p.292 Sparfloxacin, p.332
Brodimoprim, p.215 Sulfadoxine, p.338
Clemizole Penicillin, Sulbenicillin, p.335 Lomefloxacin, p.295 Tosufloxacin, p.355
Co-tetroxazine, p.257 Sulfafurazole, p.338
p.251 Sultamicillin, p.344 Marbofloxacin, p.296 Trovafloxacin, p.357
Co-trifamole p.257 Sulfaguanidine, p.339
Clometocillin, p.255 Tazobactam, p.344 Moxifloxacin, p.302
Co-trimazine, p.258 Sulfamerazine, p.339
Cloxacillin, p.256 Temocillin, p.346 Co-trimoxazole, p.258 Sulfamethizole, p.339
Dicloxacillin, p.265 Ticarcillin, p.352 Formosulfathiazole, p.278 Sulfamethoxazole, p.340
Sulfonamides and diaminopyrimidines Mafenide, p.296 Sulfamethoxypyridazine,
The sulfonamides are analogues of p-aminobenzoic acid. Ormetoprim, p.311 p.342
Quinolones The first sulfonamide of clinical importance was Pron- Phthalylsulfacetamide, Sulfamethylthiazole,
The quinolonecarboxylic acids, carboxyquinolones, or 4- tosil, an azo dye that is metabolised in vivo to sulfanila- p.315 p.342
quinolones are a group of synthetic antibacterials structur- mide. It was synthesised in Germany in 1932. Many sul- Phthalylsulfathiazole, Sulfametopyrazine, p.342
ally related to nalidixic acid. The term 4-quinolone has fonamides have since been synthesised; they differ only p.315 Sulfametrole, p.342
Succinylsulfathiazole, Sulfamonomethoxine, p.342
been used as a generic name for the common 4-oxo-1,4- slightly in their antimicrobial activity, but vary in their p.334 Sulfamoxole, p.342
dihydroquinoline skeleton. Under this system nalidixic ac- pharmacokinetic properties. The sulfonamides have been Sulfabenzamide, p.335 Sulfanilamide, p.343
id, a naphthyridene derivative, is an 8-aza-4-quinolone, classified according to their rate of excretion as short-, Sulfacarbamide, p.335 Sulfapyridine, p.343
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
162 Antibacterials
Sulfacetamide, p.335 Sulfaquinoxaline, p.343 cline may sometimes be used in multidrug regimens for Fosfomycin, p.278 Spectinomycin, p.332
Sulfachlorpyridazine, Sulfasuccinamide, p.343 leprosy. Doxycycline may be used for the treatment and Furaltadone, p.279 Sulfamazone, p.339
p.336 Sulfathiazole, p.343 prophylaxis of malaria; it is also used in the management Furazidin, p.279 Taurolidine, p.344
Sulfachrysoidine, p.336 Sulfathiazole Silver, Fusafungine, p.279 Terizidone, p.347
Sulfaclozine, p.336 p.343 of anthrax. Fusidic Acid, p.279 Thenoic Acid, p.351
Sulfadiazine, p.336 Sulfatroxazole, p.343 Described in this chapter are Gramicidin S, p.286 Thiostrepton, p.352
Sulfadiazine Silver, Sulfisomidine, p.344 Chlortetracycline, p.242 Methacycline, p.298 Gramicidin, p.286 Tiamulin, p.352
p.337 Tetroxoprim, p.350 Demeclocycline, p.264 Minocycline, p.300 Halquinol, p.286 Tigecycline, p.353
Sulfadicramide, p.337 Trimethoprim, p.355 Doxycycline, p.267 Oxytetracycline, p.312 Linezolid, p.293 Trospectomycin, p.357
Sulfadimethoxine, p.337 Lymecycline, p.296 Rolitetracycline, p.330 Magainins, p.296 Tyrothricin, p.358
Meclocycline, p.297 Tetracycline, p.347 Mandelic Acid, p.296 Valnemulin, p.358
Methenamine, p.298 Xibornol, p.361
Tetracyclines
The tetracyclines are a group of antibacterials, originally Miscellaneous Antibacterials Choice of Antibacterial
derived from certain Streptomyces spp., having the same Spectinomycin is an aminocyclitol antibacterial with some Ideally, antibacterial treatment of infections should be
tetracyclic nucleus, naphthacene, and similar properties. similarities to streptomycin although it is not an aminogly- chosen after the infecting organisms have been identi-
Unlike the penicillins and aminoglycosides they are usual- coside. Spectinomycin is active against a wide range of
fied and the results of sensitivity tests are known. In
ly bacteriostatic at the concentrations achieved in the body bacteria but its clinical use is restricted to the treatment of
but act similarly to the aminoglycosides by interfering chancroid and gonorrhoea. Trospectomycin, a water-solu- practice, empirical treatment is often necessary initial-
with protein synthesis in susceptible organisms. ble derivative, has been investigated. ly, bearing in mind local patterns of infection and re-
Tetracyclines all have a broad spectrum of activity which Mupirocin is an antibacterial produced by Pseudomonas sistance. Other factors such as site of infection and tis-
includes Gram-positive and Gram-negative bacteria, fluorescens with activity against most strains of staphylo- sue penetration are also important in deciding which
chlamydias and chlamydophilas, rickettsias, mycoplas- cocci and streptococci and also some Gram-negative bac- antibacterial to give.
mas, spirochaetes, some mycobacteria, and some proto- teria. It is applied topically. The prophylactic use of antibacterials is restricted
zoa, but the emergence of resistant strains and the develop- Fosfomycin is a derivative of phosphonic acid; it is active mainly to patients undergoing some types of surgery.
ment of other antimicrobials has often reduced their value. against a range of Gram-positive and Gram-negative bac- Other groups requiring infection prophylaxis include
Adverse effects have also restricted their usefulness. Gas- teria and is given by mouth or parenterally. patients at special risk of developing endocarditis and
trointestinal disturbances are common and other important The fusidane antibacterial fusidic acid is derived from Fu- those who have had rheumatic fever, who are splenec-
toxic effects include deposition in bones and teeth, pre- sidium coccineum and has a narrow spectrum of antibacte-
cluding their use in pregnancy and young children; anti-
tomised, or who are immunocompromised.
rial activity, but it is very active against Staphylococcus au-
anabolic effects, especially in patients with renal impair- reus and has been used both topically and systemically in
ment; fatty changes in the liver; and photosensitivity, espe- the treatment of staphylococcal infections. Resistance de- Abscess, abdominal
cially with demeclocycline. Allergic reactions are relative- velops readily and it is often used with other antibacterials. See under Abscess, Liver, below, and under Peritonitis,
ly uncommon. Because of these adverse effects The polymyxins are basic antibacterials produced by the p.184.
tetracyclines should be avoided in pregnant women, chil- growth of different strains of Bacillus polymyxa (B. aero-
dren, and, apart from doxycycline and minocycline, pa- sporus). Polymyxin B and colistin have been used clinical-
tients with renal impairment. Abscess, brain
ly, but their systemic use has been more or less abandoned Brain abscesses can result from otitis media, sinusitis, trau-
The first tetracycline to be introduced was chlortetracy- because of their toxicity, notably to the kidneys and nerv- ma, or dental sepsis, or they may be metastatic secondary
cline in 1948 and, like chloramphenicol which was discov- ous system. They are not absorbed when taken orally and to, for example, lung abscesses. Opportunistic infections
ered at about the same time, it was found to have a broad have therefore been given in gastrointestinal infections for in immunocompromised patients may present as brain ab-
spectrum of activity and to be active orally unlike ben- their bactericidal activity against Gram-negative bacteria. scesses.
zylpenicillin or streptomycin, the only other antibacterials They continue to be widely used as components of topical Treatment of brain abscesses entails removal of pus or ex-
then in use. The discovery of chlortetracycline was fol- preparations. cision and use of high doses of antibacterials. Ideally the
lowed closely by that of oxytetracycline and then tetracy- Bacitracin, gramicidin, gramicidin S, and tyrothricin are choice of antibacterial depends on the infecting organisms
cline, a reduction product of chlortetracycline which may polypeptide antibacterials also produced by certain strains and penetration by the antibacterial into brain tissue and
be produced semisynthetically. All three have very similar of Bacillus spp. but they are active against Gram-positive abscess pus. Until organisms can be cultured empirical
properties, although chlortetracycline is less well absorbed bacteria. Like the polymyxins, they are toxic when used treatment should be given.
and oxytetracycline may cause less staining of teeth. De- systemically and are therefore mainly used topically.
meclocycline, demethylated chlortetracycline, has a longer There is very little good quality published information on
The halogenated hydroxyquinoline clioquinol has antibac- the treatment of brain abscess. For many years, combined
half-life than tetracycline but is more often associated with terial, antifungal, and antiprotozoal activity. It was former-
phototoxic reactions. It has been used with some success treatment with benzylpenicillin and chloramphenicol was
ly used in gastrointestinal infections including amoebiasis the mainstay of empirical therapy, but a report by the Brit-
in patients with the syndrome of inappropriate secretion of but is of little value and can produce severe neurotoxicity.
antidiuretic hormone. ish Society for Antimicrobial Chemotherapy,1 based on
It is now mainly used locally for superficial infections of published information and the authors’ expertise, recom-
These four tetracyclines are all natural products that have the skin and external ear. Chlorquinaldol and halquinol are mended the following regimens for first-line empirical
been isolated from Streptomyces spp. The more recent tet- used similarly. treatment, according to the site of the abscess and origin of
racyclines, namely methacycline, doxycycline, and mino- Urinary antimicrobials such as nitrofurantoin, and also the infection:
cycline, are semisynthetic derivatives. Methacycline, like methenamine which has generally been given as the hippu- • for frontal lobe abscesses originating from infection of
demeclocycline, has a longer half-life than tetracycline rate or mandelate, may be used in the treatment and proph- the paranasal sinuses or teeth, a combination of metron-
and has been given twice daily. Doxycycline and minocy- ylaxis of infections of the lower urinary tract. They are idazole with one of cefuroxime, cefotaxime, or ceftriax-
cline are both more active in vitro than tetracycline against concentrated in the urine, but do not usually achieve anti- one
many species. More importantly, minocycline is active microbial concentrations in the blood.
against some tetracycline-resistant bacteria, including • for temporal lobe or cerebellar abscesses originating
The oxazolidinone linezolid has activity against Gram- from infection of the middle ear or sphenoidal sinuses,
strains of staphylococci. Both are well absorbed and, un-
positive organisms including vancomycin-resistant ente- ampicillin and metronidazole with either ceftazidime or
like the other tetracyclines, absorption is not significantly
rococci and meticillin-resistant Staphylococcus aureus. It gentamicin
affected by the presence of food. They can be given in low-
is used in infections of the skin and respiratory tract due to • for abscesses associated with penetrating trauma, flu-
er doses than the older members of the group and, having
these organisms. cloxacillin, cefuroxime, cefotaxime, or ceftriaxone
long half-lives, doxycycline is usually given once daily
and minocycline twice daily. Also, they do not accumulate The glycylcycline tigecycline has activity against Gram- • for metastatic abscesses, usually in the area supplied by
significantly in patients with renal impairment and can, positive bacteria, including meticillin-resistant Staph. au- the middle cerebral artery, one of cefuroxime, cefotaxi-
with care, be given to such patients; however, usual doses reus, and also against some Gram-negative and some me, or ceftriaxone, with or without metronidazole, or, if
of minocycline can lead to higher serum concentrations re- anaerobic bacteria. It is used in the treatment of complicat- associated with endocarditis or cyanotic congenital
sulting in possible liver toxicity. Both doxycycline and mi- ed skin and skin structure infections and complicated intra- heart disease, benzylpenicillin
nocycline are more lipid-soluble than the other tetracy- abdominal infections. Similar suggestions have been made by a more recent re-
clines and they penetrate well into tissues. The use of The pleuromutilin antibacterial retapamulin is derived view,2 which also suggested the use of oxacillin with met-
minocycline may, however, be limited by its vestibular ad- from the fungus Clitopilus passeckerianus; it has activity ronidazole and a third-generation cephalosporin for empir-
verse effects. against Staphylococcus aureus and Streptococcus pyo- ical management of abscesses associated with penetrating
Tetracyclines are not generally the antibacterials of choice genes. It is applied topically. trauma, and vancomycin plus a third-generation cepha-
in Gram-positive or Gram-negative infections because of Described in this chapter are losporin for abscess occurring postoperatively.
the emergence of resistant organisms and the discovery of Acediasulfone, p.200 Mupirocin, p.302 1. Infection in Neurosurgery Working Party of the British Society
Arsanilic Acid, p.206 Nifuroxazide, p.307 for Antimicrobial Chemotherapy. The rational use of antibiotics
drugs with narrower antimicrobial spectra. However, they Avilamycin, p.206 Nifurpirinol, p.307 in the treatment of brain abscess. Br J Neurosurg 2000; 14:
have a place in the treatment of chlamydial infections, Bacitracin, p.210 Nifurtoinol, p.307 525–30.
rickettsial infections such as typhus and the spotted fevers, Bambermycin, p.211 Nifurzide, p.307 2. Lu C-H, et al. Strategies for the management of bacterial brain
abscess. J Clin Neurosci 2006; 13: 979–85.
mycoplasmal infections such as atypical pneumonia, pel- Broxyquinoline, p.215 Nisin, p.307
vic inflammatory disease, Lyme disease, brucellosis, tu- Carbadox, p.216 Nitrofurantoin, p.308
laraemia, plague, cholera, periodontal disease, and acne. Chlorquinaldol, p.242 Nitrofurazone, p.309 Abscess, liver
Clioquinol, p.254 Nitroxoline, p.309
The tetracyclines have also been useful in the treatment of Clofoctol, p.255 Novobiocin, p.310 Bacteria commonly responsible for pyogenic liver ab-
penicillin-allergic patients suffering from venereal diseas- Colistin, p.256 Polymyxin B, p.317 scesses include Enterobacteriaceae, especially Es-
es, actinomycosis, bronchitis, and leptospirosis. Minocy- Daptomycin, p.264 Retapamulin, p.323 cherichia coli and in some countries1 Klebsiella pneumo-
 Antibacterials 163
niae; anaerobes, especially Bacteroides fragilis; and are of mixed aetiology. Abscesses are often a feature. In- ed. Although rare in western countries it remains a prob-
Streptococcus milleri (these can be microaerophilic). As fections include: brain abscess; acute necrotising gingivitis lem in many areas, including Africa, Asia, some southern
elsewhere in the abdomen (see under Peritonitis, p.184), and other periodontal infections; chronic otitis media and European countries, the Americas, and parts of Australia.
infections are often mixed. Treatment involves percutane- chronic sinusitis; aspiration pneumonia and lung abscess; Anthrax has also been used as a weapon for biological
ous aspiration and drainage of pus and the use of high dos- peritonitis and intra-abdominal abscess; bacterial vagino- warfare.
es of antibacterials.2,3 Broad-spectrum empirical therapy sis and pelvic inflammatory disease; cellulitis, ulcers, In humans anthrax presents most often in the cutaneous
should be started immediately; more specific therapy may bites, and other wound infections.1 form. Gastrointestinal or inhalation anthrax can also occur
be possible when the results of cultures following diagnos- Sensitivity testing in vitro is often impractical and treat- and in these types the prognosis is poor without prompt
tic percutaneous aspiration of the abscess are known. Gen- ment is usually empirical.1-4 Benzylpenicillin was tradi- treatment. In cutaneous anthrax symptoms may develop
tamicin with clindamycin has been commonly used4,5 but tionally considered the antibacterial of choice when B. fra- within hours, or up to 12 days, after contact and initially
other antibacterial combinations, involving cefoxitin, gilis was unlikely (infections above the diaphragm) involves a painless, pruritic papule, which enlarges to an
chloramphenicol, carboxypenicillins, third-generation ce- although resistance is increasingly a problem. Antibacteri- ulcer. Later (2 to 6 days) a vesicle with a black eschar de-
phalosporins, and metronidazole, might be appropriate.5 A als with activity against the B. fragilis group and other velops. The incubation period for inhalation anthrax is
regimen of ampicillin, gentamicin, and metronidazole has anaerobic pathogens include metronidazole and other 5- usually about 10 days. Initial symptoms are non-specific
become standard in some centres, but may be hazardous in nitroimidazole derivatives, chloramphenicol, clindamy- and resemble a flu-like illness with fever, non-productive
patients with Klebsiella-related liver abscess, in whom a cin, cefoxitin, antipseudomonal penicillins, imipenem-cil- cough, dyspnoea, fatigue, headache, malaise, sweats,
combination of an aminoglycoside with either an extend- astatin, and combinations of a beta lactam and a beta-lacta- weakness, abdominal pain, and vomiting. This initial stage
ed-spectrum beta-lactam such as piperacillin or a second- mase inhibitor.2 may last from a few hours to days and is followed in some
or third-generation cephalosporin, may be preferred.1 An- Surveys of susceptibility patterns in clinical isolates of patients by a short period of recovery while others progress
tibacterial therapy has been successful without surgical in- anaerobic bacteria have shown increasing resistance of the directly to respiratory failure. Gastrointestinal anthrax has
tervention, but may not be consistently so,6 although this B. fragilis group (including B. distasonis, B. fragilis, B. an incubation period of up to 1 week (usually 2 to 5 days)
might be due to inadequate treatment against enteric anaer- ovatus, B. thetaiotaomicron, and B. vulgatus) to clindamy- and initial symptoms are fever, abdominal pain, nausea,
obes, especially B. fragilis.5 cin, continuing penicillin resistance in non-fragilis Bacter- vomiting, gastric ulcers, haematemesis, and diarrhoea
For the treatment of amoebic liver abscess, see under oides spp. (now reclassified as Prevotella spp. and includ- (usually bloody). Systemic disease progresses rapidly and
Amoebiasis in Antiprotozoals, p.822. ing the type species P. melaninogenica), and rare beta- hypotension, shock, and death may occur 2 to 5 days after
1. Lederman ER, Crum NF. Pyogenic liver abscess with a focus on lactamase-mediated resistance of Fusobacterium to peni- initial symptoms.
Klebsiella pneumoniae as a primary pathogen: an emerging dis-
ease with unique clinical characteristics. Am J Gastroenterol cillin. Resistance of some Clostridium spp. to penicillin The treatment of naturally occurring anthrax has tradi-
2005; 100: 322–31. and clindamycin had declined, but no changes were noted tionally been with benzylpenicillin with ciprofloxacin or
2. Barakate MS, et al. Pyogenic liver abscess: a review of 10 years’ for Cl. perfringens. The emergence of multi-drug resistant doxycycline (or other tetracycline) as alternatives. Other
experience in management. Aust N Z J Surg 1999; 69: 205–9. anaerobes has been noted.5
3. Alvarez Pérez JA, et al. Clinical course, treatment, and multivar- drugs with in vitro activity are aminoglycosides, amoxicil-
iate analysis of risk factors for pyogenic liver abscess. Am J Surg The B. fragilis group are the most frequently isolated lin, chloramphenicol, clindamycin, imipenem, linezolid,
2001; 181: 177–86. anaerobic bacteria in clinical infections and all members of the macrolides, meropenem, rifampicin, and vancomy-
4. Herbert DA, et al. Pyogenic liver abscesses: successful non-sur- cin.1-3 There are currently no clinical trial data on the opti-
gical therapy. Lancet 1982; i: 134–6. the group may be pathogenic.6 Most strains produce beta
5. Herbert DA, et al. Medical management of pyogenic liver ab- lactamase and thus are resistant to penicillins and cepha- mal treatment for anthrax and treatment recommendations
scesses. Lancet 1985; i: 1384. losporins although there is varied susceptibility within the and guidelines1-3 are based largely on the experience
6. McCorkell SJ, Niles NL. Pyogenic liver abscesses: another look group.7 In a survey of susceptibility patterns8 the most ac- gained during the 1979 incident in Sverdlovsk (accidental
at medical management. Lancet 1985; i: 803–6.
tive drugs in vitro against B. fragilis group strains were im- release of biological warfare agents), the 2001 attack in the
ipenem, metronidazole, and chloramphenicol; resistance USA (deliberate release), isolated case reports of naturally
Abscess, lung to cefoxitin, clindamycin, and piperacillin was not wide- occurring disease, and in vitro data. Because of the risks of
Lung abscesses are often secondary to aspiration pneumo- spread and combinations of beta-lactamase inhibitors with engineered drug-resistant strains of B. anthracis, inducible
nia and are discussed under Pneumonia, p.186. The organ- penicillins or cephalosporins (e.g. ampicillin or cefopera- beta-lactamases, and in vitro resistance to ofloxacin,
isms involved are commonly anaerobic bacteria. zone with sulbactam; ticarcillin with clavulanate) were guidelines1-3 for the treatment of anthrax (occurring after
also very active. Others have reported similar results.7 On deliberate release) recommend the use of 2 or more anti-
Actinomycosis the basis of activity in vitro in another study9 metronida- bacterials which should be started as soon as possible. Cor-
Actinomycosis is mainly caused by the oral commensal zole, imipenem, ticarcillin with clavulanate, cefoxitin, and ticosteroids may be given as adjunctive therapy. For the
Actinomyces israelii, a Gram-positive anaerobic or micro- amoxicillin with clavulanate were considered suitable for treatment of inhalation and gastrointestinal anthrax intra-
aerophilic bacterium. Other species sometimes responsi- the treatment of B. fragilis group infections. However, a venous ciprofloxacin or oral doxycycline plus one or two
ble include A. meyeri, A. naeslundii, and A. viscosus. One more recent commentary5 suggested that cefoxitin and additional antibacterials with in vitro activity are recom-
of the commonest forms has been cervicofacial actinomy- clindamycin were no longer drugs of choice due to in- mended until antimicrobial susceptibility is known. Treat-
cosis, generally associated with poor oral hygiene and den- creasing resistance. A clinical isolate of B. fragilis, simul- ment should be given for 60 days. For cutaneous anthrax,
tal procedures.1 Other forms include abdominal, thoracic,2 taneously resistant to metronidazole, amoxicillin with cla- oral ciprofloxacin or oral doxycycline is generally recom-
and disseminated actinomycosis; pelvic actinomycosis is vulanate, and imipenem, was reported in the UK;10 mended. A change to amoxicillin, particularly in pregnant
associated with the use of intra-uterine contraceptive de- treatment with clindamycin was successful on this occa- women and children, may be considered if the organism is
vices. sion. Tigecycline is considered promising for the manage- found to be susceptible or first-line drugs cannot be taken.
ment of anaerobic infections; other drugs with potential for Treatment for 7 to 10 days is usually recommended for cu-
The antibacterial of choice is benzylpenicillin given intra-
oral therapy may include nitazoxanide, ramoplanin, and ri- taneous anthrax, but in the event of a deliberate release or
venously in high doses for 2 to 6 weeks, followed by an
oral penicillin (e.g. phenoxymethylpenicillin or amoxicil- faximin.5 if concurrent inhalation is suspected then treatment should
1. Styrt B, Gorbach SL. Recent developments in the understanding be continued for 60 days. If there are signs of systemic in-
lin) for 6 to 12 months.2 There is evidence that actinomy- of the pathogenesis and treatment of anaerobic infections (first volvement, extensive oedema, or lesions on the head or
cosis can be successfully treated with less prolonged regi- of two parts). N Engl J Med 1989; 321: 240–6.
2. Styrt B, Gorbach SL. Recent developments in the understanding neck, intravenous, and a multi-drug approach is recom-
mens of penicillin; however, short-course treatment
of the pathogenesis and treatment of anaerobic infections (sec- mended.
regimens are generally not advised for patients with large ond of two parts). N Engl J Med 1989; 321: 298–302.
lesions and/or abdominal disease unless surgical debride- 3. Finegold SM, Wexler HM. Present status of therapy for anaero-
Anthrax can be prevented by controlling and eliminating
ment is performed.2 Tetracycline is an alternative in pa- bic infections. Clin Infect Dis 1996; 23 (suppl 1): S9–S14. infected animals and vaccinating livestock. In humans,
tients allergic to penicillin; other alternatives include 4. Brook I. Anaerobic infections. Rev Med Microbiol 1999; 10: chemoprophylaxis may be given when exposure to an-
137–53. thrax is suspected. US4 and UK3 guidelines recommend
erythromycin or clindamycin. In one patient, actinomyco- 5. Boyanova L, et al. Antimicrobial resistance and the manage-
sis resistant to conventional treatment responded to a pro- ment of anaerobic infections. Expert Rev Anti Infect Ther 2007; antibacterial prophylaxis with oral ciprofloxacin or oral
longed course of ciprofloxacin.3 Other antibacterials used 5: 685–701. doxycycline for 60 days. UK guidelines suggest that
6. Brook I. The clinical importance of all members of the Bacter- amoxicillin may be considered if the organism is found to
successfully to treat actinomycosis include intravenous oides fragilis group. J Antimicrob Chemother 1990; 25: 473–4.
imipenem for 6 to 10 weeks and parenteral ceftriaxone for 7. Cuchural GJ, et al. Comparative activities of newer β-lactam be susceptible. Anthrax vaccines may be used for active
3 weeks followed by oral ampicillin for 3 months.2 agents against members of the Bacteroides fragilis group. Anti- immunisation and are recommended for persons working
microb Agents Chemother 1990; 34: 479–80. with potentially infected animals or animal products (in-
1. Anonymous. Essential drugs: systemic mycoses. WHO Drug Inf 8. Cornick NA, et al. The antimicrobial susceptibility patterns of
1991; 5: 129–36. the Bacteroides fragilis group in the United States, 1987. J An- cluding laboratory workers). The vaccine may also be giv-
2. Sudhakar SS, Ross JJ. Short-term treatment of actinomycosis: timicrob Chemother 1990; 25: 1011–19. en with antibacterials as part of a postexposure prophylax-
two cases and a review. Clin Infect Dis 2004; 38: 444–7. 9. Jacobs MR, et al. β-Lactamase production, β-lactam sensitivity is regimen.2,3,5 In such situations, antibacterial prophylaxis
3. Macfarlane DJ, et al. Treatment of recalcitrant actinomycosis and resistance to synergy with clavulanate of 737 Bacteroides
with ciprofloxacin. J Infect 1993; 27: 177–80. fragilis group organisms from thirty-three US centres. J Antimi- may be reduced to 4 to 6 weeks.3,5 In the USA, specific
crob Chemother 1990; 26: 361–70. guidelines5,6 for the use of anthrax vaccine, including its
10. Turner P, et al. Simultaneous resistance to metronidazole, co- use in response to terrorism, have been developed.
Anaerobic bacterial infections amoxiclav, and imipenem in clinical isolate of Bacteroides fra-
gilis. Lancet 1995; 345: 1275–7. 1. CDC. Update: investigation of bioterrorism-related anthrax and
Anaerobic bacteria predominate in the normal microbial interim guidelines for exposure management and antimicrobial
flora of man and are a common cause of infections, espe- therapy, October 2001. MMWR 2001; 50: 909–19. Correction.
cially those arising from the gastrointestinal tract, upper Anthrax ibid.; 962. Also available at: http://www.cdc.gov/mmwr/
preview/mmwrhtml/mm5042a1.htm (accessed 22/05/07)
respiratory tract, skin, or vagina. Common anaerobic path- Anthrax is caused by Bacillus anthracis, a spore-forming 2. Inglesby TV, et al. Anthrax as a biological weapon, 2002: updat-
ogens are Bacteroides, Prevotella (formerly non-fragilis Gram-positive aerobe found in the soil. It most commonly ed recommendations for management. JAMA 2002; 287:
Bacteroides), Fusobacterium, Clostridium, Peptostrepto- infects herbivorous mammals. Humans can become in- 2236–52.
coccus, and Actinomyces spp. Apart from single species fected by contact with infected animals or infected or con- 3. Health Protection Agency. Anthrax: guidelines for action in the
event of a deliberate release. Version 5.9; issued 16/04/07.
infections such as tetanus, gas gangrene, pseudomembra- taminated animal products, or by inhalation of anthrax Available at: http://www.hpa.org.uk/webc/HPAwebFile/
nous colitis, and actinomycosis, most anaerobic infections spores. Person-to-person transmission has not been report- HPAweb_C/1194947401128 (accessed 15/08/08)

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
164 Antibacterials
4. CDC. Update: investigation of anthrax associated with intention- • USA: More unusual organisms include Capnocytophaga cani-
al exposure and interim public health guidelines, October
2001.MMWR 2001; 50: 889–93. Also available at: http:// • oral metronidazole 500 mg twice daily or 250 mg three times morsus (formerly called dysgonic fermenter type 2 or DF-
www.cdc.gov/mmwr/preview/mmwrhtml/mm5041a1.htm (ac- daily for 7 days or 2) which has been associated in particular with dog
cessed 11/05/07) • oral clindamycin 300 mg twice daily for 7 days bites,5,6 but also with cat bites. It is an opportunistic path-
5. CDC. Use of anthrax vaccine in response to terrorism: supple- Treatment of male sex partners does not prevent the recur- ogen especially hazardous to immunocompromised pa-
mental recommendations of the Advisory Committee on Immu-
nization Practices. MMWR 2002; 51: 1024–6. Also available at: rence of bacterial vaginosis.1-3 tients including splenectomised patients; the best treat-
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5145a4.htm Patients co-infected with HIV should receive the same ment is benzylpenicillin,7 amoxicillin-clavulanic acid, or
(accessed 11/05/07) treatment as those who are HIV-negative.2 erythromycin.8 Infection with C. canimorsus following
6. CDC. Use of anthrax vaccine in the United States: recommenda-
tions of the Advisory Committee on Immunization Practices 1. Clinical Effectiveness Group (British Association for Sexual dog bites may be severe and has led to fatal septicaemia,
(ACIP). MMWR 2000; 49 (RR-15): 1–20. Also available at: Health and HIV). National guideline for the management of bac- disseminated intravascular coagulation, meningitis, or en-
terial vaginosis (2006). Available at: http://www.bashh.org/
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4915a1.htm
documents/62/62.pdf (accessed 15/08/08)
docarditis,5 highlighting the importance of early antibacte-
(accessed 11/05/07) rial treatment and debridement.
2. CDC. Sexually transmitted diseases treatment guidelines 2006.
MMWR 2006; 55(RR-11): 1–94. Also available at: http:// See also under Cat Scratch Disease (p.166).
Antibiotic-associated colitis www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 22/03/07)
3. WHO. Guidelines for the management of sexually transmitted A systematic review9 has concluded that there is no evi-
See p.171. in fe c tio ns . G e ne va : W HO , 20 03. A l so a v ai la ble at : dence that the use of prophylactic antibacterials is effective
http://whqlibdoc.who.int/publications/2003/9241546263.pdf for cat or dog bites, though, if necessary, prophylaxis or
(accessed 22/03/07)
Arthritis, bacterial 4. Hay PE. Therapy of bacterial vaginosis. J Antimicrob Chemother treatment for rabies (p.2234) should be instituted. A com-
See under Bone and Joint Infections, p.164. 1998; 41: 6–9. bined tetanus and diphtheria vaccine (see Tetanus Vaccine,
5. Anonymous. Management of bacterial vaginosis. Drug Ther p.2240) should be given to patients whose primary tetanus
Bull 1998; 36: 33–5.
6. McDonald HM, et al. Antibiotics for treating bacterial vaginosis immunisation is incomplete or unknown, or boosters are
Bacillary angiomatosis in pregnancy. Available in The Cochrane Database of Systematic not up-to-date.
See under Cat Scratch Disease, p.166. Reviews; Issue 1. Chichester: John Wiley; 2007 (accessed Among the more unusual infections acquired from ani-
17/03/07).
mals is seal finger, caused by an as yet unidentified organ-
Bacterial vaginosis ism and treated with tetracycline.10 The Gram-negative
Bacterial vaginosis (anaerobic vaginosis; non-specific Biliary-tract infections bacilli Spirillum minus (or minor) and Streptobacillus
vaginitis) results from a reduction of the normal vaginal Infections of the biliary tract are usually associated with moniliformis are both causes of rat-bite fever. In each case
bacteria (Lactobacillus spp.) and an overgrowth of anaer- obstructive and inflammatory conditions such as cholecys- the treatment of choice is benzylpenicillin;2 a tetracycline
obic bacteria (including Gardnerella vaginalis, Mycoplas- titis and cholangitis. Complications can include gangrene, or streptomycin are alternatives.
ma hominis, or Mobiluncus or Prevotella spp.). It is a com- hepatic or intraperitoneal abscesses, peritonitis, and septi- Envenomation after bites and stings by snakes, scorpions,
mon and often distressing condition that is not thought to caemia. The organisms involved are typically gut flora, in- spiders, and some marine animals is usually treated symp-
be sexually transmitted but is generally associated with cluding Gram-negative aerobes such as Escherichia coli tomatically and with specific antivenoms and antisera (see
sexual activity. Infections may be asymptomatic or result and Klebsiella spp., and anaerobes including Bacteroides Jellyfish Stings, p.2220, Scorpion Stings, p.2237, Snake
in a fishy-smelling vaginal discharge. fragilis. Bites, p.2239, Spider Bites, p.2239, and Stone Fish Venom
Various antibacterial regimens for the treatment of bacte- Treatment of uncomplicated acute cholecystitis is usually Antisera, p.2239).
rial vaginosis are recommended in guidelines issued in the conservative. Antibacterials including cephalosporins, tet- 1. Talan DA, et al. Bacteriologic analysis of infected dog and cat
racyclines, or broad-spectrum penicillins are commonly bites. N Engl J Med 1999; 340: 85–92.
UK,1 and in the USA2 and also by WHO3 but relapse is 2. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
common after any regimen. given, although some have questioned their use.1 For more book of antimicrobial therapy. 18th ed. New Rochelle NY: The
• WHO: severe infections including suppurative cholangitis, Medical Letter, 2008: 70.
prompt treatment with appropriate antibacterial drugs is 3. Elliot DL, et al. Pet-associated illness. N Engl J Med 1985; 313:
• oral metronidazole 400 or 500 mg twice daily for 7 days 985–95.
necessary. Since biliary obstruction prevents adequate 4. Richards CAL, Emmanuel FXS. Treatment of Pasteurella mul-
alternatives are:
concentrations of many antibacterials being achieved in tocida cellulitis with ciprofloxacin. J Infect 1992; 24: 216–17.
• a single oral dose of metronidazole 2 g 5. Pers C, et al. Capnocytophaga canimorsus septicemia in Den-
the bile, the main aim of treatment is to control bacterae-
• intravaginal metronidazole 5 g of a 0.75% gel twice daily for mark, 1982-1995: review of 39 cases. Clin Infect Dis 1996; 23:
5 days
mia. Antibacterials used, often in combination, include ce- 71–5.
• oral clindamycin 300 mg twice daily for 7 days
phalosporins, aminoglycosides, ampicillin (or amoxicil- 6. Le Moal G, et al. Meningitis due to Capnocytophaga canimorsus
lin), piperacillin, fluoroquinolones, metronidazole, after receipt of a dog bite: case report and review of the litera-
• intravaginal clindamycin 5 g of a 2% cream at bedtime for 7 ture. Clin Infect Dis 2003; 36: e42–e46.
days clindamycin, and imipenem or its analogues.2-5 In most 7. McCarthy M, Zumla A. DF-2 infection. BMJ 1988; 297:
• UK: cases of obstruction, definitive treatment depends on re- 1355–6.
storing drainage of bile by surgical or medical treatment of 8. Morgan MS, Cruickshank JG. Prevention of postsplenectomy
• oral metronidazole 400 or 500 mg twice daily for 5 to 7 days sepsis. Lancet 1993; 341: 700–1.
or a single oral 2-g dose gallstones (p.2409). 9. Medeiros I, Saconato H. Antibiotic prophylaxis for mammalian
Antibacterial prophylaxis is common in biliary surgery bites. Available in The Cochrane Database of Systematic Re-
alternatives are: views; Issue 2. Chichester: John Wiley; 2001 (accessed
• intravaginal metronidazole 0.75% gel once daily for 5 days (see Surgical Infection, p.195) to prevent acute cholangitis 16/05/05).
• oral clindamycin 300 mg twice daily for 7 days and wound infections. Cephalosporins are often used for 10. Hartley JW, Pitcher D. Seal finger—tetracycline is first line. J
• intravaginal clindamycin as a 2% cream once daily for 7 days
this purpose.2 Infect 2002; 45: 71–5.

• a single oral dose of tinidazole 2 g Antibacterials may also have a role as maintenance thera-
• USA: py in recurrent cholangitis. Bone and joint infections
• oral metronidazole 500 mg twice daily for 7 days, or
1. Bouchier IAD. Gallstones. BMJ 1990; 300: 592–7. In bacterial arthritis (septic arthritis) joints may be infect-
2. van den Hazel SJ, et al. Role of antibiotics in the treatment and ed via the blood with a variety of organisms, including sta-
• intravaginal metronidazole 5 g of a 0.75% gel once daily for prevention of acute and recurrent cholangitis. Clin Infect Dis
5 days, or 1994; 19: 279–86. phylococci, streptococci, enterococci, Enterobacteriaceae,
• intravaginal clindamycin 5 g of a 2% cream at bedtime for 7 3. Peña C, Gudiol F. Cholecystitis and cholangitis: spectrum of Pseudomonas aeruginosa, and anaerobes, although the
bacteria and role of antibiotics. Dig Surg 1996; 13: 317–20. commonest is probably Staphylococcus aureus. Haemo-
days 4. Westphal J-F, Brogard J-M. Biliary tract infections: a guide to
alternatives are: drug treatment. Drugs 1999; 57: 81–91. philus influenzae is a common cause in young children, as
• oral clindamycin 300 mg twice daily for 7 days 5. Jain MK, Jain R. Acute bacterial cholangitis. Curr Treat Options is Neisseria gonorrhoeae in sexually active young adults.
• intravaginal clindamycin 100 mg at bedtime for 3 days
Gastroenterol 2006; 9: 113–21. In addition to gonococcal arthritis, other specific types of
An association has been reported between bacterial vagi- bacterial arthritis include Lyme disease and meningococ-
nosis and adverse pregnancy outcomes, including miscar- Bites and stings cal, salmonellal, and tuberculous arthritis (see under the
riage and premature births of low-weight infants, and Wound infections after cat or dog bites may be due to a appropriate disease for further details).
some have advised treatment early in the second trimester mixture of organisms,1 often including the Gram-negative With the exception of N. gonorrhoeae, infecting organ-
of pregnancy.4,5 A systematic review6 of clinical studies aerobe Pasteurella multocida. The treatment of choice for isms in osteomyelitis (infection of bone) are similar to
has concluded that there is little evidence that screening P. multocida is benzylpenicillin2 and it should be given for those in bacterial arthritis.1-3
and treatment of all pregnant women for bacterial vagino- infections evident within 24 hours of a bite;3 alternatives In reactive arthritis (aseptic arthritis) joint inflammation
sis would prevent premature birth and its consequences, are amoxicillin-clavulanic acid, ampicillin-sulbactam, or a follows infection elsewhere in the body. It is generally sec-
but there is some suggestion that treatment before 20 second- or third-generation cephalosporin.2 A tetracycline ondary to sexually transmitted, especially chlamydial, in-
weeks of gestation may reduce the risk of preterm birth. In such as doxycycline is a further alternative in patients al- fections, or to enteric infections. Reactive arthritis in asso-
women with a history of a previous premature birth, treat- lergic to penicillin.2 The fluoroquinolone ciprofloxacin ciation with urethritis or cervicitis, or both, is termed
ment of bacterial vaginosis may reduce the risk of preterm has been used successfully to treat P. multocida cellulitis Reiter’s syndrome.
birth.2 Symptomatic pregnant women should be treated associated with a cat bite.4 Empirical treatment regimens for bacterial arthritis or os-
and the following regimens have been recommended: In addition to P. multocida, other bacteria involved in cat teomyelitis usually include antistaphylococcal antibacteri-
• WHO: or dog bite wound infections include Staphylococcus, als such as flucloxacillin, nafcillin, oxacillin, a first-gener-
• oral metronidazole 200 or 250 mg three times daily for 7 Streptococcus, Bacteroides, and Fusobacterium spp. and ation cephalosporin,4 clindamycin, or fusidic acid;
days, after the first trimester, or their presence will influence the choice of treatment. For vancomycin is used to combat possible meticillin-resistant
• a single oral dose of metronidazole 2 g, if treatment is needed example, a penicillinase-resistant penicillin may be neces- Staph aureus. Linezolid may be used as an alternative in
in the first trimester sary if Staph. aureus is present. Also, combinations of an- patients unable to take vancomycin.4 Children under 5
alternatives are: tibacterials may be necessary in patients allergic to penicil- years may be given amoxicillin or cefuroxime because of
• oral clindamycin 300 mg twice daily for 7 days or lin since tetracycline, the alternative suggested against P. the likelihood of H. influenzae infection. Ceftriaxone may
• intravaginal metronidazole 5 g of a 0.75% gel twice daily for multocida infection, has only limited activity against aero- be used for empirical treatment where infection is thought
7 days bic Gram-positive cocci. to be caused by Streptococcus spp. and N. gonorrhoeae.
 Antibacterials 165
Empirical antibacterial treatment for infections caused by that, although there was some benefit to be obtained this Treatment of brucellosis shortens the duration of illness,
Gram-negative bacteria includes ceftriaxone, ceftazidime, did not outweigh the risks of adverse effects and increased and reduces complications and the risk of relapse. Tetracy-
or ciprofloxacin.4 Treatment of bone and joint infection is resistance and that the use of antibacterials could therefore clines, although highly active against Brucella spp., are as-
usually started intravenously; if high bone concentrations not be advocated in otherwise healthy patients with no ev- sociated with high relapse rates when given as monothera-
can be achieved with an appropriate oral antibacterial, pa- idence of chronic disease. A systematic review10 also con- py and therefore combination therapy is now used.
tients may be switched to oral therapy. Successful treat- cluded that the modest benefit associated with antibacteri- Common regimens are: doxycycline and rifampicin both
ment of septic arthritis is generally achieved after 2 to 3 al use in acute disease needed to be considered in the orally for at least 6 weeks;4,5 doxycycline orally for 6
weeks of therapy, while osteomyelitis and prosthetic joint broader context of potential adverse effects, the necessity weeks with a parenteral aminoglycoside (streptomycin,6,7
infections may need to be treated for weeks to months.5 to treat a self-limiting condition, development of resist- gentamicin,5,8,9 or netilmicin10) for the first 1 to 2 weeks.
A systematic review and meta-analysis6 of antibacterial ance, and cost of treatment. If antibacterials are given it is Fewer relapses have been reported with doxycycline and
treatment of bone and joint infections concluded that most common practice to give a 7- to 10-day oral course of a streptomycin than with doxycycline and rifampicin, per-
studies were methodologically flawed and that there was broad-spectrum drug such as amoxicillin (alone or with haps due to rifampicin reducing plasma concentrations of
little high-quality evidence regarding treatment. Ri- clavulanic acid), ampicillin, an oral cephalosporin such as doxycycline.11 Higher relapse rates have been reported
fampicin has also been used, sometimes with other drugs; cefaclor or cefuroxime axetil, co-trimoxazole, erythromy- with netilmicin than with gentamicin.10 Studies12,13 have
in one study7 use of rifampicin with ciprofloxacin im- cin or a newer macrolide such as azithromycin or clarithro- shown that combination treatment with a fluoroquinolone
proved control of staphylococcal bone infections related to mycin, tetracycline, or trimethoprim (preferred to co-tri- plus either doxycycline or rifampicin is effective although
orthopaedic devices in comparison with ciprofloxacin moxazole in the UK), the choice depending on local fluoroquinolone monotherapy is not. A review of the liter-
alone. patterns of resistance. ature on fluoroquinolone-based combination treatment did
For reference to infection prophylaxis in orthopaedic pa- Long-term prophylaxis in patients with frequent exacerba- not support their use as first-line treatment,13 but they can
tients, see under Surgical Infection, below. tions of bronchitis is controversial. A systematic review11 be considered as part of an alternative regimen for patients
Reactive arthritis is treated with anti-inflammatories; the of the value of antibacterial prophylaxis in chronic bron- who experience relapse or toxicity problems with the usual
role of antibacterials is less certain.8 Results in arthritis as- chitis concluded that it did have a small but significant ef- first-line antibacterials. Co-trimoxazole when used is usu-
sociated with chlamydial infections have been more prom- fect in reducing the number of days of illness, but that it ally given in triple-drug regimens.3 A systematic review
ising than in that triggered by enteric infections.9 Long- had no place in routine therapy because of concerns over and meta-analysis14 of 30 randomised controlled studies
term treatment with a tetracycline in addition to an NSAID adverse effects and the development of resistance. on the treatment of brucellosis found that a triple drug reg-
has been reported to shorten the duration of reactive arthri- Bronchitis associated with Chlamydophila pneumoniae imen of doxycycline, gentamicin, and rifampicin was bet-
tis resulting from Chlamydia trachomatis infection.10 (Chlamydia pneumoniae) and responding to tetracycline ter than doxycycline plus an aminoglycoside. It also found
For mention of the use of tetracyclines, usually minocy- or erythromycin has also been reported.12 that 6 weeks of treatment was associated with a lower rate
cline, in the treatment of rheumatoid arthritis, see under 1. Wenzel RP, Fowler AA. Acute bronchitis. N Engl J Med 2006; of relapse than treatment regimens of 30 days or less.
355: 2125–30. Tetracyclines should be avoided in young children (usual-
Musculoskeletal and Joint Disorders, p.350. 2. Anonymous. Antibiotics for exacerbations of chronic bronchi-
1. Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997; tis? Lancet 1987; ii: 23–4. ly specified as below 8 years of age in the US and below
336: 999–1007. 3. Staley H, et al. Is an objective assessment of antibiotic therapy 12 years in the UK). The preferred regimens for these chil-
2. Mader JT, et al. A practical guide to the diagnosis and manage- in exacerbations of chronic bronchitis possible? J Antimicrob dren appear to be co-trimoxazole with rifampicin both
ment of bone and joint infections. Drugs 1997; 54: 253–64. Chemother 1993; 31: 193–7.
3. Goldenberg DL. Septic arthritis. Lancet 1998; 351: 197–202. 4. Gonzales R, Sande M. What will it take to stop physicians from orally for at least 6 weeks or co-trimoxazole orally with
4. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand- prescribing antibiotics in acute bronchitis? Lancet 1995; 345: parenteral gentamicin for the first 2 weeks.5,6 Alternative
book of antimicrobial therapy. 18th ed. New Rochelle NY: The 665–6. regimens include rifampicin orally for at least 6 weeks
Medical Letter; 2008. 5. Hahn DL. Antibiotics in acute bronchitis. Lancet 1995; 345:
5. Darley ESR, MacGowan AP. Antibiotic treatment of gram-pos- 1244–5. with either gentamicin or netilmicin for the first 5 days.6
itive bone and joint infections. J Antimicrob Chemother 2004; 6. O’Brien KL, et al. Cough illness/bronchitis—principles of judi- For the treatment of brucellosis during pregnancy, WHO
53: 928–35. cious use of antimicrobial agents. Pediatrics 1998; 101 (suppl):
6. Stengel D, et al. Systematic review and meta-analysis of antibi- 178–81. recommends rifampicin monotherapy for 6 weeks as the
otic therapy for bone and joint infections. Lancet Infect Dis 7. Anthonisen NR, et al. Antibiotic therapy in exacerbations of drug of choice and that co-trimoxazole or tetracycline
2001; 1: 175–88. Correction. ibid. 2002; 2: 125. chronic obstructive pulmonary disease. Ann Intern Med 1987; should only be given if rifampicin is unavailable; strepto-
7. Zimmerli W, et al. Role of rifampin for treatment of orthopedic 106: 196–204.
implant-related staphylococcal infections: a randomized con- 8. Saint S, et al. Antibiotics in chronic obstructive pulmonary dis- mycin is contra-indicated.4 Co-trimoxazole with ri-
trolled trial. JAMA 1998; 279: 1537–41. ease exacerbations: a meta-analysis. JAMA 1995; 273: 957–60. fampicin for 4 weeks has also been tried.6
8. Toivanen A. Bacteria-triggered reactive arthritis: implications 9. Bent S, et al. Antibiotics in acute bronchitis: a meta-analysis.
for antibacterial treatment. Drugs 2001; 61: 343–51. Am J Med 1999; 107: 62–7.
No one antibacterial combination has been found to be su-
9. Svenungsson B. Reactive arthritis. BMJ 1994; 308: 671–2. 10. Fahey T, et al. Antibiotics for acute bronchitis. Available in The perior for the treatment of spondylitis although a 3-month
10. Lauhio A. Reactive arthritis: consider combination treatment. Cochrane Database of Systematic Reviews; Issue 4. Chichester: course of doxycycline with ciprofloxacin has been pro-
BMJ 1994; 308: 1302–3. John Wiley; 2004 (accessed 17/08/05).
11. Staykova T, et al. Prophylactic antibiotic therapy for chronic
posed based on an evaluation of the literature.15 In the
bronchitis. Available in The Cochrane Database of Systematic treatment of neurobrucellosis, the length of therapy ap-
Botulism Reviews; Issue 2. Chichester: John Wiley; 2001 (accessed pears to be of critical importance; relapses may occur after
For a discussion of botulism and its management, see 16/05/05).
12. Grayston JT, et al. A new respiratory tract pathogen: Chlamydia
treatment lasting only 2 to 3 weeks and it is recommended
p.2207. pneumoniae strain TWAR. J Infect Dis 1990; 161: 618–25. that doxycycline be given with 2 or more other drugs (ri-
fampicin, an aminoglycoside, co-trimoxazole, or ceftriax-
Bronchitis one) for several months depending on the response. Corti-
Brucellosis
Bronchitis may be defined as inflammation of the bronchi costeroids are often given but their efficacy is unproven. A
Brucellosis (also known as undulant or Mediterranean fe-
and is associated with excessive sputum production and similar treatment regimen is used in the management of
ver) is caused by Brucella spp., aerobic Gram-negative
cough. The bronchi of healthy people are said to be nearly bacteria found primarily in livestock and domestic ani- paediatric neurobrucellosis and a 3-drug regimen (doxycy-
always sterile whereas the upper respiratory tract is often cline, rifampicin, and an aminoglycoside) given for 3
mals. Humans can become infected by direct contact with
colonised with commensal bacteria including Streptococ- months has been shown to be effective. In young children
infected animals or animal material (such as the placenta),
cus pneumoniae and Haemophilus influenzae. doxycycline should be replaced with co-trimoxazole.16
indirectly by consuming infected and unpasteurised milk
Acute bronchitis1 in previously healthy subjects is com- Treatment of endocarditis in adults generally requires
products, or by inhalation of contaminated dust or drop-
monly associated with viral respiratory infections such as long-term triple or quadruple drug regimens (a tetracy-
lets. Rarely, human infection has been reported from expo-
cline, an aminoglycoside, rifampicin, and/or co-trimoxa-
colds and influenza. There may sometimes be secondary sure to some live veterinary vaccines.1,2 The principal Bru-
bacterial infection that responds to antibacterial therapy as zole) usually with surgical valve replacement.17,18 Treat-
cella spp. affecting humans are B. melitensis, from sheep,
for acute exacerbations of chronic bronchitis (see below). ment should be continued for 3 months or longer and some
goats, camels, and sometimes cattle; B. abortus, from
Acute bronchiolitis occurs in infants as a result mainly of recommend the addition of ceftriaxone and/or a fluoroqui-
cattle, buffalo, camels, and yaks; B. suis, from pigs; and
viral infection and antibacterials are not given routinely nolone to reduce the need for surgery. Cardiac complica-
rarely B. canis, from dogs. Although rare or controlled in
(see Respiratory Syncytial Virus Infection, p.860). tions in children are generally less severe than in adults and
countries such as the UK brucellosis remains a problem in
treatment with tetracycline for 3 weeks with streptomycin
Chronic bronchitis and emphysema often occur together many areas, including eastern Europe, the Mediterranean
for 2 weeks has been found to be effective.18
and have been termed chronic obstructive pulmonary dis- region, South and Central America, Mexico, the Carib-
ease (p.1112). Acute exacerbations of chronic bronchitis bean, the Indian subcontinent, parts of Africa and Asia, Brucellosis can be prevented by controlling and eliminat-
may be viral in origin, but bacteria are often present in pu- and the Middle East. ing infected animals, pasteurising milk products, and vac-
rulent sputum, the commonest being Str. pneumoniae and Symptoms usually develop 2 to 8 weeks after infection cinating cattle and other livestock. There is no human vac-
H. influenzae; Moraxella catarrhalis (Branhamella ca- and resemble a flu-like illness with anorexia, fever, head- cine currently available for brucellosis, although many
tarrhalis) is increasingly reported. ache, lethargy, malaise, depression, myalgia and back have been tested and some have been available from time
The value of antibacterial treatment in both acute bronchi- pain, sweating, and weakness. Laboratory findings include to time in various countries.3
1. Blasco JM, Díaz R. Brucella melitensis Rev-1 vaccine as a
tis and acute exacerbation of chronic disease has been con- anaemia, leucopenia, lymphocytosis, pancytopenia, and cause of human brucellosis. Lancet 1993; 342: 805.
troversial and difficult to assess.1-6 After a comparison of a thrombocytopenia. Brucellosis may be acute, relapsing, or 2. Ashford DA, et al. Adverse events in humans associated with
broad-spectrum antibacterial (amoxicillin, co-trimoxa- chronic (disease duration of more than 1 year) and can af- accidental exposure to the livestock brucellosis vaccine RB51.
Vaccine 2004; 22: 3435–9.
zole, or doxycycline) with placebo,7 it was considered that fect any part of the body, including joints (peripheral ar- 3. Pappas G, et al. Brucellosis. N Engl J Med 2005; 352: 2325–36.
antibacterials were justified in exacerbations of chronic thritis, sacroiliitis, and spondylitis), heart (endocarditis), 4. FAO/WHO. Joint FAO/WHO expert committee on brucellosis:
obstructive pulmonary disease characterised by increased liver (hepatitis), the CNS (meningitis, encephalitis, menin- sixth report. WHO Tech Rep Ser 740 1986. Also available at:
http://libdoc.who.int/trs/WHO_TRS_740.pdf (accessed 21/05/07)
dyspnoea, sputum production, and sputum purulence. Al- goencephalitis, meningovascular disease, brain abscesses, 5. Health Protection Agency. Guidelines for action in the event of
so, a meta-analysis of randomised studies indicated a small and demyelinating syndrome), and the reproductive sys- a deliberate release: brucellosis. Version 1.5, 18 June 2007.
improvement due to therapy in patients with exacerbations tem (epididymo-orchitis). Relapses occur in about 10% of Available at: http://www.hpa.org.uk/webc/HPAwebFile/
HPAweb_C/1194947355003 (accessed 15/08/08)
of disease.8 However, a further meta-analysis9 assessing patients, usually in the first year after infection, and typi- 6. Solera J, et al. Recognition and optimum treatment of brucello-
the use of antibacterials for acute bronchitis concluded cally cause milder symptoms.3 sis. Drugs 1997; 53: 245–56.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
166 Antibacterials
7. Solera J, et al. Doxycycline-rifampin versus doxycycline-strep- 10. Kemper CA, et al. Visceral bacillary epithelioid angiomatosis: • UK:
tomycin in treatment of human brucellosis due to Brucella possible manifestations of disseminated cat scratch disease in
melitensis. Antimicrob Agents Chemother 1995; 39: 2061–7. the immunocompromised host: a report of two cases. Am J Med • as for WHO, or
8. Solera J, et al. Treatment of human brucellosis with doxycycline 1990; 89: 216–22. • oral erythromycin 500 mg twice daily for 14 days, or
and gentamicin. Antimicrob Agents Chemother 1997; 41: 11. Mui BSK, et al. Response of HIV-associated disseminated cat
80–84. scratch disease to treatment with doxycycline. Am J Med 1990; • a single oral dose of azithromycin 1 g
9. Solera J, et al. A randomized, double-blind study to assess the 89: 229–31. • USA:
optimal duration of doxycycline treatment for human brucello- 12. Taylor AG, et al. Cat-scratch, Kaposi’s sarcoma, and bacillary
sis. Clin Infect Dis 2004; 39: 1776–82. angiomatosis. Lancet 1993; 342: 686. • a single oral dose of azithromycin 1 g or
10. Solera J, et al. Treatment of human brucellosis with netilmicin • oral amoxicillin 500 mg three times daily for 7 days
and doxycycline. Clin Infect Dis 1996; 22: 441–5.
11. Colmenero JD, et al. Possible implications of doxycycline-ri- Cellulitis alternatives are:
fampin interaction for treatment of brucellosis. Antimicrob • erythromycin-containing regimens
Agents Chemother 1994; 38: 2798–2802. See under Skin Infections, p.194.
12. Karabay O, et al. Ofloxacin plus rifampicin versus doxycycline Sexual partners of those infected with C. trachomatis
plus rifampicin in the treatment of brucellosis: a randomized should be tested and treated.2-4
clinical trial [ISRCTN11871179]. BMC Infect Dis 2004; 4: 18. Cervicitis For further reference to sexually transmitted C. trachoma-
Available at: http://www.biomedcentral.com/1471-2334/4/18 Gonorrhoea in women occurs mainly as cervicitis, but mu-
(accessed 22/05/07) tis infections, see under Epididymitis (p.170), Pelvic In-
13. Falagas ME, Bliziotis IA. Quinolones for treatment of human copurulent cervicitis is frequently caused by sexually
flammatory Disease (p.184), and Urethritis (p.199)
brucellosis: critical review of the evidence from microbiologi- transmitted Chlamydia trachomatis. The two infections
cal and clinical studies. Antimicrob Agents Chemother 2006; often occur together and should be treated concurrently. Specific serotypes of C. trachomatis are responsible for
50: 22–33. another sexually transmitted disease, lymphogranuloma
14. Skalsky K, et al. Treatment of human brucellosis: systematic Guidelines for treatment are given under Gonorrhoea,
review and meta-analysis of randomised controlled trials. BMJ p.191, and Chlamydial Infections, below. venereum (p.192).
2008; 336: 701–4. Reactive arthritis (see Bone and Joint Infections, p.164)
15. Pappas G, et al. Treatment of brucella spondylitis: lessons from
an impossible meta-analysis and initial report of efficacy of a may be secondary to chlamydial infections.
fluoroquinolone-containing regimen. Int J Antimicrob Agents Chancroid
See under Sexually Transmitted Diseases, p.191 Other C. trachomatis infections that are not sexually trans-
2004; 24: 502–7.
16. Habeeb YKR, et al. Paediatric neurobrucellosis: case report and mitted include trachoma and inclusion conjunctivitis in
literature review. J Infect 1998; 37: 59–62. adults (see Trachoma, p.196).
17. Reguera JM, et al. Brucella endocarditis: clinical, diagnostic, Chlamydial infections 1. US Preventive Services Task Force. Screening for chlamydial in-
and therapeutic approach. Eur J Clin Microbiol Infect Dis 2003;
22: 647–50. The chlamydia organism belongs to the family Chlamy- fection (June 2007). Available at: http://www.ahcpr.gov/clinic/
diaceae. Species that are pathogenic in man are Chlamydo- uspstf/uspschlm.htm (accessed 03/08/07)
18. Al Dahouk S, et al. Brucella endocarditis in prosthetic valves.
Can J Cardiol 2006; 22: 971–4. 2. CDC. Sexually transmitted diseases treatment guidelines 2006.
phila pneumoniae, Chlamydophila psittaci, and Chlamy- MMWR 2006; 55(RR-11): 1–94. Also available at: http://
dia trachomatis; they are generally sensitive to www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07)
Campylobacter enteritis tetracyclines or erythromycin. 3. WHO. Guidelines for the management of sexually transmitted
i n f e c t i o n s . G e n e v a: W HO , 2 0 0 3 . A l s o a v a i l a b l e a t :
See p.172. C. pneumoniae (formerly classified as a TWAR strain of http://whqlibdoc.who.int/publications/2003/9241546263.pdf
C. psittaci) is a respiratory pathogen. It was first described (accessed 22/03/07)
Cat scratch disease as a cause of community-acquired pneumonia (see Pneu- 4. Clinical Effectiveness Group (British Association for Sexual
monia, p.186), but has since been associated with other Health and HIV). 2006 UK national guideline for the manage-
Cat scratch disease usually occurs after a cat scratch or ment of genital tract infection with Chlamydia trachomatis.
bite. The condition is characterised by regional lymphade- clinical presentations including pharyngitis (see p.185) Available at: http://www.bashh.org/documents/61/61.pdf (ac-
nopathy and is often self-limiting, but may be disseminat- and has been implicated in the pathogenesis of ischaemic cessed 18/08/08)

ed in immunocompromised patients. heart disease (see Atherosclerosis, p.1159).

In the 1980s a Gram-negative bacillus presumed to be re- C. psittaci is transmitted to man from birds and causes psit- Cholera and other vibrio infections
sponsible for cat scratch disease was isolated and subse- tacosis, which also affects the lungs (see Psittacosis, See p.172.
quently named Afipia felis. However, it now appears that p.188).
Bartonella henselae (formerly Rochalimaea henselae) is C. trachomatis causes a wide range of diseases. Many are
sexually transmitted and the spectrum is similar to that Cystic fibrosis
the main cause of cat scratch disease1 and that A. felis caus- Cystic fibrosis is a genetic disorder associated with the
es few, if any, cases, although there is some evidence for a with Neisseria gonorrhoeae (see Gonorrhoea, p.191); in-
fections with the two organisms often occur concurrently. production of abnormally viscous mucus. The underlying
joint role.2 With uncertainty over aetiology there has been defect is mutation in the gene which codes for cystic fibro-
no specific antibacterial therapy and treatment with anti- In women C. trachomatis may cause endometritis, pelvic
inflammatory disease, ectopic pregnancy, and infertility. In sis transmembrane conductance regulator (CFTR), a pro-
bacterials is generally not recommended in patients with tein which functions as a chloride channel. Mutations re-
mild to moderate infection.1 There are, however, reports of the USA1,2 routine screening for C. trachomatis infection
is recommended in all sexually active women aged 25 sult in defective ion transport with reduced chloride ion
successful treatment with gentamicin3 or co-trimoxazole4 secretion and accelerated sodium ion absorption, and relat-
in children and with ciprofloxacin5 in adults. Azithromy- years or less, whether or not they are pregnant, and in
women aged over 25 years if they are considered to be at ed changes in the composition and properties of mucin se-
cin has also been found to be of benefit in adults6 and is creted. Now that patients with cystic fibrosis usually sur-
considered the treatment of choice in both adults and chil- increased risk of infection.
Guidelines produced by WHO,3 by an expert group in the vive into adulthood, it is increasingly seen to be a
dren with extensive lymphadenopathy. Doxycycline with multisystem disease. However, the main clinical manifes-
rifampicin may be given as an alternative for these patients UK,4 and by the CDC in the USA2 for the treatment of
uncomplicated anogenital infection with C. trachomatis tations are still pulmonary disease, with recurrent bacterial
and is the recommended treatment for complicated cat infections and the production of copious viscous sputum,
scratch disease.1 are as follows:
and malabsorption due to pancreatic insufficiency. Other
Bacillary angiomatosis, in which both B. henselae and B. • WHO: complications include male infertility and hepatobiliary
quintana7 (the causative organism of trench fever) have • oral doxycycline 100 mg twice daily for 7 days, or
disease. There is increased salt loss in sweat.
been implicated, resembles a disseminated form of cat • a single oral dose of azithromycin 1 g
Pulmonary disease is the major cause of mortality. Cystic
scratch disease but occurs predominantly in HIV-infected alternatives, given for 7 days, are:
fibrosis is an underlying cause of bronchiectasis (chronic
patients. Disseminated disease in immunocompromised • oral amoxicillin 500 mg three times daily
dilatation of the bronchi) as a result of excessive secretion
patients has not responded to ciprofloxacin,8,9 but has • oral erythromycin 500 mg four times daily
of mucus and recurrent infections. Cough and excessive
responded to treatment with doxycycline 8-11 or • oral ofloxacin 300 mg twice daily
production of sputum are characteristic of cystic fibrosis
erythromycin8 or azithromycin. Erythromycin for 3 • oral tetracycline 500 mg four times daily
and the lungs are generally colonised with bacterial patho-
months is the drug of choice for bacillary angiomatosis; • UK: gens, especially mucoid strains of Pseudomonas aerugi-
doxycycline may be given as an alternative. Immunocom- • first-line therapy is the same as WHO nosa. Pseudomonal pulmonary infection is the major
promised patients with acute, life-threatening infection alternatives are: cause of morbidity and mortality in cystic fibrosis. Moni-
should be treated with rifampicin plus erythromycin or • oral erythromycin 500 mg twice daily for 10 to 14 days toring of bacterial pathogens in the sputum, including their
doxycycline.1 Care is required in patients with AIDS since • oral ofloxacin 200 mg twice daily or 400 mg once daily for 7 sensitivity, is necessary for rational treatment. Apart from
the lesions of bacillary angiomatosis closely resemble days Ps. aeruginosa, Staphylococcus aureus is often present
those of Kaposi’s sarcoma, and if the diagnosis is missed, • USA: and may be the predominant pathogen in infants. Burkhol-
life-saving antibacterial therapy may not be given.12 • first-line therapy is the same as WHO deria cepacia complex (Pseudomonas cepacia) has been
1. Rolain JM, et al. Recommendations for treatment of human in-
fections caused by Bartonella species. Antimicrob Agents alternatives, given for 7 days, are: recognised as a cause of serious lung infection in cystic
Chemother 2004; 48: 1921–33. • oral erythromycin 500 mg four times daily fibrosis and is readily transmitted by social contact. In a
2. Alkan S, et al. Dual role for Afipia felis and Rochalimaea hense- • oral erythromycin ethylsuccinate 800 mg four times daily proportion who acquire it, B. cepacia has been associated
lae in cat-scratch disease. Lancet 1995; 345: 385.
3. Bogue CW, et al. Antibiotic therapy for cat-scratch disease? • oral ofloxacin 300 mg twice daily with rapid deterioration and death. Other bacteria isolated
JAMA 1989; 262: 813–16. • oral levofloxacin 500 mg once daily include Haemophilus influenzae and atypical Mycobacte-
4. Collipp PJ. Cat-scratch disease therapy. Am J Dis Child 1989; ria spp.
143: 1261. Pregnant women infected with C. trachomatis may be at
5. Holley HP. Successful treatment of cat-scratch disease with cip- risk of premature rupture of membranes and preterm la- Various diagnostic methods are available1-3 and clinical di-
rofloxacin. JAMA 1991; 265: 1563–5. bour (see Premature Labour, p.188). They may also infect agnosis of cystic fibrosis may be confirmed by establish-
6. Bass JW, et al. Prospective randomized double blind placebo-
controlled evaluation of azithromycin for treatment of cat- their offspring to cause ophthalmia neonatorum (see Neo- ing that chloride concentrations in sweat are raised. This
scratch disease. Pediatr Infect Dis J 1998; 17: 447–52. natal Conjunctivitis, p.180) or pneumonia (p.186). Infect- may be done by using the pilocarpine sweat test (see Pilo-
7. Koehler JE, et al. Isolation of Rochalimaea species from cuta- ed pregnant women should be treated and the following carpine, p.1885). Identification of gene mutation is possi-
neous and osseous lesions of bacillary angiomatosis. N Engl J
Med 1992; 327: 1625–31. regimens have been recommended: ble and may be used for further confirmation of the diag-
8. Tappero JW, Koehler JE. Cat-scratch disease and bacillary angi- • WHO: treatment for 7 days with: nosis and identification of carrier status.4 In some areas
omatosis. JAMA 1991; 266: 1938–9.
9. Tucker RM, et al. Cat-scratch disease and bacillary angiomato- • oral erythromycin 500 mg four times daily or neonatal screening programs have been instituted, to allow
sis. JAMA 1991; 266: 1939. • oral amoxicillin 500 mg three times daily for early intervention.
 Antibacterials 167
The reduced morbidity and improved survival in patients macrolides in cystic fibrosis found evidence of a small but CFTR gene sequence into cells of affected tissue. Most ef-
with cystic fibrosis are largely due to the management of significant improvement in respiratory function at 6 fort has been directed at gene delivery to the lungs using
pulmonary disease with antibacterials and physiotherapy months with azithromycin compared with placebo; the adenovirus vectors or liposomes, but results have been
and to nutritional management. Several reviews have dis- role of other macrolides was unclear. A small anti-inflam- variable.50-53 Difficulties encountered include inefficient
cussed both established and experimental therapy.5-9 De- matory benefit has also been reported from treatment with gene transfer, immunity to viral vectors, and a systemic in-
spite the successes, the evidence base for some procedures high-dose oral ibuprofen,24 and this is used in some cen- flammatory reaction provoked by plasmid DNA.4 For a
is scanty,9 and there may be variations in management be- tres, particularly in the USA.9 However, there are some discussion of the general principles of gene therapy, see
tween centres. However, the cornerstones of current man- concerns about the potential for adverse effects; it has been p.2310.
agement are:8,9 recommended that if used, such therapy be stopped in pa- 1. Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 1997;
tients who require intravenous aminoglycosides, and 336: 487–91.
• mechanical airway clearance, with the use of adjuncts 2. Wallis C. Diagnosing cystic fibrosis: blood, sweat, and tears.
such as dornase alfa and hypertonic saline should be avoided in those with gastrointestinal risk fac- Arch Dis Child 1997; 76: 85–91.
• prevention or eradication of pulmonary infections in tors.24 There is no evidence supporting a role for cortico- 3. Rosenstein BJ, et al. The diagnosis of cystic fibrosis: a consen-
early disease steroid therapy,25,26 except in the management of patients sus statement. J Pediatr 1998; 132: 589–95.
4. Geddes DM, Alton EWFW. The CF gene: 10 years on. Thorax
who develop allergic bronchopulmonary aspergillosis.9 1999; 54: 1052–3.
• suppression of bacterial load through antibacterial treat-
Aggressive management of exacerbations with appro- 5. Doull IJM. Recent advances in cystic fibrosis. Arch Dis Child
ment of chronic infection in more advanced disease 2001; 85: 62–6.
priate antibacterials is crucial.8,9,27,28 Treatment should be 6. Tonelli MR, Aitken ML. New and emerging therapies for pul-
• use of ibuprofen or azithromycin to control lung inflam-
based on recent culture results, but there appears to be no monary complications of cystic fibrosis. Drugs 2001; 61:
mation 1379–85.
additional value in combination antibacterial sensitivity
• aggressive antibacterial treatment of pulmonary exacer- testing.29 In patients with Ps. aeruginosa infection a com- 7. Ratjen F, Döring G. Cystic fibrosis. Lancet 2003; 361: 681–9.
bations 8. Boyle MP. Adult cystic fibrosis. JAMA 2007; 298: 1787–93.
bination of intravenous antibacterials, typically an 9. Davies JC, et al. Cystic fibrosis. BMJ 2007; 335: 1255–9.
• nutritional support to ensure an adequate intake of calo- aminoglycoside such as tobramycin and a beta-lactam 10. Jones AP, et al. Recombinant human deoxyribonuclease for
ries and salt, with supplementation of pancreatic en- cystic fibrosis. Available in The Cochrane Database of System-
with antipseudomonal activity such as ceftazidime, is fa- atic Reviews; Issue 3. Chichester: John Wiley; 2003 (accessed
zymes and the fat-soluble vitamins A, D, E, and K voured.27,28,30 Once-daily dosing with the aminoglycoside 16/05/05).
• maintaining regular physical activity is as effective as giving it in divided doses, and may be 11. Quan JM, et al. A two-year randomized, placebo-controlled trial
of dornase alfa in young patients with cystic fibrosis with mild
Airway clearance by manual chest percussion and me- associated with less nephrotoxicity in children.31 High lung function abnormalities. J Pediatr 2001; 139: 813–20.
chanical techniques including chest-wall or airway oscilla- doses are necessary because of the poor penetration of 12. Duijvestijn YCM, Brand PLP. Systematic review of N-acetyl-
tion helps to loosen secretions and aid their removal. Dor- these antipseudomonal antibacterials into the site of infec- cysteine in cystic fibrosis. Acta Paediatr 1999; 88: 38–41.
tion and their increased renal clearance in patients with 13. McCaffery K, et al. Systematic review of antistaphylococcal an-
nase alfa10 is given by aerosol inhalation and reduces the tibiotic therapy in cystic fibrosis. Thorax 1999; 54: 380–3.
viscosity of the sputum by breaking down the large quan- cystic fibrosis.32,33 Treatment is generally given for 2 to 3 14. Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis.
tities of DNA released by degenerating inflammatory weeks although there is no good evidence to support a par- Available in The Cochrane Database of Systematic Reviews; Is-
sue 3. Chichester: John Wiley; 2003 (accessed 16/05/05).
cells. The use of dornase alfa has been associated with ticular length of therapy.34 Intermittent elective intrave- 15. Stutman HR, et al. Antibiotic prophylaxis in infants and young
some improvement in lung function and it might be a use- nous therapy has become more practical with the develop- children with cystic fibrosis: a randomized controlled trial. J
ful adjunct to bronchial drainage, although it is unclear ment of regimens that enable patients to be treated at Pediatr 2002; 140: 299–305.
home.30,35 16. Elborn JS. Treatment of Staphylococcus aureus in cystic fibro-
whether it prevents the development of progressive lung sis. Thorax 1999; 54: 377–8.
damage. However, a randomised, multicentre, placebo- Infection with B. cepacia complex is difficult to treat be- 17. Conway SP. Evidence for using nebulised antibiotics in cystic
controlled study in children showed that dornase alfa fibrosis. Arch Dis Child 1999; 80: 307–9.
cause the majority of antipseudomonal antibacterials are 18. Campbell PW, Saiman L. Use of aerosolized antibiotics in pa-
maintained lung function and reduced the risk of exacerba- not effective. Co-trimoxazole has been suggested36 and tients with cystic fibrosis. Chest 1999; 116: 775–88.
tions over a period of 96 weeks.11 Mucolytics such as acet- can be given orally;28 meropenem and ceftazidime have 19. Beringer P. The clinical use of colistin in patients with cystic
ylcysteine are generally not considered to be effective in some in-vitro activity, and temocillin has been tried.28 Oth- fibrosis. Curr Opin Pulm Med 2001; 7: 434–40.
20. Ryan G, et al. Nebulised anti-pseudomonal antibiotics for cystic
cystic fibrosis.12 Inhalation of hypertonic saline has, how- er problems may include meticillin-resistant Staph. aureus fibrosis. Available in The Cochrane Database of Systematic Re-
ever, been shown to be of benefit (see p.1687) and has be- infections; intravenous teicoplanin has been used, as have views; Issue 3. Chichester: John Wiley; 2003 (accessed
come part of management in many centres.8,9 The time re- oral doxycycline or linezolid where sensitivity patterns 25/06/08).
21. Remmington T, et al. Oral anti-pseudomonal antibiotics for
quired for such therapies and their associated monitoring permit.28 The possibility of fungal or viral infections cystic fibrosis. Available in The Cochrane Database of System-
may prove challenging to patients and their families.8 should also be considered.28 atic Reviews; Issue 3. Chichester: John Wiley; 2007 (accessed
25/06/08).
In young patients with early disease, prevention or erad- Nutritional management of cystic fibrosis should ensure 22. Giamarellos-Bourboulis EJ. Macrolides beyond the convention-
ication of infection for as long as possible is a reasonable adequate calorie intake from a balanced diet in order to al antimicrobials: a class of potent immunomodulators. Int J An-
aim, in order to maintain good lung function.9 Staphylo- timicrob Agents 2008; 31: 12–20.
counteract malabsorption due to pancreatic insufficiency 23. Southern KW, et al. Macrolide antibiotics for cystic fibrosis.
coccal infections commonly develop during the first dec- and the increased metabolic requirements of patients with Available in the Cochrane Database of Systematic Reviews; Is-
ade of life, and some clinicians start antistaphylococcal an- cystic fibrosis.37,38 Supplements of the fat-soluble vita- sue 2. Chichester: John Wiley; 2004 (accessed 02/03/07).
tibacterials on diagnosis of cystic fibrosis. Others wait mins A, D, and E, and sometimes vitamin K, may be nec- 24. Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory
drug therapy for cystic fibrosis. Available in The Cochrane Da-
until the first clinical infection occurs before starting treat- essary. Investigation of bone mineral density39 and direct tabase of Systematic Reviews; Issue 4. Chichester: John Wiley;
ment. Once started, antistaphylococcal therapy is contin- assessment of vitamin status40 suggest that current supple- 2007 (accessed 25/06/08).
ued indefinitely in some centres, while others only treat ments may be inadequate. Pancreatic enzymes, as pancre- 25. Cheng K, et al. Oral steroids for cystic fibrosis. Available in The
Cochrane Database of Systematic Reviews; Issue 4. Chichester:
when symptomatic exacerbations or positive sputum cul- atin or pancrelipase, are taken before or with each meal or John Wiley; 1999 (accessed 16/05/05).
tures occur. Systematic reviews confirmed that antistaphy- snack.41 26. Balfour-Lynn I, et al. Inhaled corticosteroids for cystic fibrosis.
lococcal treatment is effective and also concluded that Available in The Cochrane Database of Systematic Reviews; Is-
Many other interventions have been tried.42,43 sue 1. Chichester: John Wiley; 2000 (accessed 16/05/05).
prophylaxis is likely to be beneficial in young children 27. Ferkol T, et al. Cystic fibrosis pulmonary exacerbations. J Pedi-
with cystic fibrosis.13,14 In the UK, flucloxacillin or co- Bronchodilators including both beta agonists and antimus- atr 2006; 148: 259–64.
amoxiclav are commonly given.9 It is unclear whether in- carinics may be useful in selected patients although there 28. Smyth A, Elborn JS. Exacerbations in cystic fibrosis: 3. Man-
termittent or continuous therapy produces the best clinical are few meaningful clinical trial results.44 A therapeutic agement. Thorax 2008; 63: 180–4.
trial is often justified in individual patients since it is diffi- 29. Aaron SD, et al. Combination antibiotic susceptibility testing to
outcome. Other potential disadvantages to prophylaxis are treat exacerbations of cystic fibrosis associated with multiresist-
the possible early acquisition of Ps. aeruginosa infection15 cult to predict which patients will respond.42 While use by ant bacteria: a randomised, double-blind, controlled clinical tri-
nebuliser is regarded as most effective, inhalers may be al. Lancet 2005; 366: 463–71.
(this seems to be a risk mainly if broad spectrum cepha- 30. Banerjee D, Stableforth D. The treatment of respiratory Pseu-
losporins are given) and an increased incidence of drug- more practical where compatibility with other nebulised domonas infection in cystic fibrosis: what drug and which way?
resistant staphylococci with continuous therapy.16 drugs could be a problem.43 Alpha1-proteinase inhibitor, Drugs 2000; 60: 1053–64.
the main inhibitor of neutrophil elastase in the lung has 31. Smyth AR, Tan KH. Once-daily versus multiple-daily dosing
Management of chronic infection is aimed at control of also been investigated45 as has pentoxifylline,46 a drug with intravenous aminoglycosides for cystic fibrosis. Available
bacterial load,9 since permanent eradication is impossible. with anticytokine activity.
in The Cochrane Database of Systematic Reviews; Issue 3.
Chichester: John Wiley; 2006 (accessed 25/06/08).
Selection of an antibacterial must be individualised, and 32. Rey E, et al. Drug disposition in cystic fibrosis. Clin Pharma-
will depend on the infecting organisms,9 and local pre- Experimental treatment aimed at modifying the pulmo- cokinet 1998; 35: 313–29.
scribing policies and availability. Long-term intermittent nary disease process has also included ion transport thera- 33. Touw DJ, et al. Pharmacokinetic optimisation of antibacterial
py. This involves the use of aerosolised drugs that either treatment in patients with cystic fibrosis: current practice and
treatment with inhaled antibacterials, particularly to- suggestions for future directions. Clin Pharmacokinet 1998; 35:
bramycin, is favoured;8,9,17,18 other nebulised antibacteri- inhibit sodium ion absorption across airway epithelia (for 437–59.
als that may be of benefit include aztreonam and colis- example the sodium channel blocker amiloride) or induce 34. Fernandes B, et al. Duration of intravenous antibiotic therapy in
chloride ion secretion. However, nebulised amiloride was people with cystic fibrosis. Available in The Cochrane Database
tin.8,19 A systematic review confirmed that inhaled of Systematic Reviews; Issue 2. Chichester: John Wiley; 2008
antipseudomonal antibacterials improved lung function not found to be a useful adjunct in patients on optimal (accessed 25/06/08).
and reduced the frequency of exacerbations.20 Although treatment.47 35. Wolter JM, et al. Home intravenous therapy in cystic fibrosis: a
prospective randomized trial examining clinical, quality of life
there is some evidence of an increase in resistance with In patients with severe lung disease, oxygen therapy may and cost aspects. Eur Respir J 1997; 10: 896–900.
such treatment,20 it is claimed to be less frequent than give some relief of symptoms but its effect on mortality 36. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
feared.8 In contrast, oral antipseudomonal therapy has not and morbidity is uncertain.48 At present the only available book of antimicrobial therapy. 18th ed. New Rochelle NY: The
Medical Letter, 2008: 67.
been conclusively shown to be of benefit in chronic infec- treatment for patients with end stage pulmonary disease is 37. Bowler IM, et al. Resting energy expenditure and substrate ox-
tion,21 and is generally avoided because of fears of resist- lung transplantation. Although individuals with cystic fi- idation rates in cystic fibrosis. Arch Dis Child 1993; 68: 754–9.
ance.8 brosis do as well as those referred for transplantation with 38. Green MR, et al. Nutritional management of the infant with
cystic fibrosis. Arch Dis Child 1995; 72: 452–6.
The macrolide azithromycin is, however, used orally in other lung diseases, the 5-year survival rate after the pro- 39. Haworth CS, et al. Low bone mineral density in adults with
chronic infection, but may be acting as an immunomodu- cedure is reported to be only 50%.8 cystic fibrosis. Thorax 1999; 54: 961–7.
40. Feranchak AP, et al. Prospective, long-term study of fat-soluble
lator to reduce inflammation rather than specifically as Somatic gene therapy represents the nearest approach to vitamin status in children with cystic fibrosis identified by new-
an antibacterial.8,9,22 A systematic review23 on the use of a cure for cystic fibrosis.49 It aims to introduce the normal born screen. J Pediatr 1999; 135: 601–10.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
168 Antibacterials
41. Stallings VA, et al. Clinical Practice Guidelines on Growth and fied was Sennetsu fever, a disease found in Japan and Ma- 9. Krause PJ, et al. Successful treatment of human granulocytic
Nutrition Subcommittee. Ad Hoc Working Group. Evidence- ehrlichiosis in children using rifampin. Abstract: Pediatrics
based practice recommendations for nutrition-related manage- laysia, and which is caused by N. sennetsu (E. sennetsu). 2003; 112: 667. Full version: http://www.pediatrics.org/
ment of children and adults with cystic fibrosis and pancreatic Subsequently Anaplasma phagocytophilum (E. phagocy- cgi/content/full/112/3/e252 (accessed 09/10/06)
insufficiency: results of a systematic review. J Am Diet Assoc tophila), E. chaffeensis, E. ewingii, and possibly E. canis 10. Klein MB, et al. Antibiotic susceptibility of the newly cultivat-
2008; 108: 832–9. ed agent of human granulocytic ehrlichiosis: promising activity
42. Conway SP, Watson A. Nebulised bronchodilators, corticoster- have emerged as tick-borne human pathogens. of quinolones and rifamycins. Antimicrob Agents Chemother
oids, and rhDNase in adult patients with cystic fibrosis. Thorax E. chaffeensis mainly infects mononuclear cells and in hu- 1997; 41: 76–9.
1997; 52 (suppl 2): S64–8.
43. Spencer DA. Nebulised bronchodilators, antibiotics and rhD- mans the resulting disease is commonly called human
Nase for children with cystic fibrosis. Thorax 1997; 52 (suppl monocytic (or monocytotropic) ehrlichiosis (HME) Endocarditis
2): S89–S91. whereas A. phagocytophilum mainly infects granulocytes
44. Halfhide C, et al. Inhaled bronchodilators for cystic fibrosis. Infective endocarditis is an infection of the endocardium
Available in The Cochrane Database of Systematic Reviews; Is- and in humans produces human granulocytic (or granulo- after invasion of the bloodstream by bacteria or fungi, and
sue 4. Chichester: John Wiley; 2005 (accessed 25/06/08). cytotropic) ehrlichiosis (HGE), now also known as human particularly affects the heart valves. Infection has tradi-
45. McElvaney NG, et al. Aerosol α-1-antitrypsin treatment for granulocytic anaplasmosis (HGA). E. ewingii and E. canis
cystic fibrosis. Lancet 1991; 337: 392–4. tionally been classified as acute or subacute; however,
46. Aronoff SC, et al. Effects of pentoxifylline on sputum neu- mainly infect granulocytes and mononuclear cells respec- changes in the clinical spectrum of infection have meant
trophil elastase and pulmonary function in patients with cystic tively. that some now prefer to classify it into the categories:1
fibrosis: preliminary observations. J Pediatr 1994; 125: 992–7.
47. Burrows E, et al. Sodium channel blockers for cystic fibrosis. Some patients with HGA may also be co-infected with • native-valve endocarditis (often associated with con-
Available in The Cochrane Database of Systematic Reviews; Is- Borrelia burgdorferi, the cause of Lyme disease, and/or genital or chronic rheumatic heart disease, and classical-
sue 3. Chichester: John Wiley; 2006 (accessed 25/06/08). Babesia microti, the cause of babesiosis, as they are all
48. Mallory GB, et al. Oxygen therapy for cystic fibrosis. Available ly due to streptococci although cases due to staphylo-
in The Cochrane Database of Systematic Reviews; Issue 4. transmitted by tick bites from the same Ixodes spp. For de- coccal infection are increasingly frequent)
Chichester: John Wiley; 2005 (accessed 25/06/08). tails on the treatment of patients with HGA co-infected • prosthetic valve endocarditis (which may occur early,
49. Jaffé A, et al. Prospects for gene therapy in cystic fibrosis. Arch
Dis Child 1999; 80: 286–9. with Lyme disease, see p.177. within 60 days of surgery, which is often due to staphy-
50. Colledge WH, Evans MJ. Cystic fibrosis gene therapy. Br Med Human ehrlichiosis is characterised by fever, headache, lococci, or late, in which case it is often due to strepto-
Bull 1995; 51: 82–90.
51. Coutelle C. Gene therapy approaches for cystic fibrosis. Biolog- myalgia, and malaise. Laboratory findings include leuco- cocci or more exotic organisms such as the HACEK
icals 1995; 23: 21–5. penia, thrombocytopenia, and elevated liver enzymes.1,2 group)
52. Southern KW. Gene therapy for cystic fibrosis: current issues. Symptoms more commonly seen in patients with HME are
Br J Hosp Med 1996; 55: 495–9. • endocarditis in intravenous drug users (usually associat-
53. Flotte TR, Laube BL. Gene therapy in cystic fibrosis. Chest gastrointestinal disturbances, cough, confusion, and skin ed with infection by skin pathogens, especially Staphy-
2001; 120: 124S–131S. rash. HME is a relatively severe infection and patients may lococcus aureus)
require hospitalisation for complications such as acute res- • nosocomial endocarditis (related to catheter implanta-
Diarrhoea, infective piratory distress, coagulopathy, hepatitis, hepatic failure, tion or other invasive medical or surgical procedures; it
See Gastro-enteritis, p.171. meningoencephalitis, acute renal failure, and shock. Ful- is usually due to staphylococci or enterococci and has a
minant infections may give rise to other opportunistic in- high mortality rate). An increasing incidence is also
fections, particularly in immunocompromised patients. seen in patients undergoing haemodialysis
Diphtheria Fatalities have been reported in 2 to 3% of patients with
Diphtheria is caused by infection, usually of the upper res- HME. Clinical symptoms of infections with E. ewingii or Treatment of infective endocarditis is essential, as infec-
piratory tract or the skin, with the Gram-positive aerobe A. phagocytophilum are generally similar to those of E. tion can result in heart failure, embolisation and infarction
Corynebacterium diphtheriae. It occurs worldwide and, chaffeensis3,4 although usually less severe. Cough, confu- of major organs, and death. Diagnosis is often difficult as
despite the effectiveness of immunisation (see Diphtheria sion, and skin rash have not been seen with infections many of the symptoms (which include fever, malaise,
Vaccines, p.2209), is still common in parts of the world, caused by E. ewingii and most cases have been diagnosed headache, petechiae, and splinter haemorrhages under the
including the tropics. Although the risk to travellers is said in immunocompromised patients; no deaths have been re- nails) are nonspecific. A set of diagnostic criteria known as
to be low, diphtheria should be considered in patients re- ported. HGA is generally a mild, self-limiting disease, but the Duke criteria have been developed, and some modifi-
turning from endemic areas with a sore throat. may be severe in about 5 to 7% of patients and reported cations subsequently proposed.2 The Duke criteria identify
The most serious manifestations of infection are due to exo- fatalities are less than 1%. Most severe cases have been endocarditis primarily on the basis of microbiological data
toxin produced by toxigenic strains and thus treatment is diagnosed in immunocompromised patients. Skin rash, (blood culture of the infecting organism) and anatomical
primarily with diphtheria antitoxin. Erythromycin or ben- gastrointestinal and respiratory disturbances, and CNS in- lesions of the valves (identified by echocardiography or
zylpenicillin are also given to eliminate C. diphtheriae, volvement are less frequent with HGA.1 the development of new valvular regurgitation); minor cri-
thereby terminating toxin production and preventing the teria such as development of fever, or presence of predis-
Prompt treatment is recommended due to the potential for posing conditions such as heart defects or intravenous drug
spread of infection to contacts. Close contacts of primary serious complications. Treatment for all infections is with
cases of diphtheria may be given a 7-day prophylactic use, are also considered.2
a tetracycline, preferably doxycycline, given for 7 to 10
course of erythromycin orally or a single intramuscular Virtually any organism can cause endocarditis but strepto-
days or for at least 3 days after the patient has become afeb-
dose of benzylpenicillin,1 in addition to boosters or prima- cocci, enterococci, and staphylococci continue to be major
rile. Chloramphenicol has been used as an alternative for
ry immunisation with diphtheria vaccine. Non-toxigenic culprits.
HME, although its efficacy is controversial and it should
C. diphtheriae is the most common isolate in clinical cas- not be considered as a first-line treatment.1,5 It is also not • Among the commonest causes are the alpha-haemolytic
es in the UK1,2 and generally causes a less severe form of effective against A. phagocytophilum in vitro. Despite the streptococci originating mainly from the mouth and
the disease; it does, however, have the potential to cause known adverse effects of doxycycline in children, the throat; they have been called viridans streptococci or
invasive disease in some patients.3 American Academy of Pediatrics6 and the Infectious Dis- even ‘Streptococcus viridans’ (although this is not a true
Asymptomatic carriers may harbour non-toxigenic strains eases Society of America (IDSA)7 state that a shortened species) and include Str. mitis, Str. mutans, Str. oralis, Str.
of C. diphtheriae that can be converted to toxigenic strains. course may be given to those who are less than 8 years of salivarius, and Str. sanguis. Other streptococci originate
A single intramuscular injection of benzathine benzylpen- age who are severely ill and not co-infected with Lyme dis- in the gut and include Str. bovis.
icillin has been less effective than oral erythromycin, but ease; the dose is 4 mg/kg daily in two divided doses and • Also increasingly common is endocarditis due to sta-
may be used if compliance is uncertain;4 clindamycin for should be given for at least 3 days after the patient has be- phylococci such as Staphylococcus aureus, a common
7 days by mouth has also eliminated the carrier state,4 but come afebrile (a total of about 5 to 10 days). Successful cause in intravenous drug abusers, but endocarditis may
erythromycin remains the drug of choice. Bacteriological treatment of HGA with rifampicin has been reported in also be caused by coagulase-negative staphylococci,
follow-up should be carried out 2 weeks after completing pregnancy (gestational age of 10 to 36 weeks)8 and in 2 particularly Staph. lugdunensis. Prosthetic valve infec-
treatment to be certain C. diphtheriae has been eradicated children with non-life-threatening infection.9 The IDSA7 tion is often caused by Staph. epidermidis or other sta-
from carriers.5 recommends that patients with mild disease who cannot be phylococci.
1. Bonnet JM, Begg NT. Control of diphtheria: guidance for con- given a tetracycline may be given rifampicin 300 mg twice • Enterococci (faecal streptococci) originate in the gut
sultants in communicable disease control. Commun Dis Public daily for 7 to 10 days; children may be given 10 mg/kg and include Enterococcus faecalis and, to a lesser ex-
Health 1999; 2: 242–9.
2. Begg N, Balraj V. Diphtheria: are we ready for it? Arch Dis Child twice daily. Antibacterial susceptibility testing has sug- tent, E. faecium. Endocarditis due to any of these bacte-
1995; 73: 568–72. gested that rifamycins and fluoroquinolones are promising ria is commonly subacute or insidious.
3. Efstratiou A, et al. Non-toxigenic Corynebacterium diphtheriae alternatives in the treatment of HGA.10 Less common causes of endocarditis include:3
var gravis in England. Lancet 1993; 341: 1592–3.
4. McCloskey RV, et al. Treatment of diphtheria carriers: benza- 1. Paddock CD, Childs JE. Ehrlichia chaffeensis: a prototypical • Gram-negative bacteria such as the Enterobacteriaceae
thine penicillin, erythromycin, and clindamycin. Ann Intern Med emerging pathogen. Clin Microbiol Rev 2003; 16: 37–64.
2. Dumler JS, et al. Human granulocytic anaplasmosis and Ana-
and
1974; 81: 788–91.
5. Miller LW, et al. Diphtheria carriers and the effect of erythromy- plasma phagocytophilum. Emerg Infect Dis 2005; 11: 1828–34. • Pseudomonas spp.
cin therapy. Antimicrob Agents Chemother 1974; 6: 166–9. 3. Blanco JR, Oteo JA. Human granulocytic ehrlichiosis in Eu- • the HACEK group of slow-growing organisms (Hae-
rope. Clin Microbiol Infect 2002; 8: 763–72.
4. Buller RS, et al. Ehrlichia ewingii, a newly recognized agent of mophilus, Actinobacillus, Cardiobacterium, Eikenella,
Ear infections human ehrlichiosis. N Engl J Med 1999; 341: 148–55. Kingella)
See Otitis Externa, and Otitis Media, p.182. 5. Schaffner W, Standaert SM. Ehrlichiosis—in pursuit of an • the rickettsia Coxiella burnetii (the cause of Q fever,
emerging infection. N Engl J Med 1996; 334: 262–3.
6. Pickering L, et al. eds. Red Book: 2006 Report of the Committee p.188)
on Infectious Diseases. 27th ed. Elk Grove Village, IL: Ameri- • Bartonella spp. (also formerly classified as rickettsia)
Ehrlichiosis can Academy of Pediatrics, 2006.
Ehrlichioses are a group of diseases produced by infection 7. Wormser GP, et al. The clinical assessment, treatment, and pre- • fungi such as Candida and Aspergillus (see p.519).
with rickettsia-like bacteria of the family Anaplasmatace- vention of Lyme disease, human granulocytic anaplasmosis, and Guidelines for the treatment and prophylaxis of endocardi-
babesiosis: clinical practice guidelines by the Infectious Diseas-
ae, a family that contains the genera Anaplasma, Ehrli- es Society of America. Clin Infect Dis 2006; 43: 1089–1134. tis have been issued by bodies in many countries. Al-
chia, Neorickettsia, and Wolbachia. At one time such or- Also available at: http://www.journals.uchicago.edu/ though some common principles can be identified, recom-
ganisms were considered to be only animal pathogens but doi/pdf/10.1086/508667 (accessed 18/08/08) mendations must be localised because of differences in
8. Dhand A, et al. Human granulocytic anaplasmosis during preg-
it is now recognised that humans may also become infect- nancy: case series and literature review. Clin Infect Dis 2007; patterns of infection and drug resistance, variations in the
ed. One of the earliest human forms of ehrlichiosis identi- 45: 589–93. availability of antibacterials and local policies for their use,
 Antibacterials 169
and differences in medical practice. Countries also vary in • Staphylococcal endocarditis. The treatment of staphy- ciprofloxacin for 4 weeks, by mouth or intravenously,
the degree to which such guidelines are accepted in prac- lococcal endocarditis is based on the use of an isoxa- may also be effective.8
tice. zolyl penicillin or a glycopeptide. In contrast to strepto- • Endocarditis due to other organisms. Treatment of
Endocarditis treatment. coccal or enterococcal endocarditis, the benefits of endocarditis due to other organisms depends greatly on
Treatment of endocarditis relies on prompt identification adding an aminoglycoside are uncertain, and guidelines the organism and its susceptibility; early surgery is often
of the infecting organisms and their sensitivity to antibac- differ in whether they recommend this. Combination required. For endocarditis due to Pseudomonas spp. a
terials. Three sets of blood cultures, each from a separate therapy is recommended where prosthetic valves or oth- combination of an antipseudomonal beta-lactam with
venepuncture, should be taken before antimicrobial treat- er intracardiac prostheses are present. tobramycin has been suggested.5,7 Endocarditis associ-
ment is started; MICs for the causative organism should be For meticillin sensitive staphylococci, typically cloxa- ated with the intracellular pathogen Coxiella burnetii re-
measured. As already mentioned, guidelines vary,4-8 but in cillin, dicloxacillin, or flucloxacillin is given in a dose of quires very prolonged therapy with doxycycline,6,7 in
general: 2 g every 4 to 6 hours for at least 4 weeks.4-8 Some combination with rifampicin7 or a fluoroquinolone such
• a microbicidal antibacterial, or combination of antibac- guidelines continue to recommend addition of gen- as ciprofloxacin.6 Regimens suggested for Bartonella
terials, should be used for treatment; many regimens are tamicin for the first 3 to 5 days of therapy.7,8 Patients endocarditis have included a penicillin or ceftriaxone in
based on a beta-lactam or glycopeptide plus an with right-sided endocarditis due to intravenous drug combination with gentamicin, or doxycycline plus gen-
aminoglycoside abuse may respond to shorter courses of 2 weeks of tamicin.6,8 For other potential causes of culture-negative
combination therapy with an isoxazolyl penicillin plus endocarditis, empirical treatment with a penicillin or
• treatment should be given at high doses, and by the in-
gentamicin.4,6-8 vancomycin plus gentamicin, sometimes in combina-
travenous route tion with a third antibiotic such as rifampicin or cipro-
• except in the most sensitive infections, treatment should For staphylococci resistant to meticillin/oxacillin, van-
comycin may be given alone for 6 weeks,4,7,8 or with floxacin, has been suggested.4,7,8
be given for at least 4 weeks (or at least 6 weeks if the Endocarditis prophylaxis.
patient has prosthetic valves or other prosthetic material rifampicin or perhaps gentamicin or sodium fusidate
implanted in the heart) (depending on sensitivity) for at least 4 weeks.5-8 Such Because of the potentially severe consequences of endo-
combinations may also be appropriate in patients with carditis, prophylaxis is widely practised in patients consid-
• ideally, it is preferable to wait for the results of blood penicillin allergy. Teicoplanin should not be used as the ered to be at increased risk when they are exposed to pro-
culture before starting therapy; however, empirical reported incidence of treatment failure is unacceptably cedures likely to produce bacteraemia, although much of
treatment is given to patients presenting with acute or high.6 the evidence to support the practice is circumstantial and
severe disease
For staphylococcal endocarditis in the presence of int- the benefits and risks therefore hard to calculate. Patients
• associated complications such as heart failure should be who have been considered to be at risk of developing en-
racardiac prostheses either an isoxazolyl penicillin or
managed appropriately; management may include re- docarditis include those with:4,7,9
vancomycin may be used with rifampicin or gentamicin
ferral for early surgical intervention
or both; an indicative regimen might be intravenous • acquired valvular heart disease
If empirical treatment is to be given until the laboratory doses of 2 g of the penicillin every 4 to 6 hours, or 1 g of
results are known, then it is most likely to be with gen- • congenital heart disease, including septal defects, tetral-
vancomycin every 12 hours, plus rifampicin 300 mg by ogy of Fallot, or aortic stenosis
tamicin plus benzylpenicillin.4-6 An isoxazolyl penicillin mouth every 8 hours, both given for 6 to 8 weeks, plus
(cloxacillin, dicloxacillin, flucloxacillin, or oxacillin) may • hypertrophic cardiomyopathy
gentamicin 1 mg/kg intravenously every 8 hours for the
be added, or used instead of benzylpenicillin, in more se- first 2 weeks.6-8 Gentamicin may be given for the entire • mitral valve prolapse with valvular regurgitation
vere or acute presentations. Vancomycin is likely to be the period of treatment if the infection is due to more recal- • prosthetic valves or shunts
antibacterial of choice in penicillin-allergic patients requir- citrant strains of meticillin-resistant Staph. aureus or co- • a history of endocarditis
ing empirical treatment,5 and may be used empirically agulase-negative staphylococci.6
with an aminoglycoside in patients with prosthetic valves Traditionally, these groups have been subdivided into
or where penicillin resistance is suspected.4,6 (UK guide- • Enterococcal endocarditis. Treatment of enterococcal those at moderate and high risk, but some guidelines no
lines also add rifampicin in these situations.6) endocarditis is based on combinations of an aminogly- longer make such a distinction.
coside with another antibacterial, usually a beta lactam As for treatment, guidelines have been periodically issued
Once the causative organism and its antibiotic susceptibil- or a glycopeptide, depending on the sensitivity of the
ity have been identified, appropriate pathogen-directed to guide the selection of antibacterials for prophylaxis be-
isolated organism. fore various procedures in patients at risk.4,7,9-11 Proce-
therapy may be begun.
For gentamicin sensitive, penicillin sensitive enterococ- dures that have been thought likely to produce bacteraemia
• Streptococcal endocarditis. Streptococci vary in their
ci: intravenous bolus injections of ampicillin or amoxi- and therefore to require prophylactic treatment include any
susceptibility to penicillin, and guidelines generally di-
cillin 2 g (or benzylpenicillin 2.4 g) every 4 hours and dental intervention likely to cause bleeding, other oral or
vide regimens according to whether the organism is of
gentamicin 1 mg/kg every 8 or 12 hours, both given for upper-respiratory tract operations such as tonsillectomy,
low, intermediate, or high penicillin resistance, although
at least 4 weeks.4,6,8 certain gastrointestinal procedures such as sclerotherapy
at what MIC these categories are defined varies between
guidelines. If the patient is allergic to penicillin, or the isolate is for oesophageal varices or biliary-tract surgery, and some
penicillin resistant but gentamicin sensitive, then a com- urinary-tract surgery.4,7,9 Whether prophylaxis is truly
For uncomplicated cases of infection with the most pen- needed before dental procedures is a subject of controver-
icillin sensitive streptococci, benzylpenicillin may be bination of vancomycin or teicoplanin with gentamicin
may be given for at least 4 weeks.6-8 sy. US guidelines10 recommend antibacterial prophylaxis
used, with or without gentamicin.4-8 Typically, if used only for dental procedures that involve manipulation of
alone in native-valve infection it would be given for 4 For enterococci with high level gentamicin resistance, a gingival tissues or periapical region of teeth, or perforation
weeks, whereas the combination regimen is given only penicillin as above may be used with streptomycin of oral mucosa in patients considered to be at the highest
for 2 weeks.6-8 Indicative doses would be 1.2 to 2.4 g of 7.5 mg/kg twice daily (intramuscularly or intravenous- risk of developing adverse outcomes from endocarditis
benzylpenicillin every 4 hours, and gentamicin 1 mg/kg ly) for at least 4 weeks.6,8 If there is also penicillin resist- (such as those with a history of infective endocarditis, car-
every 8 hours. Ceftriaxone or vancomycin may be con- ance, or the patient is penicillin allergic, streptomycin as diac valve replacement surgery, or some patients with con-
sidered as an alternative,6 although these are more often above may be given with vancomycin or teicoplanin.6 If genital heart disease). US guidelines also recommend an-
given to treat less sensitive strains, or in patients unable streptomycin cannot be used then treatment should be tibacterial prophylaxis for high-risk patients for
to tolerate penicillin. given for at least 8 weeks.6 procedures on respiratory tract or infected skin, skin struc-
For streptococci less sensitive to penicillin benzylpeni- Endocarditis due to multiply resistant enterococci not tures, or musculoskeletal tissue, but do not recommend
cillin may be given as above but for 4 to 6 weeks,4,6,7 susceptible to penicillin, gentamicin, or vancomycin, is prophylaxis for genitourinary or gastrointestinal tract pro-
usually with gentamicin for at least the first 2 weeks. still infrequent and there seem to be no established reg- cedures. Similar recommendations were made in the UK
Alternatively, 4 weeks of treatment with ceftriaxone or imens; options may include the use of linezolid or quin- by the British Society for Antimicrobial Chemotherapy in
vancomycin may be considered.6-8 Typical doses are 2 g upristin/dalfopristin where available.6,8 A combination 20069 but subsequent guidelines issued by NICE11 and
daily of ceftriaxone as a single injection, or 30 mg/kg of of ampicillin with ceftriaxone or imipenem-cilastatin, adopted by the BNF essentially abolished the requirement
vancomycin daily (up to a usual maximum of 2 g daily), given for at least 8 weeks, has been suggested for multi- for standard antibacterial prophylaxis in any procedure.
in 2 divided doses. ply resistant E. faecalis infection in US guidelines.8 Antibacterial prophylaxis is aimed mainly at viridans
For penicillin resistant streptococci treatment is similar • HACEK endocarditis. The HACEK organisms are streptococci and HACEK organisms before dental, oral,
to that for enterococcal endocarditis.6,7 A combination slow and difficult to culture and treatment must often, respiratory, and oesophageal procedures, and at enterococ-
of vancomycin and gentamicin may be given for 4 to 6 therefore, be empirical. Traditionally, treatment for this ci, Strep. bovis, and the Enterobacteriaceae before gas-
weeks. Streptomycin is a possible alternative to gen- group of organisms was based on ampicillin and gen- trointestinal and genito-urinary procedures.7 Drugs should
tamicin for gentamicin resistant isolates.6 tamicin. However, because of the emergence of beta- be given in a regimen that assures adequate blood concen-
For streptococci in penicillin-allergic patients, vanco- lactamase producing strains, empirical treatment is now trations throughout the procedure. They are generally giv-
mycin for 4 to 6 weeks may be given; UK guidelines based on beta-lactamase-stable cephalosporins. en as a single dose before the procedure, sometimes re-
advise 4 weeks of treatment combined with gentamicin Preferred treatment for native-valve endocarditis due to peated about 6 hours later; the oral route is used if possible.
for the first 2 weeks.6 Teicoplanin, typically in doses of HACEK organisms is therefore with intramuscular or • A penicillin such as amoxicillin is the basis for prophy-
6 to 10 mg/kg daily (higher loading doses should be giv- intravenous ceftriaxone (usually in a dose of 2 g once lactic therapy, typically in a single dose of 2 to 3 g by
en initially to establish a suitable trough concentration) daily) for 4 weeks,4,6-8 although cefotaxime4 or other mouth or 1 to 2 g intravenously.4,7,9,10 For dental proce-
is a possible alternative to vancomycin.6 Some patients third-generation cephalosporin may be used instead. dures it may be replaced, in patients allergic to penicillin
may tolerate ceftriaxone.4 UK guidelines recommend addition of gentamicin for or who have received more than a single dose in the pre-
For patients with prosthetic valve endocarditis, a regi- the first 2 weeks of therapy.6 Alternatively, if the isolate vious month, by clindamycin 600 mg orally or 300 to
men similar to that for less sensitive streptococci is penicillin sensitive, ampicillin plus 2 weeks of gen- 600 mg intravenously, or by azithromycin 500 mg oral-
(above) has been suggested, given for at least 6 tamicin,6 or ampicillin-sulbactam8 have been suggested. ly. All oral drugs should be given 1 hour before the pro-
weeks.6-8 US guidelines consider that a fluoroquinolone such as cedure.4,7,9,10
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
170 Antibacterials
• For gastrointestinal or genito-urinary procedures the isms may also be responsible including genital mycoplas- urinary-tract instrumentation or surgery, systemic disease,
penicillin is usually combined with a single dose of gen- mas and, to a lesser extent, facultative and anaerobic or immunosuppression.
tamicin 1.5 or 2 mg/kg intravenously or intramuscularly bacteria.4 Guidelines produced by WHO,1 by an expert group in the
before the procedure; a second dose of amoxicillin (typ- In the USA, standard empirical therapy for postpartum en- UK,2 and by the CDC in the USA3 for the treatment of
ically half the initial dose) may be given after 6 hours. In dometritis has been a short course of intravenous antibac- epididymitis are as follows, although recommendations
patients allergic to penicillin, or who have received terials, often clindamycin with gentamicin, given until the may need to be localised because of differences in patterns
more than a single dose of penicillin in the previous patient has been afebrile and asymptomatic for 24 to 48 of infection and drug resistance:
month, amoxicillin may be substituted with an infusion hours and sometimes followed by a course of oral treat- • WHO:
of 1 g of vancomycin over 1 to 2 hours before the pro- ment, often amoxicillin. A systematic review5 has con- for chlamydial epididymitis:
cedure, or injection of 400 mg of teicoplanin immedi- firmed the suitability of clindamycin with gentamicin and • oral doxycycline 100 mg twice daily for 7 days, or
ately beforehand.4,7,9 indicated that oral therapy is not necessary after successful • a single dose of oral azithromycin 1 g
• For nasal packing and intubation flucloxacillin 1 g in- intravenous therapy. It may, however, be recommended in alternatives, given for 7 days, are:
travenously is given; in penicillin allergic patients clin- patients with staphylococcal bacteraemia.2 • oral amoxicillin 500 mg three times daily
damycin 600 mg intravenously may be used.9 1. Smaill F, Hofmeyr GJ. Antibiotic prophylaxis for cesarean sec- • oral erythromycin 500 mg four times daily
• For infected skin, skin structure, or musculoskeletal tis- tion. Available in The Cochrane Database of Systematic Re-
views; Issue 3. Chichester: John Wiley; 2002 (accessed • oral ofloxacin 300 mg twice daily
sue procedures a penicillin such as amoxicillin is usual- 16/05/05). • oral tetracycline 500 mg four times daily
ly given in a single oral or intravenous dose of 2 g, or a 2. American College of Obstetricians and Gynecologists. Antimi- Unless it can be excluded, patients should also be treated
cephalosporin such as cefalexin is given in a single oral crobial therapy for obstetric patients. Int J Gynecol Obstet 1998; concurrently for gonorrhoea (p.191).
dose of 2 g. Vancomycin or clindamycin may be given 61: 299–308.
3. Rosene K, et al. Polymicrobial early postpartum endometritis • UK:
to patients allergic to penicillin or who are known or with facultative and anaerobic bacteria, genital mycoplasmas, for probable chlamydial infections or infections with
suspected of having an infection caused by a meticillin- and Chlamydia trachomatis: treatment with piperacillin or cefox-
other non-gonococcal, non-enteric organisms:
resistant strain of staphylococcus.10 itin. J Infect Dis 1986; 153: 1028–37.
4. Hoyme UB, et al. Microbiology and treatment of late postpartum • oral doxycycline 100 mg twice daily for 10 to 14 days is rec-
1. Moreillon P, Que Y-A. Infective endocarditis. Lancet 2004; 363:
139–49. endometritis. Obstet Gynecol 1986; 68: 226–32. ommended
2. Li JS, et al. Proposed modifications to the Duke criteria for the 5. French LM, Smaill FM. Antibiotic regimens for endometritis af- for infections with enteric organisms:
diagnosis of infective endocarditis. Clin Infect Dis 2000; 30: ter delivery. Available in The Cochrane Database of Systematic
Reviews; Issue 4. Chichester: John Wiley; 2004 (accessed • oral ofloxacin 200 mg twice daily for 14 days, or
633–8.
3. Brouqui P, Raoult D. Endocarditis due to rare and fastidious 18/08/05). • oral ciprofloxacin 500 mg twice daily for 10 days
bacteria. Clin Microbiol Rev 2001; 14: 177–207. for disease most probably due to gonococcal infection:
4. Spicer J, et al. Therapeutic Guidelines: Antibiotic (12th ed.) • a single intramuscular dose of ceftriaxone 250 mg, or
Melbourne: Therapeutic Guidelines Ltd.; 2003. Enterococcal infections
5. Department of Health. Endocarditis, infective. In: Standard treat- • a single oral dose of ciprofloxacin 500 mg plus oral doxycy-
ment guidelines and essential drugs list for South Africa, adult hos-
Enterococcal infections are causing increasing concern, cline 100 mg twice daily for 10 to 14 days
pital level, 1998 ed. Available at: http://www.doh.gov.za/docs/ particularly with the emergence of drug-resistant strains.1-6
factsheets/pharma/adult_hospital/edladult71-105.pdf (accessed Enterococci, principally Enterococcus faecalis (formerly in patients allergic to cephalosporins and/or tetracy-
7/03/06) Streptococcus faecalis) but also E. faecium and E. avium, clines infections from all causes may be treated with:
6. Elliott TSJ, et al. Guidelines for the antibiotic treatment of endocar- • oral ofloxacin 200 mg twice daily for 14 days
ditis in adults: report of the Working Party of the British Society for can cause infections including those of the biliary tract and
Antimicrobial Chemotherapy. J Antimicrob Chemother 2004; 54: urinary tract, endocarditis, and peritonitis. Since they are • USA: empirical treatment recommended:
971–81. Also available at: http://jac.oxfordjournals.org/cgi/ frequently present in the gut flora they are a common cause likely cause gonococcal or chlamydial infection:
reprint/54/6/971.pdf (accessed 16/03/06)
7. The Task Force on Infective Endocarditis of the European Society of nosocomial infections. Enterococci are resistant to ce- • a single intramuscular dose of ceftriaxone 250 mg plus oral
of Cardiology. Guidelines on prevention, diagnosis and treatment phalosporins, tetracyclines, macrolides, and chloramphen- doxycycline 100 mg twice daily for 10 days
of infective endocarditis. Executive summary. Eur Heart J 2004;
icol. The emergence of resistance to gentamicin, penicil- likely cause an enteric organism or in patients allergic to
25: 267–76. Full version: http://www.escardio.org/knowledge/
guidelines/Guidelines_Infective_Endocarditis.htm (accessed lins, and the glycopeptide antimicrobials vancomycin and cephalosporins and/or tetracyclines:
07/03/06) teicoplanin has compromised the previously standard • oral ofloxacin 300 mg twice daily for 10 days, or
8. Baddour LM, et al. American Heart Association. Infective en- • oral levofloxacin 500 mg once daily for 10 days
docarditis: diagnosis, antimicrobial therapy, and management of treatment for enterococcal infections of a penicillin or
complications: a statement for healthcare professionals from the glycopeptide with gentamicin. Further therapeutic options Sexual contacts should also be treated if epididymitis is
Committee on Rheumatic Fever, Endocarditis, and Kawasaki have more recently emerged with the development of lin- caused by a sexually transmitted pathogen.2,3
Disease, Council on Cardiovascular Disease in the Young, and
the Councils on Clinical Cardiology, Stroke, and Cardiovascular ezolid, daptomycin, tigecycline, and quinupristin/dalfo- Patients co-infected with HIV should receive the same
Surgery and Anesthesia, American Heart Association (endorsed pristin for the treatment of vancomycin-resistant entero- treatment as those who are HIV-negative.3
by the Infectious Diseases Society of America). Executive sum- coccal infections,7 although the latter is active against E. 1. WHO. Guidelines for the management of sexually transmitted
mary. Circulation 2005; 111: 3167–84. Correction. ibid.; 112: i n f e c t i o n s . G e n e v a: W HO , 2 0 0 3 . A l s o a v a i l a b l e a t :
2373. Full version: http://circ.ahajournals.org/cgi/reprint/111/ faecium but not against E. faecalis. There has, however, http://whqlibdoc.who.int/publications/2003/9241546263.pdf
23/e394.pdf (accessed 07/03/06) been a report of enterococcal resistance to linezolid.8 In (accessed 22/03/07)
9. Gould FK, et al. Guidelines for the prevention of endocarditis: general, there can be no recommendations for treatment at 2. Clinical Effectiveness Group (Association for Genitourinary Medi-
report of the Working Party of the British Society for Antimicro- cine and the Medical Society for the Study of Venereal Diseases –
bial Chemotherapy. J Antimicrob Chemother 2006; 57: present and the choice of antibacterial should be made ac-
now British Association for Sexual Health and HIV). 2001 National
1035–42. Also available at: http://jac.oxfordjournals.org/cgi/ cording to local patterns of resistance and antibacterial guideline for the management of epididymo-orchitis. Available at:
reprint/dkl121v1.pdf (accessed 06/07/06)
10. Wilson W, et al. Prevention of infective endocarditis: guidelines
sensitivity tests. The lack of effective antibacterials has http://www.bashh.org/documents/31/31.pdf (accessed 18/08/08)
from the American Heart Association: a guideline from the placed emphasis on measures to prevent the spread of van- 3. CDC. Sexually transmitted diseases treatment guidelines 2006.
MMWR 2006; 55(RR-11): 1–94. Also available at: http://
American Heart Association Rheumatic Fever, Endocarditis, comycin-resistant enterococci.9 www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 22/03/07)
and Kawasaki Disease Committee, Council on Cardiovascular
Disease in the Young, and the Council on Clinical Cardiology, 1. Landman D, Quale JM. Management of infections due to resist- Updated recommended treatment regimens for gonococcal in-
Council on Cardiovascular Surgery and Anesthesia, and the ant enterococci: a review of therapeutic options. J Antimicrob fections and associated conditions—United States, April 2007.
Quality of Care and Outcomes Research Interdisciplinary Chemother 1997; 40: 161–70. Available at: http://www.cdc.gov/std/treat ment/2006/
Working Group. Circulation 2007; 116: 1736–54. 2. Murray BE. Vancomycin-resistant enterococci. Am J Med 1997; GonUpdateApril2007.pdf (accessed 12/04/07)
11. NICE. Prophylaxis against infective endocarditis: antimicrobial 102: 284–93.
prophylaxis against infective endocarditis in adults and children 3. Antony SJ. Multidrug-resistant enterococci: the dawn of a new
undergoing interventional procedures (issued March 2008). era in resistant pathogens. J Natl Med Assoc 1998; 90: 537–40. Epiglottitis
Availabl e at: http:/ /www.nice.org.uk/niceme dia/pdf/ 4. Moellering RC. Vancomycin-resistant enterococci. Clin Infect In acute epiglottitis rapid swelling of the epiglottis and sur-
CG64NICEguidance.pdf (accessed 16/06/08) Dis 1998; 26: 1196–9.
5. Linden PK, Miller CB. Vancomycin-resistant enterococci: the
rounding soft tissues results in sudden airway obstruction
clinical effect of a common nosocomial pathogen. Diagn Micro- which can be fatal. It is often due to bacteraemic infection
Endometritis biol Infect Dis 1999; 33: 113–20. with Haemophilus influenzae type b (see p.174) and has
Endometritis (or endomyometritis) is a uterine infection 6. Murray BE. Vancomycin-resistant enterococcal infections. N occurred mainly in young children, although the incidence
that may be a part of pelvic inflammatory disease (p.184) Engl J Med 2000; 342: 710–21.
7. Zirakzadeh A, Patel R. Vancomycin-resistant enterococci: colo-
has decreased in this age group since the introduction of
or may be a postoperative complication of caesarean sec- nization, infection, detection, and treatment. Mayo Clin Proc Haemophilus influenzae vaccine.1 Acute epiglottitis also
tion. 2006; 81: 529–36. occurs in adults.1
Antibacterial prophylaxis may be given at caesarean sec- 8. Auckland C, et al. Linezolid-resistant enterococci: report of the Treatment and prophylaxis is similar to that for Haemo-
first isolates in the United Kingdom. J Antimicrob Chemother
tion after cord clamping to prevent postpartum endometri- 2002; 50: 743–6. philus influenzae meningitis (see under Meningitis,
tis as well as wound infection. While the use of antimicro- 9. Siegel JD, et al. Healthcare Infection Control Practices Advisory p.178). Immediate management includes the maintenance
bial prophylaxis in patients at high risk of infection is well Committee (HICPAC). Management of multidrug-resistant organ- of an adequate airway and the intravenous use of antibac-
established, prophylaxis in low-risk patients remains con- isms in healthcare settings, 2006. Available at: http://www.cdc.gov/
ncidod/dhqp/pdf/ar/MDROGuideline2006.pdf (accessed 05/08/08) terials active against H. influenzae type b. Chlorampheni-
troversial. A systematic literature review1 has shown col has been the drug of choice, but third-generation ce-
prophylaxis to be beneficial after both elective and non- phalosporins such as cefotaxime and ceftriaxone are
elective caesarean section, but USA surgical guidelines do Epididymitis increasingly used.2,3 Prophylaxis with rifampicin may be
not recommend routine prophylaxis in low-risk patients.2 Epididymitis is often associated with urethritis, and in given to index cases and contacts.
A penicillin or first-generation cephalosporin such as ce- young men (less than 35 years) occurs most commonly as 1. Frantz TD, et al. Acute epiglottitis in adults: analysis of 129 cas-
fazolin is often used.2 a complication of sexually transmitted infection with Neis- es. JAMA 1994; 272: 1358–60.
seria gonorrhoeae and Chlamydia trachomatis, but may 2. Sawyer SM, et al. Successful treatment of epiglottitis with two
Early postpartum endometritis has a polymicrobial aetiol- doses of ceftriaxone. Arch Dis Child 1994; 70: 129–32.
ogy. In one study the most common organisms isolated in- occur in homosexual males as a result of infection with en- 3. Pino Rivero V, et al. Epiglotitis aguda en adultos: nuestra expe-
cluded Gardnerella vaginalis, Peptococcus spp., Bacter- teric organisms, particularly Escherichia coli. riencia clínica en 30 casos. Acta Otorrinolaringol Esp 2007; 58:
263–5.
oides spp., Staphylococcus epidermidis, group B In men over 35 years and in children, epididymitis is not
streptococci, and Ureaplasma urealyticum.3 Chlamydia usually sexually transmitted but generally results from
trachomatis has been implicated more often in late post- bacteriuria secondary to urinary-tract infection with Pseu- Escherichia coli enteritis
partum endometritis, but a wide variety of micro-organ- domonas aeruginosa and other Gram-negative bacilli, See p.173.
 Antibacterials 171
Eye infections perfringens is the species most frequently responsible. Gas ‘Food poisoning’ is generally a self-limiting form of gas-
Conjunctivitis is a common superficial eye disorder and gangrene is usually associated with traumatic or surgical tro-enteritis, although serious outbreaks of foodborne ill-
may be caused by infection with bacteria, viruses, or, less wounds. The main treatment is surgical debridement of all ness have been associated with bacteria such as Salmonel-
often, fungi. Acute bacterial conjunctivitis is often caused necrotic muscle and large doses of benzylpenicillin. Alter- la enteritidis. Other common food-poisoning organisms
by staphylococci or streptococci in adults, and Haemophil- native antibacterials have included clindamycin, metroni- include Listeria monocytogenes, Campylobacter spp.,
us influenzae and Moraxella catarrhalis (Branhamella ca- dazole, imipenem, a tetracycline, or chloramphenicol. Hy- Yersinia enterocolitica, Vibrio parahaemolyticus, and E.
tarrhalis) in children. Other causes of bacterial conjuncti- perbaric oxygen is used as an adjunct to surgical coli. An enterotoxin is responsible for food poisoning as-
vitis include gonococci (see Gonorrhoea, p.191) and debridement. Gas-gangrene antitoxins are rarely used sociated with Staphylococcus aureus, Clostridium spp.,
Chlamydia trachomatis (see Trachoma, p.196). Neonatal nowadays. and Bacillus spp.8,9
chlamydial and gonococcal conjunctivitis are discussed Benzylpenicillin is also recommended as prophylaxis Travellers’ diarrhoea. Acute diarrhoea associated with
under Neonatal Conjunctivitis, p.180. Uncomplicated bac- against gas gangrene in patients undergoing high amputa- travel occurs worldwide. The most common bacterial
terial conjunctivitis may be self-limiting but empirical tions of lower limbs or after major trauma; metronidazole pathogen is enterotoxigenic E. coli, although enteroadher-
treatment with topical antibacterials is often given. In the is an alternative in patients allergic to penicillin. ent E. coli is also sometimes involved. Other bacteria in-
UK, topical chloramphenicol remains the treatment of clude Campylobacter jejuni, Salmonella and Shigella spp.,
choice despite concerns over the potential risk of aplastic Vibrio cholerae, and non-cholera vibrios such as V. para-
anaemia (see Ocular Use under Precautions of Chloram- Gastro-enteritis haemolyticus. Viruses and the protozoa Giardia intestina-
phenicol, p.240). Alternatives include gentamicin, to- Diarrhoea is a symptom of simple gastro-enteritis and of lis, Entamoeba histolytica, and Cryptosporidium may also
bramycin, erythromycin (especially when infection with most intestinal infections. It is a major problem in develop- be responsible. Recommendations for the management of
Gram-positive organisms is suspected), fluoroquinolones ing countries, but is common worldwide. Although viruses travellers’ diarrhoea are published by national and interna-
including ciprofloxacin and ofloxacin, framycetin, fusidic are often responsible, the severest forms of infectious diar- tional bodies including WHO, the Department of Health in
acid (especially for staphylococcal infections), and poly- rhoea are generally those due to bacteria. Common bacte- the UK, and the Centers for Disease Control in the USA.
myxin B in combination with bacitracin, trimethoprim, or rial pathogens include Campylobacter jejuni, Escherichia Clinical features depend on the pathogen responsible and
neomycin. coli, Salmonella enteritidis, Shigella spp., Vibrio cholerae, treatment varies according to severity and duration of diar-
Blepharitis is an infection of the lid margins. It usually and Yersinia enterocolitica. Intestinal protozoa also cause rhoea. Onset of diarrhoea is generally delayed with Gia-
presents as a chronic condition and may require prolonged diarrhoea and are important in AIDS-associated diarrhoea. rdia and Entamoeba because of the incubation period. Di-
treatment, typically involving local hygiene to remove en- For discussions of viral and protozoal gastro-enteritis and arrhoea is often mild and self-limiting and increased fluid
crustations and topical application of a broad-spectrum their treatment, see p.850 and p.824, respectively. intake or oral rehydration therapy is usually all that will be
antibacterial ointment. required. Symptomatic treatment with antimotility drugs
In acute diarrhoea (p.1694) of any aetiology the priority is such as loperamide may be of benefit in mild to moderate
Keratitis may be caused by infection of the cornea by bac- to maintain hydration by prevention or treatment of fluid
teria, fungi, viruses, or protozoa, usually after trauma to the diarrhoea. Bismuth salicylate may be used to reduce the
and electrolyte depletion, especially in infants and the eld- frequency of diarrhoea. Although antimicrobial therapy is
surface of the eye, including that due to contact lens wear erly. Acute, watery diarrhoea caused by non-invasive path-
(see Contact Lens Care, p.1622). Common bacterial path- not indicated in most cases of infective diarrhoea, empiri-
ogens is usually self-limiting and may be treated conserv- cal treatment with a fluoroquinolone has been effective for
ogens include staphylococci, streptococci, Pseudomonas atively. Inflammatory diarrhoea, predominantly caused by
spp., and Enterobacteriaceae. Bacterial keratitis is poten- moderate to severe attacks. Co-trimoxazole has also been
invasive pathogens and affecting the colon, often requires used, but its use is restricted by its toxicity and increasingly
tially sight-threatening and requires prompt aggressive treatment with antibacterials. Guidelines published in the
treatment with broad-spectrum antibacterials. It is custom- widespread bacterial resistance is of concern. When the in-
UK1 recommended that empirical treatment of acute diar- fecting bacteria are known, specific therapy may be neces-
ary to obtain material for sensitivity testing, but increas- rhoea with antibacterials should be reserved for patients
ingly, empirical treatment is then begun without delay. sary, as described below.
with symptoms suggesting infection with invasive patho-
Frequent or continuous topical application of drops or the gens and those at high risk of complications. Similarly an- The risk of developing travellers’ diarrhoea can be reduced
use of local drug delivery devices have been used to ensure tibacterial treatment was considered appropriate in tropical by avoiding possibly contaminated foods as embodied in
prolonged elevated drug concentrations. Subconjunctival regions for diarrhoea due to invasive but not non-invasive the advice to ‘cook it, boil it, peel it, or forget it’. Prophy-
or systemic therapy may occasionally be necessary. Topi- organisms.2 Nevertheless, some clinicians consider such lactic drug regimens have been suggested, including vari-
cal treatment with cefazolin and either gentamicin or to- an approach to be unnecessarily conservative in adults ous antibacterials, usually a fluoroquinolone or co-trimox-
bramycin has traditionally been used when Pseudomonas with severe acute diarrhoea in developed countries3 in azole, in addition to bismuth salicylate. However, routine
is not suspected. More recently, fluoroquinolones or whom empirical treatment with fluoroquinolones can re- antimicrobial prophylaxis is not generally recommended
ceftazidime have been used, and semisynthetic penicillins lieve symptoms and shorten the illness without significant because of the danger of drug reactions, superinfections,
or vancomycin are other alternatives. For the treatment of adverse effects. In the USA, empirical therapy is consid- and increasing bacterial resistance; it should be reserved
Acanthamoeba keratitis, see p.822. ered for any patients in whom a bacterial cause is suspect- for those at special risk.10 Many authorities prefer early
Endophthalmitis is a devastating ocular disease resulting ed; stool samples should be obtained for identification of treatment, including self-medication, with clear instruc-
from infection of the ocular cavity, usually after penetrat- the causative organism.4 tions on when medical help should be sought.
ing trauma or surgery. Depending on the route of infection, 1. Farthing M, et al. The management of infective gastroenteritis
In infants and children oral rehydration therapy is univer- in adults: a consensus statement by an expert panel convened by
causative organisms often include staphylococci, strepto- the British Society for the Study of Infection. J Infect 1996; 33:
cocci, H. influenzae, Bacillus cereus, and Propionibacteri- sally recognised as appropriate initial treatment of acute 143–52.
um acnes. Fungal infections occur less commonly. Bacte- diarrhoea, but it has been underutilised in both developed 2. Mathan VI. Diarrhoeal diseases. Br Med Bull 1998; 54: 407–19.
rial endophthalmitis requires immediate aggressive and developing countries.2,5,6 Nutritional support and 3. Gorbach SL. Treating diarrhoea. BMJ 1997; 314: 1776–7.
4. Guerrant RL, et al. Infectious Diseases Society of America.
treatment with antibacterials, usually given intravitreally. management of secondary complications, including sys- Practice guidelines for the management of infectious diarrhea.
The value of concurrent parenteral antibacterials is un- temic infections, is also particularly important in this age Clin Infect Dis 2001; 32: 331–50. Also available at: http://
clear. The choice of antibacterial for intravitreal use de- group.2 Antibacterials have little place in management in www.journals.uchicago.edu/doi/pdf/10.1086/318514 (accessed
18/08/08)
pends on the most likely pathogen. Third-generation ce- most cases and their inappropriate use has contributed to a 5. Walker-Smith JA. Underutilisation of oral rehydration in the
p h a l o s p o r i n s o r v a n c o my c i n ar e u se d , b u t high prevalence of resistance in commensal bacteria.5 treatment of gastroenteritis. Drugs 1988; 36 (suppl 4): 61–4.
aminoglycosides may produce retinal toxicity. Clindamy- WHO6,7 has stipulated that antibacterials should only be 6. WHO. The rational use of drugs in the management of acute
diarrhoea in children. Geneva: WHO, 1990.
cin may be effective if B. cereus is suspected. Adjunctive used in children with acute diarrhoea when there is dysen- 7. WHO. The management and prevention of diarrhoea: practical
treatment includes vitrectomy, surgical removal of infect- tery or suspected cholera; Shigella is the most important guidelines. 3rd ed. Geneva: WHO, 1993.
cause of dysentery in young children. Giardiasis and 8. Waites WM, Arbuthnott JP. Foodborne illness: an overview.
ed lens structures, and corticosteroids to control inflamma- Lancet 1990; 336: 722–5.
tory and immune responses. amoebiasis should also be treated. WHO emphasised6 that 9. Roberts D. Sources of infection: food. Lancet 1990; 336:
oral preparations containing streptomycin or dihydrostrep- 859–61.
For a discussion of fungal infections of the eye, see p.519; tomycin, neomycin, halogenated hydroxyquinolines, or 10. Rendi-Wagner P, Kollaritsch H. Drug prophylaxis for travelers’
for cytomegalovirus retinitis and ocular herpes simplex in- diarrhea. Clin Infect Dis 2002; 34: 628–33.
nonabsorbable sulfonamides (sulfaguanidine, succinylsul-
fections, see under Cytomegalovirus Infections, p.853, fathiazole, phthalylsulfathiazole) should not be used. Antibiotic-associated colitis. Although other organ-
and Herpes Simplex Infections, p.854, respectively. isms, including Candida spp.,1 have been implicated in an-
Some general references are given below. Persistent or prolonged diarrhoea may not have an infec- tibiotic-associated diarrhoea, colonisation of the colon
1. Baum J. Infections of the eye. Clin Infect Dis 1995; 21: 479–88.
tive cause and antibacterial treatment should not be started with Clostridium difficile, a toxin-producing Gram-posi-
2. Leeming JP. Treatment of ocular infections with topical antibac- unless a pathogen can be identified. Tropical sprue, a syn- tive anaerobe, is the most common identifiable cause of
terials. Clin Pharmacokinet 1999; 37: 351–60. drome characterised by malabsorption often presenting as antibiotic-associated colitis and pseudomembranous coli-
3. Robert P-Y, Adenis J-P. Comparative review of topical ophthal- chronic diarrhoea, is believed to have an infective compo- tis. Restrictive antibacterial policies have decreased the in-
mic antibacterial preparations. Drugs 2001; 61: 175–85. nent and may respond to tetracycline, although this may be
4. Sheikh A, Hurwitz B. Antibiotics versus placebo for acute bac- cidence of Cl. difficile-associated diarrhoea in some
terial conjunctivitis. Available in The Cochrane Database of Sys- less effective in indigenous populations than in expatri- hospitals2 but it remains a major hazard of antibacterial
tematic Reviews; Issue 2. Chichester: John Wiley; 2006 (ac- ates.2 use. Antibiotic-associated colitis has been associated with
cessed 12/06/08).
5. Suwan-apichon O, et al. Topical corticosteroids as adjunctive HIV-associated diarrhoea. Diarrhoea is common in HIV the use of most antibacterials, but particularly with clin-
therapy for bacterial keratitis. Available in The Cochrane Data- infection and AIDS (p.856) and causative organisms may damycin, lincomycin, ampicillin, amoxicillin, and cepha-
base of Systematic Reviews; Issue 4. Chichester: John Wiley; be bacterial, protozoal, or viral. The most common bacte- losporins and, less frequently, with fluoroquinolones, tet-
2007 (accessed 13/06/08).
rial cause is the Mycobacterium avium complex (see Non- racycline, carbapenems, and trimethoprim. The diarrhoea
tuberculous Mycobacterial Infections, p.181); others in- may be mild and self-limiting or debilitating and persistent
Gas gangrene clude Campylobacter, Salmonella, and Shigella spp. and can be life-threatening. Although the diarrhoea gener-
Clostridium spp. are anaerobic Gram-positive bacteria Supportive care and appropriate conventional antibacterial ally resolves within a few days of stopping the offending
some of which cause gas gangrene with muscle necrosis therapy may be adequate, as described under the specific drug, together with fluid and electrolyte replacement, early
and systemic toxicity as a result of toxin formation. Cl. infections, below. specific antibacterial therapy should be given to patients
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
172 Antibacterials
with severe illness characterised by high fever, marked ab- 14. Dudley MN, et al. Oral bacitracin vs vancomycin therapy for pandemic is caused by V. cholerae O1 biotype El Tor. In
Clostridium difficile-induced diarrhea: a randomized double-
dominal pain, and marked leucocytosis and to elderly, tox- blind trial. Arch Intern Med 1986; 146: 1101–4. late 1992 and 1993 epidemic cholera caused by V. choler-
ic, or debilitated patients, or those unresponsive to support- 15. Pruksananonda P, Powell KR. Multiple relapses of Clostridium ae O139 was reported in India and Bangladesh and subse-
ive therapy.3,4 Antibacterials are probably unnecessary in difficile-associated diarrhea responding to an extended course quently identified in Thailand and other Asian countries. V.
of cholestyramine. Pediatr Infect Dis J 1989; 8: 175–8.
mild disease.5 Antidiarrhoeal drugs should be avoided 16. Shwed JA, Rodvold KA. Anion-exchange resins and oral van-
cholerae O139 became the dominant strain in India in less
since they may aggravate the condition and may occasion- comycin in pseudomembranous colitis. DICP Ann Pharmacoth- than 2 months and some workers declared it responsible
ally increase the possibility of toxic megacolon.3 er 1989; 23: 70–1. for the eighth cholera pandemic.2 However, there was
17. Tjellström B, et al. Oral immunoglobulin A supplement in treat- some evidence that by 1994 it was abating and that by
Vancomycin or metronidazole are widely used when anti- ment of Clostridium difficile enteritis. Lancet 1993; 341;
bacterial treatment is necessary.3,4,6,7 Metronidazole tends 701–2. 1996 O1 was again the prevalent type in India and Bang-
to be the drug of first choice and vancomycin is reserved 18. Salcedo J, et al. Intravenous immunoglobulin therapy for severe ladesh. There appears to be no cross-immunity between
Clostridium difficile colitis. Gut 1997; 41: 366–70.
for those who do not respond to, or who cannot tolerate, 19. Vanderhoof JA, et al. Lactobacillus GG in the prevention of an-
O1 and the O139 serogroup.
metronidazole, for those who are severely immunocom- tibiotic-associated diarrhea in children. J Pediatr 1999; 135: Individuals can reduce the risk of contracting cholera by
promised, and for those with severe illness.3,4,6-8 This view 564–8. good personal hygiene, avoiding possibly contaminated
20. Schellenberg D, et al. Treatment of Clostridium difficile diar-
is also endorsed by expert bodies in the USA whose aim is rhoea with brewer’s yeast. Lancet 1994; 343: 171–2. foodstuffs, and by boiling or otherwise disinfecting drink-
to provide guidelines for preventing the spread of vanco- ing water. Methods of preventing or containing cholera ep-
mycin resistance.9 Metronidazole can be given orally or Campylobacter enteritis. Campylobacter jejuni is a idemics include ensuring a safe water supply, providing
intravenously as appropriate. Vancomycin is only given major cause of acute diarrhoea. C. coli is less common and good sanitation, and promoting safe handling and prepara-
orally; it should not be given intravenously since it does C. upsaliensis has more recently been identified as an en- tion of foods. Mass chemoprophylaxis, vaccination, and
not give rise to adequate concentrations of the drug in the teropathogen.1,2 Food is a common source of infection.3,4 travel and trade restrictions are not effective7 although oral
bowel lumen.3 The severity of the diarrhoea often decreas- In the UK, several sources are responsible5 including con- vaccines show more promise.
es within 48 to 72 hours, but may not stop for a week or taminated food and water and one important source is
from doorstep deliveries of foil-topped bottled milk that Most cases of vibrio gastro-enteritis are mild to moderate
more. Treatment is usually continued for 10 days.6 Relaps- and generally require no therapy other than fluid and elec-
es are quite common,8 but usually respond to re-treatment have been pecked by birds.5-7
trolyte replacement with an appropriate oral rehydration
with vancomycin or metronidazole.3,8 The macrolides erythromycin or azithromycin are of solution (see Diarrhoea, p.1694). Patients with severe gas-
Other drugs that have been investigated in the treatment of benefit8 in severely affected patients, but the infection is tro-enteritis, dehydration, and shock should receive vigor-
antibiotic-associated colitis include teicoplanin,10-12 fusid- usually self-limiting and fluid and electrolyte replacement ous fluid replacement, preferably intravenously.8 Antimi-
ic acid,12,13 and bacitracin,14 although experience with is generally sufficient. A fluoroquinolone, a tetracycline, crobial therapy has been shown to decrease the duration
their use remains limited. A systematic review5 found that or gentamicin may be alternative antimicrobials.8 Treat- and volume of diarrhoea in cholera and may also decrease
metronidazole, bacitracin, rifaximin, nitazoxanide, or fu- ment with erythromycin can eradicate the organism from the duration of other vibrio diarrhoeas.9 WHO recom-
sidic acid seemed to be as effective as vancomycin in the faeces,9-11 but may not reduce the duration of symp- mends a single dose of doxycycline as the treatment of
terms of symptomatic cure, and teicoplanin might be toms unless treatment is started early in the course of the choice for adults except pregnant women. Tetracycline,
slightly more effective. Bacitracin and fusidic acid seemed disease.9-11 Some strains of Campylobacter are resistant to ciprofloxacin, co-trimoxazole, furazolidone, erythromy-
to be less effective than vancomycin in terms of bacterio- erythromycin,12 and resistance is also an increasing prob- cin, and chloramphenicol are alternatives, with furazo-
logical cure and resolution.5 Ramoplanin and tiacumicin B lem with ciprofloxacin.13,14 Multiple drug resistance has lidone being preferred for pregnant women and erythro-
(OPT-80) have also been investigated.7 been reported.15,16 mycin for children. Recommendations from the USA for
The anion-exchange resins colestyramine and colestipol Severe systemic infections with C. fetus require parenteral adults specify a tetracycline as the first choice with co-tri-
hydrochloride have been shown to bind the Cl. difficile therapy with a third-generation cephalosporin or gen- moxazole or a fluoroquinolone such as ciprofloxacin as al-
toxin in vitro, and colestyramine has been used to treat tamicin,8 depending on susceptibility. ternatives.10 One study has suggested that single-dose cip-
pseudomembranous colitis.15 The use of vancomycin to- There is some evidence of an association between C. jejuni rofloxacin might be preferred to doxycycline, particularly
gether with colestyramine has been suggested,16 but the infection and the Guillain-Barré syndrome.17,18 in areas of tetracycline resistance,11 and in Bangladesh,
value of the combination is uncertain. In general, the use 1. Bourke B, et al. Campylobacter upsaliensis: waiting in the ampicillin has been found to be as effective as either eryth-
of colestyramine is not recommended.6 An experimental wings. Clin Microbiol Rev 1998; 11: 440–9. romycin or tetracycline12 and may be a useful alternative
2. Jenkin GA, Tee W. Campylobacter upsaliensis-associated di-
toxin-binding polymer, tolevamer has also been investi- arrhea in human immunodeficiency virus-infected patients. Clin in children. Studies13-15 in Bangladesh and India found sin-
gated.7 Infect Dis 1998; 27: 816–21. gle-dose azithromycin to be effective in children and
3. Skirrow MB. Foodborne illness: Campylobacter. Lancet 1990; adults. The O139 strain is reported to be sensitive to cipro-
Oral immunoglobulin A, used with vancomycin, was ef- 336: 921–3.
fective in controlling severe diarrhoea in a child who had 4. Allos BM. Campylobacter jejuni infections: update on emerging floxacin,16 erythromycin,16 and tetracyclines,2 but resist-
not responded to other therapies.17 Normal immunoglobu- issues and trends. Clin Infect Dis 2001; 32: 1201–6. ant to co-trimoxazole.2 There has also been some resist-
lin given intravenously was also effective when added to 5. Pebody RG, et al. Outbreaks of campylobacter infection: rare ance to furazolidone.2 Multiple drug resistance may be a
events for a common pathogen. Commun Dis Rep 1997; 7:
vancomycin and metronidazole therapy in 2 elderly pa- R33–R37. problem; differing sensitivity and resistance patterns have
tients unresponsive to antibacterials alone.18 Vaccines 6. Phillips CA. Bird attacks on milk bottles and campylobacter in- been reported for the 2 biotypes classical and El Tor V.
against C. difficile have also been investigated.7 fection. Lancet 1995; 346: 386. cholerae.17 The outbreak strain in Rwandan refugees was
7. Stuart J, et al. Outbreak of campylobacter enteritis in a residen-
Treatment and prevention strategies aimed at colonising tial school associated with bird pecked bottle tops. Commun Dis resistant to tetracycline, doxycycline, co-trimoxazole,
the gut with non-pathogenic organisms have included use Rep 1997; 7: R38–R40. chloramphenicol, and ampicillin.2
8. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
of lactic-acid-producing organisms such as Lactobacil- book of antimicrobial therapy. 18th ed. New York: The Medical Mass chemoprophylaxis is not recommended but may be
lus,4,19 and the yeasts Saccharomyces boulardii,4 and S. Letter, 2008: 62. justified for household contacts,1,18 especially those at
cerevisiae.20 9. Anders BJ, et al. Double-blind placebo controlled trial of eryth- high risk because of age or pregnancy.1 The type of cholera
romycin for treatment of campylobacter enteritis. Lancet 1982;
1. Danna PL, et al. Role of candida in pathogenesis of antibiotic- i: 131–2. vaccines traditionally available are not very effective al-
associated diarrhoea in elderly inpatients. Lancet 1991; 337: 10. Mandal BK, et al. Double-blind placebo-controlled trial of though promising results have been reported with the use
511–14. erythromycin in the treatment of clinical campylobacter infec- of oral vaccines in areas where cholera is endemic.
2. Gorbach SL. Antibiotics and Clostridium difficile. N Engl J tion. J Antimicrob Chemother 1984; 13: 619–23.
Med 1999; 341: 1690–1. 11. Williams D, et al. Early treatment of Campylobacter jejuni en- Marine or halophilic Vibrio spp. known to cause gastro-
3. Tabaqchali S, Jumaa P. Diagnosis and management of Clostrid- teritis. Antimicrob Agents Chemother 1989; 33: 248–50. enteritis include V. parahaemolyticus which is responsible
ium difficile infection. BMJ 1995; 310: 1375–80. 12. Taylor DN, et al. Erythromycin-resistant campylobacter infec-
4. Malnick SDH, Zimhony O. Treatment of Clostridium difficile- tions in Thailand. Antimicrob Agents Chemother 1987; 31:
for food poisoning from raw or undercooked seafood, es-
associated diarrhea. Ann Pharmacother 2002; 36: 1767–75. 438–42. pecially in Japan.19,20 Another halophilic sp., V. vulnificus,
269: 71–5. 13. Piddock LJV. Quinolone resistance and Campylobacter spp. J is increasingly associated with wound infection and septi-
5. Nelson R. Antibiotic treatment for Clostridium difficile-associ- Antimicrob Chemother 1995; 36: 891–8.
ated diarrhea in adults. Available in The Cochrane Database of caemia.19 On the basis of in-vitro sensitivity testing21 and
14. Campylobacter Sentinel Surveillance Scheme Collaborators.
Systematic Reviews; Issue 3. Chichester: John Wiley; 2007 (ac- Ciprofloxacin resistance in Campylobacter jejuni: case-case anecdotal clinical experience, empirical therapy with
cessed 05/08/08). analysis as a tool for elucidating risks at home and abroad. J aminoglycosides, ceftazidime, imipenem, or ciprofloxacin
6. ASHP. ASHP therapeutic position statement on the preferential Antimicrob Chemother 2002; 50: 561–8.
use of metronidazole for the treatment of Clostridium difficile- should all be effective.22
15. Winstanley TG, et al. Multiple antibiotic resistance in a strain of
associated disease. Am J Health-Syst Pharm 1998; 55: 1407–11. Campylobacter jejuni acquired in Jordan. J Antimicrob Chem- 1. Anonymous. Cholera. Commun Dis Rep 1991; 1: R48–50.
7. Gerding DN, et al. Treatment of Clostridium difficile infection. other 1993; 31: 178–9. 2. Crowcroft NS. Cholera: current epidemiology. Commun Dis
Clin Infect Dis 2008; 46 (suppl 1): S32–42. 16. Gaudreau C, Michaud S. Cluster of erythromycin- and cipro- Rep 1994; 4: R157–64.
8. Fekety R. Guidelines for the diagnosis and management of floxacin-resistant Campylobacter jejuni subsp jejuni from 1999 3. Swerdlow SL, Ries AA. Vibrio cholerae non-O1—the eighth
Clostridium difficile-associated diarrhea and colitis. Am J Gas- to 2001 in men who have sex with men, Quebec, Canada. Clin pandemic? Lancet 1993; 342: 382–3.
troenterol 1997; 92: 739–50. Infect Dis 2003; 37: 131–6. 4. Mahon BE, et al. Reported cholera in the United States, 1992-
9. Hospital Infection Control Practices Advisory Committee 17. Rees JH, et al. Campylobacter jejuni infection and Guillain- 1994: a reflection of global changes in cholera epidemiology.
(HICPAC). Recommendations for preventing the spread of van- Barré syndrome. N Engl J Med 1995; 333: 1374–9. JAMA 1996; 276: 307–12.
comycin resistance. MMWR 1995; 44 (RR-12): 1–13. Also 18. Allos BM. Association between Campylobacter infection and 5. Seas C, Gotuzzo E. Cholera: overview of epidemiologic, thera-
available at: http://www.cdc.gov/mmwr/PDF/rr/rr4412.pdf (ac- Guillain-Barré syndrome. J Infect Dis 1997; 176 (suppl 2): peutic, and preventive issues learned from recent epidemics. Int
cessed 18/05/04) S125–S128. J Infect Dis 1996; 1: 37–46.
10. de Lalla F, et al. Treatment of Clostridium difficile-associated
disease with teicoplanin. Antimicrob Agents Chemother 1989; 6. Sánchez JL, Taylor DN. Cholera. Lancet 1997; 349: 1825–30.
Cholera and other vibrio infections. Cholera results 7. WHO. Guidelines for cholera control. Geneva: WHO, 1993.
33: 1125–7.
11. de Lalla F, et al. Prospective study of oral teicoplanin versus from infection with the enterotoxin-producing Gram-neg- 8. Morris JG, Black RE. Cholera and other vibrioses in the United
oral vancomycin for therapy of pseudomembranous colitis and ative bacillus Vibrio cholerae which causes acute secre- States. N Engl J Med 1985; 312: 343–50.
Clostridium difficile-associated diarrhea. Antimicrob Agents tory diarrhoea. It can be associated with two serogroups of 9. Blake PA. Vibrios on the half shell: what the walrus and the
Chemother 1992; 36: 2192–6. carpenter didn’t know. Ann Intern Med 1983; 99: 558–9.
12. Wenisch C, et al. Comparison of vancomycin, teicoplanin, met- V. cholerae, O1 and O139. Serogroup O1 can then be di- 10. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
ronidazole, and fusidic acid for the treatment of Clostridium dif- vided into two biotypes (classical and El Tor) and each of book of antimicrobial therapy. 18th ed. New Rochelle NY: The
ficile-associated diarrhea. Clin Infect Dis 1996; 22: 813–18. these has three serotypes (Inaba, Ogawa, and Hikojima). Medical Letter, 2008: 71.
13. Cronberg S, et al. Fusidic acid for the treatment of antibiotic- 11. Khan WA, et al. Randomised controlled comparison of single-
associated colitis induced by Clostridium difficile. Infection The seventh pandemic1-6 began in 1961 in South East dose ciprofloxacin and doxycycline for cholera caused by Vi-
1984; 12: 276–9. Asia, and reached South America in January 1991. This brio cholerae O1 or O139. Lancet 1996; 348: 296–300.
 Antibacterials 173
12. Roy SK, et al. A randomized clinical trial to compare the effi- 5. Hill SM, et al. Enteropathogenic Escherichia coli and life present as septicaemia or localised infections such as men-
cacy of erythromycin, ampicillin and tetracycline for the treat- threatening chronic diarrhoea. Gut 1991; 32: 154–8.
ment of cholera in children. Trans R Soc Trop Med Hyg 1998; 6. Mead PS, Griffin PM. Escherichia coli O157:H7. Lancet 1998; ingitis or osteomyelitis.
92: 460–2. 352: 1207–12. Uncomplicated non-typhoid Salmonella enteritis is usual-
13. Khan WA, et al. Comparison of single-dose azithromycin and 7. Subcommittee of the PHLS Advisory Committee on Gastroin- ly managed by fluid and electrolyte replacement. Antibac-
12-dose, 3-day erythromycin for childhood cholera: a ran- testinal Infections. Guidelines for the control of infection with
domised, double-blind trial. Lancet 2002; 360: 1722–7. Vero cytotoxin producing Escherichia coli (VTEC). Commun terial therapy produces no clinical benefit in uncomplicat-
14. Bhattacharya MK, et al. Azithromycin in the treatment of chol- Dis Public Health 2000; 3: 14–23. Also available at: ed Salmonella enteritis3 and may prolong Salmonella
era in children. Acta Paediatr 2003; 92: 676–8. http://www.hpa.org.uk/cdph/issues/CDPHvol3/No1/vtec.pdf
15. Saha D, et al. Single-dose azithromycin for the treatment of (accessed 18/08/08)
detection in stools.3 Attempts to eradicate the carrier state
cholera in adults. N Engl J Med 2006; 354: 2452–62. 8. Isaäcson M, et al. Haemorrhagic colitis epidemic in Africa. with antibacterial therapy (for example fluoroquinolones)
16. Dhar U, et al. Clinical features, antimicrobial susceptibility and Lancet 1993; 341: 961. appear to have been unsuccessful so far4 and routine use is
toxin production in Vibrio cholerae O139 infection: comparison 9. Paquet C, et al. Aetiology of haemorrhagic colitis epidemic in
with V. cholerae O1 infection. Trans R Soc Trop Med Hyg 1996; Africa. Lancet 1993; 342: 175. not recommended.5 Patients with underlying debility or
90: 402–5. 10. Safdar N, et al. Risk of hemolytic uremic syndrome after antibi- evidence of invasive salmonellosis should be given anti-
17. Siddique AK, et al. Simultaneous outbreaks of contrasting drug otic treatment of Escherichia coli O157:H7 enteritis: a meta- bacterial therapy. Amoxicillin, ampicillin, or co-trimoxa-
resistant classic and El Tor Vibrio cholerae O1 in Bangladesh. analysis. JAMA 2002; 288: 996–1001.
Lancet 1989; ii: 396. 11. Farthing M, et al. The management of infective gastroenteritis zole have been suggested6,7 as have trimethoprim, ceftri-
18. WHO. WHO expert committee on cholera: second report. WHO in adults: a consensus statement by an expert panel convened by axone,7 azithromycin,7 a fluoroquinolone7 such as
Tech Rep Ser 352 1967. Available at: http://libdoc.who.int/trs/
WHO_TRS_352.pdf (accessed 18/08/08)
the British Society for the Study of Infection. J Infect 1996; 33: ciprofloxacin,8 or chloramphenicol.7 However, there is
143–52.
19. Anonymous. Shuck your oysters with care. Lancet 1990; 336: concern over the emergence of resistant strains, particular-
215–16. Necrotising enterocolitis. Necrotising enterocolitis in ly to the fluoroquinolones.9,10 Resistance to cepha-
20. Doyle MP. Foodborne illness: pathogenic Escherichia coli, the newborn is thought to result from hypoxia or ischaemic losporins has also been recognised.11,12 Multiresistant R-
Yersinia enterocolitica, and Vibrio parahaemolyticus. Lancet
1990; 336: 1111–15. injury to the intestinal mucosa with subsequent infection. type strains of S. typhimurium DT 104 (another common
21. French GL, et al. Antimicrobial susceptibilities of halophilic vi- Bacteria implicated in the disease include Pseudomonas, cause of Salmonella enteritis in the UK) have severely lim-
brios. J Antimicrob Chemother 1989; 24: 183–94. Escherichia coli, Klebsiella, Salmonella spp., and
22. French GL. Antibiotics for marine vibrios. Lancet 1990; 336:
ited the treatment options for infections with this organ-
568–9. Clostridium spp. Treatment involves suspension of oral ism.13-16
feeding, intravenous fluid therapy, and surgical excision of 1. Baird-Parker AC. Foodborne salmonellosis. Lancet 1990; 336:
Escherichia coli enteritis. Escherichia coli is a normal the affected gut. References to the use of oral vancomycin 1231–5.
intestinal commensal and member of the Gram-negative for the treatment1 of neonatal necrotising enterocolitis in- 2. Rodrigue DC, et al. International increase in Salmonella enteri-
family of bacteria the Enterobacteriaceae. Pathogenic tidis: a new pandemic? Epidemiol Infect 1990; 105: 21–7.
dicate that it may be of benefit. In a comparison of intrave- 3. Sirinavin S, Garner P. Antibiotics for treating salmonella gut in-
strains causing distinct syndromes of diarrhoeal disease nous regimens to treat the condition it was reported that fections. Available in The Cochrane Database of Systematic Re-
and also associated with foodborne illness include: enter- ampicillin with gentamicin appeared as effective as vanco-
views; Issue 1. Chichester: John Wiley; 1999 (accessed
opathogenic E. coli (EPEC)—an important cause of infan- 16/05/05).
mycin with cefotaxime in neonates over 2.2 kg birth- 4. Nagler JM, et al. Salmonella gastroenteritis: longterm follow-
tile diarrhoea in many developing countries; enteroinva- weight, but in smaller neonates results were better with up of an outbreak after treatment with norfloxacin or co-trimox-
sive E. coli (EIEC)—producing an invasive type of vancomycin and cefotaxime.2 A systematic review has
azole. J Antimicrob Chemother 1994; 34: 291–4.
diarrhoea resembling that of Shigella dysentery; entero- 5. Farthing M. The management of infective gastroenteritis in
concluded that prophylactic oral antibacterials might well adults: a consensus statement by an expert panel convened by
toxigenic E. coli (ETEC)—an important cause of travel- reduce the incidence of necrotising enterocolitis in low the British Society for the Study of Infection. J Infect 1996; 33:
lers’ diarrhoea (see Gastro-enteritis, above); and entero- 143–52.
birth-weight or preterm infants in a high-risk environ- 6. Gorbach SL. Bacterial diarrhoea and its treatment. Lancet 1987;
haemorrhagic E. coli (EHEC)—associated with ment,3 but there are concerns about adverse outcomes, and ii: 1378–82.
haemorrhagic colitis, haemolytic-uraemic syndrome, and prophylactic use (particularly of vancomycin) is not gen- 7. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
thrombotic thrombocytopenic purpura.1 Enteroadherent E. erally recommended because of the risk of inducing resist-
book of antimicrobial therapy. 18th ed. New Rochelle NY: The
Medical Letter, 2008: 65.
coli (EAEC) is a cause of chronic diarrhoea in young chil- ance. It has been suggested4 that oral immunoglobulins 8. Leigh DA. The treatment of a large outbreak of acute bacterial
dren.2 may prevent necrotising enterocolitis in low-birth-weight gastroenteritis with ciprofloxacin. J Antimicrob Chemother
Although these organisms are generally sensitive to a wide 1992; 30: 733–5.
infants; however, a systematic review5 concluded that the 9. Wilcox MH, Spencer RC. Quinolones and salmonella gastroen-
range of antibacterials only special categories of E. coli di- available evidence did not support this claim. There is, teritis. J Antimicrob Chemother 1992; 30: 221–8.
arrhoea should be treated.2 however, some evidence6 of the value of probiotics in this 10. Frost JA, et al. Increasing ciprofloxacin resistance in salmonel-
las in England and Wales 1991-1994. J Antimicrob Chemother
Neonates with severe EPEC diarrhoea have been given group. Supplementation with arginine has also been inves- 1996; 37: 85–91.
oral non-absorbable antibacterials such as neomycin or tigated,7 but there is insufficient evidence to determine its 11. Tzouvelekis LS, et al. Emergence of resistance to third-genera-
gentamicin although in older children or adults this diar- tion cephalosporins amongst Salmonella typhimurium isolates
value. in Greece: report of the first three cases. J Antimicrob Chemoth-
rhoea may be self-limiting.2 Evidence for the efficacy of Necrotising enteritis in older children and adults, known as er 1998; 42: 273–5.
neomycin is largely limited to uncontrolled studies.3 How- pigbel, has been attributed to toxins produced by Clostrid- 12. Dunne EF, et al. Emergence of domestically acquired ceftriax-
ever, improvement with antibacterials has been noted be- one-resistant Salmonella infections associated with AmpC beta-
ium perfringens. Both sporadic and epidemic forms are lactamase. JAMA 2000; 284: 3151–6.
yond the neonatal period;4 EPEC infection has been re- mainly seen in the highlands of Papua New Guinea, but 13. Threlfall EJ, et al. Increasing spectrum of resistance in multire-
ported to be a common treatable cause of life-threatening sporadic cases have been reported elsewhere. Treatment is sistant Salmonella typhimurium. Lancet 1996; 347: 1053–4.
chronic diarrhoea in infancy, possibly associated with trav- 14. Anonymous. Multidrug-resistant Salmonella serotype typhimu-
supportive with surgical intervention where necessary. A rium—United States, 1996. JAMA 1996; 277: 1513.
el to a developing country.5 Symptoms could become per- vaccine is available for prophylaxis. 15. Anonymous. Emergence of multidrug-resistant salmonella.
sistent and life-threatening in previously healthy infants, 1. Han VKM. An outbreak of Clostridium difficile necrotizing en- WHO Drug Inf 1997; 11: 21.
requiring intravenous rehydration and parenteral antibac- terocolitis: a case for oral vancomycin therapy? Pediatrics 1983; 16. Threlfall EJ, et al. Multiresistant Salmonella typhimurium DT
104 and salmonella bacteraemia. Lancet 1998; 352: 287–8.
terials such as gentamicin and penicillin.5 71: 935–41.
2. Scheifele DW, et al. Comparison of two antibiotic regimens for Shigellosis. Shigellosis (bacillary dysentery) is an enteric
Vero cytotoxin-producing strains of EHEC (VTEC; Shiga neonatal necrotizing enterocolitis. J Antimicrob Chemother
toxin producing E. coli; STEC), in particular serotype 1987; 20: 421–9. infection caused by the Shigella spp. S. dysenteriae, S.
O157, have been associated with bloody diarrhoea, haem- 3. Bury RG, Tudehope D. Enteral antibiotics for preventing necro- flexneri, S. boydii, or S. sonnei. They are Gram-negative
tizing enterocolitis in low birthweight or preterm infants. Avail- bacteria belonging to the Enterobacteriaceae family and
orrhagic colitis, and haemolytic-uraemic syndrome.6,7 able in The Cochrane Database of Systematic Reviews; Issue 1.
Children and the elderly are at greater risk of severe dis- Chichester: John Wiley; 2001 (accessed 16/05/05). are able to invade the colon. Depending on the species in-
ease,6 but the illness is usually self-limiting.7 Cases have 4. Eibl MM, et al. Prevention of necrotizing enterocolitis in low- volved, the disease ranges from mild self-limiting secre-
birth-weight infants by IgA-IgG feeding. N Engl J Med 1988; tory diarrhoea to severe colitis and dysentery with blood
generally been linked with the consumption of foods de- 319: 1–7.
rived from cattle, especially undercooked beef and unpas- 5. Foster J, Cole M. Oral immunoglobulin for preventing necrotiz- and mucus in the stools. S. dysenteriae is the most com-
teurised milk, although there have been outbreaks associ- ing enterocolitis in preterm and low birth-weight neonates. mon in the developing world and causes the most severe
ated with the consumption of fresh vegetables and Available in The Cochrane Database of Systematic Reviews; Is- disease. In developed countries S. flexneri and S. sonnei
sue 1. Chichester: John Wiley; 2004 (accessed 16/05/05). are more common. Some S. flexneri can cause severe col-
unpasteurised juices, probably as a result of faecal contam- 6. Deshpande G, et al. Probiotics for prevention of necrotising en-
ination. Person-to-person spread is also common, and di- terocolitis in preterm neonates with very low birthweight: a sys- itis and toxic dilatation of the colon has been reported in
rect spread from infected animals may occur. E. coli O157 tematic review of randomised controlled trials. Lancet 2007; travellers.1 S. sonnei is the least pathogenic of the species.
369: 1614–20.
has also been reported as a cause of epidemic haemorrhag- 7. Shah P, Shah V. Arginine supplementation for prevention of As with any form of diarrhoea, rehydration is the key to
ic colitis in Africa, where it may be difficult to distinguish necrotising enterocolitis in preterm infants. Available in The Co- treatment.2 Antibacterial therapy may be with ampicillin
from shigellosis.8,9 Treatment is generally supportive, in- chrane Database of Systematic Reviews; Issue 3. Chichester: (amoxicillin appears to be less effective), co-trimoxazole
John Wiley; 2007 (accessed 05/08/08). (or trimethoprim), nalidixic acid, or fluoroquinolones such
cluding correcting and maintaining the fluid and electro-
lyte balance.7 Antibacterial treatment is controversial and Salmonella enteritis. Salmonella spp. are Gram-nega- as ciprofloxacin, but will depend on the prevailing resist-
there is uncertainty as to whether it influences the course tive bacteria belonging to the Enterobacteriaceae family. ance patterns (see below) and the severity of the disease.
of enterohaemorrhagic E. coli infection and the develop- They can be divided into those causing enteric fever, Bacterial resistance is common and some consider that an-
ment of haemolytic-uraemic syndrome10 or thrombotic namely S. typhi and S. paratyphi, where infection is sys- tibacterials should be restricted to the most severe cases,
thrombocytopenic purpura;6,7,11 the non-antibacterial temic although affecting the gastrointestinal tract (see un- particularly those due to S. dysenteriae;3 in the UK, the
treatment of these two latter complications is discussed in der Typhoid and Paratyphoid Fever, p.198) and non-ty- Public Health Laboratory Services (PHLS) Working
Plasma, under Thrombotic Microangiopathies, p.1076. phoid Salmonella, including S. enteritidis and S. Group has concluded that therapy is seldom indicated for
Oral preparations of Vero cytotoxin-binding resins are un- typhimurium which cause acute gastro-enteritis, usually S. sonnei infections.4 WHO5 has advised that children with
der investigation. through food poisoning. There are numerous Salmonella Shigella dysentery should be given antimicrobial therapy
1. Doyle MP. Pathogenic Escherichia coli, Yersinia enterocolitica, serotypes identified with food poisoning and they have of- and recommended co-trimoxazole as treatment of choice
and Vibrio parahaemolyticus. Lancet 1990; 336: 1111–15. ten been named according to the place where they were with nalidixic acid or ampicillin as alternatives; it was not-
2. Gorbach SL. Bacterial diarrhoea and its treatment. Lancet 1987;
ii: 1378–82. first isolated. The increase in salmonellosis in Great Brit- ed that resistance to ampicillin is frequent.6
3. WHO. The rational use of drugs in the management of acute ain has been almost entirely due to S. enteritidis1 and this The rapid development of resistance and the emergence of
diarrhoea in children. Geneva: WHO, 1990.
4. Hill SM, et al. Antibiotics for Escherichia coli gastroenteritis. reflects an increase internationally.2 Non-typhoid Salmo- multiresistant strains of Shigella, particularly in develop-
Lancet 1988; i: 771–2. nella spp. can cause invasive salmonellosis which may ing countries, has led to some changes in treatment recom-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
174 Antibacterials
mendations.6 In 1992, nalidixic acid had become the pre- 2. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989; tion, or splenectomy may all cause neutropenia and im-
321: 16–24.
ferred drug in developing countries unless ampicillin or 3. Doyle MP. Pathogenic Escherichia coli, Yersinia enterocolitica,
paired humoral and cellular immunity in varying degrees.
co-trimoxazole were known to be effective in the region.7 and Vibrio parahaemolyticus. Lancet 1990; 336: 1111–15. The risk and severity of infections depends upon the dura-
For S. dysenteriae it might be necessary to use pivmecil- 4. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand- tion of compromised immunity, the degree to which im-
linam. It was concluded that the fluoroquinolones should book of antimicrobial therapy. 18th ed. New Rochelle NY: The mune function is compromised, whether cellular or hu-
Medical Letter, 2008: 65.
continue to be reserved for infections resistant to nalidixic 5. Read RC, Barry RE. Relapsing yersinia infection. BMJ 1990;
moral functions are affected, and upon breaches in
acid or pivmecillinam.7 Reduced susceptibility to fluoro- 300: 1694. physical barriers, for example due to severe mucositis or
quinolones of some strains of S. sonnei has been reported prolonged vascular access. Thus patients with profound
from Japan,8 and fluoroquinolone-resistant S. dysenteriae neutropenia or a history of splenectomy are prone to rap-
has been reported.2 Fluoroquinolones are generally not Gonorrhoea idly progressive and potentially life-threatening infections;
used in children, although a study9 in Bangladesh has used See under Sexually Transmitted Diseases, p.191. those with neutropenia induced by cytotoxic chemothera-
ciprofloxacin in children with shigellosis and found it to be py or by preparation for transplantation are particularly
of similar efficacy to pivmecillinam. In studies from Israel, Granuloma inguinale vulnerable to acute infections whereas those in whom im-
the third-generation cephalosporins ceftriaxone10 or See under Sexually Transmitted Diseases, p.192. munosuppression results from viral infections or congeni-
cefixime11 were more effective than ampicillin or co-tri- tal defects are at lower risk of acute infections.1 Patients in
moxazole, respectively, in children with shigellosis. Other whom neutropenia persists for more than 10 days are not
studies in adults in Bangladesh found cefixime to be inef- Haemophilus influenzae infections only at risk of opportunistic bacterial infections but also
fective compared with pivmecillinam12 and azithromycin Haemophilus influenzae is a Gram-negative bacterium susceptible to viral, fungal, and parasitic infections.
to be effective, although slightly less so, than cipro- that colonises the upper respiratory tract in the majority of
healthy people. Most are carriers of non-encapsulated Infectious diseases are a major cause of morbidity and
floxacin.13 Rifaximin has also been investigated.2 mortality in patients with AIDS (see HIV-associated Infec-
strains, but a small proportion carry H. influenzae type b,
Vitamin A may be a useful adjunct to treatment, especially tions, p.857). Some are due to common pathogens, but
the commonest encapsulated strain. Serious invasive in-
in children in developing countries (see Diarrhoea, under others are opportunistic and are caused by normally aviru-
fections have usually been caused by type b strains and
Vitamin A, p.1973). lent commensals. Children with HIV infection appear to
have occurred mainly in young children. They include the
Oral shigella vaccines are being studied for prophylaxis. bacteraemic diseases meningitis, pneumonia, epiglottitis, be at special risk of serious bacterial infections with com-
1. Wilson APR, et al. Toxic dilatation of the colon in shigellosis.
cellulitis, and arthritis. Non-encapsulated strains common- mon encapsulated bacteria. For further reference to some
BMJ 1990; 301: 1325–6. bacterial infections associated with AIDS, see Gastro-en-
2. Niyogi SK. Shigellosis. J Microbiol 2005; 43: 133–43. ly cause otitis media, sinusitis, and conjunctivitis and in-
3. Kaya IS, et al. Danger of antibiotic resistance in shigellosis. fect patients with chronic bronchitis. However, they too teritis (p.171), Nontuberculous Mycobacterial Infections
Lancet 1990; 336: 186.
can cause invasive infections such as pneumonia, septicae- (p.181), and Tuberculosis (p.196). Fungal, protozoal, and
4. PHLS Working Group on the control of Shigella sonnei infec- viral infections which can affect immunocompromised pa-
tion. Revised guidelines for the control of Shigella sonnei infec- mia, and meningitis and, with the introduction of H. influ-
tion and other infective diarrhoeas. Commun Dis Rep 1993; 3: enzae type b vaccines, non-encapsulated strains may be re- tients are discussed in the relevant chapters under Infec-
R69–70. Also available at: http://www.hpa.org.uk/cdr/
sponsible for a greater proportion of invasive H. influenzae tions in Immunocompromised Patients, p.520, p.824, and
archives/CDRreview/1993/cdrr0593.pdf (accessed 18/08/08) p.859, respectively.
5. WHO. The rational use of drugs in the management of acute disease.
diarrhoea in children. Geneva: WHO, 1990.
For further details of these infections and their manage- Common causative organisms of unexplained fever in
6. WHO. The management and prevention of diarrhoea: practical neutropenic patients include the Gram-negative bacteria
guidelines. 3rd ed. Geneva: WHO, 1993. ment, see under the specific disease side-headings.
7. Bennish ML, Salam MA. Rethinking options for the treatment Pseudomonas aeruginosa, Escherichia coli, and Klebsiel-
of shigellosis. J Antimicrob Chemother 1992; 30: 243–7.
Ampicillin and chloramphenicol have been the antibacte- la spp. and Gram-positive organisms particularly staphy-
8. Horiuchi S, et al. Reduced susceptibilities of Shigella sonnei rials of choice against H. influenzae, but increasing resist- lococci, streptococci, enterococci, and Corynebacterium
strains isolated from patients with dysentery to fluoroquinolo- ance, especially to ampicillin, should be borne in mind; spp. Gram-negative organisms have historically been re-
nes. Antimicrob Agents Chemother 1993; 37: 2486–9. there have been several reports of multiresistant strains.1-4
9. Salam MA, et al. Randomised comparison of ciprofloxacin sus- sponsible for most immediate life-threatening infections,
pension and pivmecillinam for childhood shigellosis. Lancet Injectable cephalosporins are popular alternatives for mul- but Gram-positive infections are increasing in importance
1998; 352: 522–7. tiresistant type b organisms although there is controversy and now predominate in many areas.1,2 Factors influenc-
10. Varsano I, et al. Comparative efficacy of ceftriaxone and ampi- over their effectiveness against fully sensitive strains when
cillin for treatment of severe shigellosis in children. J Pediatr ing this change include the wider use of selective gut de-
1991; 118: 627–32. compared with ampicillin or chloramphenicol or both; ex- contamination and of central venous catheters,3 and possi-
11. Ashkenazi S, et al. A randomized, double-blind study compar- perience has been favourable with cefotaxime and ceftri- bly the prophylactic use of quinolones.
ing cefixime and trimethoprim-sulfamethoxazole in the treat-
ment of childhood shigellosis. J Pediatr 1993; 123: 817–21. axone, but there have been treatment failures in H. influen-
TREATMENT. Onset of fever in neutropenic patients is in-
12. Salam MA, et al. Treatment of shigellosis: IV. Cefixime is inef- zae meningitis with cefuroxime and there is argument over
fective in shigellosis in adults. Ann Intern Med 1995; 123: its efficacy.5 Meropenem is a further alternative.6 dicative of potentially serious infection which may
505–8. progress to septicaemia and death. The severity of infec-
13. Khan WA, et al. Treatment of shigellosis: V. Comparison of azi- For serious H. influenzae infections cefotaxime or ceftri-
tions depends on numerous factors (see above) and it is
thromycin and ciprofloxacin. Ann Intern Med 1997; 126: axone are currently preferred. For upper respiratory infec-
697–703. therefore difficult to produce a standard drug regimen; in
tions and bronchitis, co-trimoxazole (or trimethoprim in
addition, the choice of empirical therapy must be adapted
Yersinia enteritis. Yersinia enterocolitica is a Gram- the UK) is preferred; ampicillin, amoxicillin (with or with-
according to prevailing local antibacterial susceptibility
negative bacteria of the Enterobacteriaceae family and the out clavulanic acid), oral second- or third-generation ce-
patterns. Guidelines have been produced in many coun-
species most commonly responsible for yersiniosis. The phalosporins, a tetracycline, a fluoroquinolone, or the
tries, of which those issued by the Infectious Diseases So-
predominant form of infection is an enteric illness with or macrolides azithromycin or clarithromycin are suggested
ciety of America4 for both the initial and subsequent man-
without mesenteric adenitis1 although clinical manifesta- alternatives.6
agement of febrile neutropenic patients are fairly typical:
tions can range from self-limited enterocolitis to potential- In the UK, secondary prophylaxis with rifampicin is given
ly fatal systemic infection, and post-infection complica- • the patient’s risk of life-threatening infection should first
after H. influenzae type b meningitis (see p.178). A vac-
tions can include erythema nodosum and reactive be assessed. If the risk is considered high, empirical in-
cine against H. influenzae type b is available and vaccina-
arthritis.2 Y. enterocolitica is a recognised foodborne travenous antibacterial therapy should be started imme-
tion is included in the infant immunisation schedules in
pathogen3 and in some temperate countries rivals Salmo- diately
some countries including the UK and USA.
nella and exceeds Shigella as a cause of acute gastro-en- 1. Sturm AW, et al. Outbreak of multiresistant non-encapsulated • secondly, consideration should be given to whether the
teritis; pigs are a major reservoir. Increased susceptibility Haemophilus influenzae infections in a pulmonary rehabilitation patient requires vancomycin therapy. If so, treatment
centre. Lancet 1990; 335: 214–16. should begin with vancomycin plus cefepime, ceftazi-
to Yersinia infection has occurred in patients with iron 2. Brightman CAJ, et al. Family outbreak of chloramphenicol-
overload treated with desferrioxamine (see p.1440). ampicillin resistant Haemophilus influenzae type b disease. Lan-
dime, or a carbapenem, with or without an aminoglyco-
Isolates of Y. enterocolitica are reported to be susceptible cet 1990; 335: 351–2. side.
to co-trimoxazole, aminoglycosides, chloramphenicol, tet- 3. Barclay K, et al. Multiresistant Haemophilus influenzae. Lancet • if vancomycin is not indicated, intravenous monothera-
1990; 335: 549.
racycline, third-generation cephalosporins, and quinolo- 4. Scott GM, et al. Outbreaks of multiresistant Haemophilus influ-
py should be given with
nes in vitro.1,2 As with any form of diarrhoea, rehydration enzae infection. Lancet 1990; 335: 925. • either a cephalosporin (cefepime, although concerns
is the key to treatment and most forms of mild uncompli- 5. Powell M. Chemotherapy for infections caused by Haemophilus have been raised about its safety,5 or ceftazidime) or
influenzae: current problems and future prospects. J Antimicrob
cated enteritis do not require antibacterial treatment. There Chemother 1991; 27: 3–7. a carbapenem (imipenem-cilastatin or meropenem)
has been no general consensus concerning the antibacterial 6. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand- for uncomplicated cases
of choice when treatment becomes necessary: as with book of antimicrobial therapy. 18th ed. New Rochelle NY: The • in more complicated cases, or where resistance is a
many other enteric infections there is a lack of good clini- Medical Letter, 2008: 69.
problem, combined treatment should be given with
cal evidence. Drugs with good intracellular activity such an aminoglycoside and one of cefepime, ceftazidime,
as trimethoprim, co-trimoxazole, tetracycline, chloram- Helicobacter pylori infections a carbapenem, or an antipseudomonal penicillin such
phenicol, or fluoroquinolones may be preferred.1 Doxycy- Antibacterial therapy is used to eradicate Helicobacter py- as ticarcillin with clavulanic acid or piperacillin with
cline or co-trimoxazole have been recommended2 for lori infection in peptic ulcer disease (p.1702) and MALT tazobactam.
complicated gastrointestinal and focal extra-intestinal in- lymphoma of the stomach (p.657). The role of H. pylori • low-risk patients may be treated empirically either oral-
fections or doxycycline and an aminoglycoside empirical- and the value of its eradication in dyspepsia (p.1695) and ly with ciprofloxacin and amoxicillin with clavulanic
ly in bacteraemia. Co-trimoxazole as first choice or alter- gastro-oesophageal reflux disease (p.1696) is less clear. acid, or intravenously as for uncomplicated cases above.
natively a fluoroquinolone, an aminoglycoside, or
Initial treatment with oral antibacterials alone is, howev-
cefotaxime have also been recommended.4 A patient with
Infections in immunocompromised patients er, not recommended for children4
chronic Yersinia infection who responded well to tetracy-
cline or co-trimoxazole, but relapsed on withdrawal, was Patients with a defective immune system are at increased The initial regimen usually needs to be given for 3 to 5
treated successfully with ciprofloxacin.5 risk of infection. Primary immune deficiency is rare, days in order to determine its efficacy. In patients in whom
1. Hoogkamp-Korstanje JAA. Antibiotics in Yersinia enterocoliti- whereas secondary deficiency is more common: immuno- fever resolves and in whom a causative organism is identi-
ca infections. J Antimicrob Chemother 1987; 20: 123–31. suppressive therapy, cancer and its treatment, HIV infec- fied, antibacterial treatment should be modified for the
 Antibacterials 175
specific organisms and broad-spectrum antibacterials con- prophylactic regimens have included selective decontami- drugs, for example colistin, neomycin, norfloxacin, or pol-
tinued for at least 7 days or until culture results are nega- nation of the alimentary tract using oral nonabsorbable an- ymyxin, with an antifungal, usually amphotericin B. The
tive and the patient has clinically recovered.4 In afebrile tibacterials (see also under Intensive Care, below). Co-tri- drugs are usually applied topically to the oropharyngeal
patients in whom no causative organism is found but who moxazole has also been widely used.9 More recently, mucosa in addition to oral or intragastric dosage, although
were considered at high risk at the onset of treatment, the prophylaxis with fluoroquinolones has been commonly local application to the oropharynx alone is also reported
same antibacterials should be continued intravenously; used although, generally, prophylaxis with these drugs has to be effective.7,8 A parenteral third-generation cepha-
those considered at low risk initially may be switched to resulted in reduction in Gram-negative but not in Gram- losporin, usually cefotaxime, may be given for a few days
oral therapy with ciprofloxacin plus either amoxicillin-cla- positive infections in immunocompromised patients,10 and until oral medication takes effect.9,10 Strict adherence to
vulanic acid (adults) or cefixime (children).4 improved morbidity and mortality has not been ob- the protocol is reported to be necessary for maximum
Patients in whom fever persists throughout the first 3 to 5 served.11 Combination prophylaxis with fluoroquinolones efficacy11 and constant monitoring for the emergence of
days but for whom no aetiology is determined may have a and phenoxymethylpenicillin12 or rifampicin13 has been antimicrobial resistance is considered essential10,11 al-
non-bacterial infection, a bacterial infection that is refrac- tried to improve cover against Gram-positive organisms. though this has rarely been seen in practice.11,12 However,
tory to treatment, the emergence of a second infection, or Nevertheless, concern about the emergence of resistant or- most regimens have little or no activity against potential
drug fever.4 Such patients should be reassessed and then ganisms has led to the recommendation that routine proph- Gram-positive pathogens such as Enterococcus spp., and
one of three options followed. If the patient’s condition is ylaxis should be avoided.4 so their use may increase the risk for colonisation and in-
clinically stable, the same antibacterial treatment may be Immunocompromised patients may benefit from appropri- fection with these organisms.13 There is particular concern
continued; if there is still no change in the patient’s condi- ate immunisation against common infections, although over the emergence of vancomycin-resistant strains.
tion, consideration should be given to stopping vancomy- precautions relating to the use of live vaccines in such pa- Despite numerous clinical studies, many of which have
cin if it has been given. Alternatively, if there is evidence tients should be observed (p.2202). shown a reduction in potential Gram-negative
of progressive disease or drug toxicity, the antibacterials The duration and severity of neutropenia can be reduced pathogens9,10,14 and in the incidence of respiratory-tract in-
given may be changed; if vancomycin has not been given, by the use granulocyte or granulocyte-macrophage colo- fections,7,8 it has been difficult to demonstrate that SDD or
it may be added to the regimen. The third option is to add ny-stimulating factors, and this may be a useful adjunct in SPEAR reduces mortality. 1 5 -1 8 Although meta-
an antifungal drug (amphotericin B) with or without a infection control in selected patients.6 Bone marrow pro- analyses19,20 of randomised controlled trials concluded
change to the antibacterial regimen if the patient is febrile tective agents such as amifostine are also being studied. that a combination of a systemic and topical antibacterial
through days 5 to 7 and resolution of neutropenia is not For further reference to prophylaxis in high-risk patients, could be beneficial it has been argued that the effect was
imminent.4 see Intensive Care, below. largely due to the systemic component of the treatment.21
The optimum duration of therapy is governed by the clin- 1. Pizzo PA. Fever in immunocompromised patients. N Engl J Med It has been suggested22 that equivalent infection control
ical situation. The most important determinant of success- 1999; 341: 893–900. could be achieved more economically by emphasis on
fully stopping antibacterials is the neutrophil count:4 2. Plunkett T, et al. Complications of chemotherapy 1: the man- high standards of hygiene and avoidance of histamine H2-
agement of neutropenia and febrile neutropenia. CME Oncol
• if no infection is identified after day 3, the neutrophil 1998; 1: 40–4. receptor antagonists, which could allow overgrowth of po-
count exceeds 500 cells/mm3 for 2 consecutive days, 3. Oppenheim BA. The changing pattern of infection in neutropen- tentially pathogenic bacteria as a result of the change in
and the patient has been afebrile for at least 48 hours, ic patients. J Antimicrob Chemother 1998; 41 (suppl D): 7–11. gastric pH. Oral decontamination with chlorhexidine may
4. Hughes WT, et al. Infectious Diseases Society of America. 2002
then antibacterial treatment may be stopped Guidelines for the use of antimicrobial agents in neutropenic be useful in preventing ventilator-associated pneumonia.23
• if neutropenia persists in the absence of fever, it is rea- patients with cancer. Clin Infect Dis 2002; 34: 730–51. Also Another potential source of infection in intensive care is
available at: http://www.journals.uchicago.edu/doi/pdf/
sonable to stop antibacterial treatment after 5 to 7 days 10.1086/339215 (accessed 18/08/08) from the use of intravascular catheters. The organisms
in patients who were initially considered at low risk and 5. Paul M, et al. Empirical antibiotic monotherapy for febrile neu- implicated most frequently have been coagulase-negative
who are clinically well, though such patients should be tropenia: systematic review and meta-analysis of randomized staphylococci.24 Prevention and control of infection de-
controlled trials. J Antimicrob Chemother 2006; 57: 176–89.
closely monitored and intravenous antibacterials reinsti- 6. Smith TJ, et al. American Society of Clinical Oncology. 2006 up-
pend on good aseptic technique and care of the insertion
gated immediately on recurrence of fever or evidence of date of recommendations for the use of white blood cell growth site, and also catheter design;24-27 guidelines have been
infection.4 In afebrile patients with profound neutrope- factors: an evidence-based clinical practice guideline. J Clin Oncol produced in the USA for the prevention of infection.28
2006; 24: 3187–3205. Also available at: http://www.jco.org/cgi/
nia (less than 100 cells/mm3), or in those with mucositis reprint/JCO.2006.06.4451v2.pdf (accessed 18/08/08) Catheters should be removed as soon as possible (often af-
or other risk factors, continuous antibacterial treatment 7. Aapro MS, et al. European Organisation for Research and Treat- ter 48 to 72 hours for peripheral lines) and any infections
should be considered throughout the entire neutropenic ment of Cancer (EORTC) Granulocyte Colony-Stimulating Fac- treated promptly with antibacterials; vancomycin or teico-
tor (G-CSF) Guidelines Working Party. EORTC guidelines for
period the use of granulocyte-colony stimulating factor to reduce the planin are appropriate for empirical treatment provided re-
• in patients with persistent fever and prolonged neutrope- incidence of chemotherapy-induced febrile neutropenia in adult sistance is not a problem.24 There have been some favour-
nia in whom haematological recovery cannot be antici- patients with lymphomas and solid tumours. Eur J Cancer 2006; able results with antibacterial prophylaxis, but such use is
42: 2433–53.
pated, consideration may be given to stopping antibac- 8. Clark OAC, et al. Colony stimulating factors for chemotherapy discouraged because of concern over the emergence of re-
terials after 2 weeks if no infection has been identified induced febrile neutropenia. Available in The Cochrane Data- sistant organisms.29 Topical antiseptics and antibacterials
and careful observation is possible.4 base of Systematic Reviews; Issue 4. Chichester: John Wiley; have produced promising results.24 Antibacterials could
2000 (accessed 16/05/05).
• clinically well patients with persistent fever may have 9. Kerr KG. The prophylaxis of bacterial infections in neutropenic also prove useful in reducing or eliminating colonisation
their antibacterials stopped after 4 to 5 days if the neu- patients. J Antimicrob Chemother 1999; 44: 587–91. of the catheter lumen 30 and catheters coated with
trophil count remains at least 500 cells/mm3 throughout 10. Engels EA, et al. Efficacy of quinolone prophylaxis in neutro- antibacterials31 or heparin32 are under investigation. Ran-
penic cancer patients: a meta-analysis. J Clin Oncol 1998; 16:
this period and there is no sign of infection and no re- 1179–87. domised clinical studies have shown that the use of cathe-
sponse to therapy; such patients should be closely mon- 11. Cruciani M, et al. Prophylaxis with fluoroquinolones for bacte- ters coated with minocycline and rifampicin33 or with an-
rial infections in neutropenic patients: a meta-analysis. Clin In- tiseptics (p.1624) can reduce the risk of systemic
itored for subsequent infections which are usually easily fect Dis 1996; 23: 795–805.
treatable, and empirical amphotericin B should be con- 12. International Antimicrobial Therapy Cooperative Group of the
infections. Some evidence suggests that catheters impreg-
sidered despite cessation of antibacterials if fever per- European Organization for Research and Treatment of Cancer nated with minocycline and rifampicin are more effective
(EORTC). Reduction of fever and streptococcal bacteremia in in minimising risk of infection than those coated with
sists for 5 to 7 days after the start of initial therapy4 granulocytopenic patients with cancer: a trial of oral penicillin
• patients who remain febrile after recovery from neutro- V or placebo combined with pefloxacin. JAMA 1994; 272: chlorhexidine or sulfadiazine silver.34
penia and despite broad-spectrum antibacterials should 1183–9. The importance of maintaining high standards of infection
13. Bow EJ, et al. Quinolone-based antibacterial chemoprophylaxis
be reassessed for undiagnosed infection which may be in neutropenic patients: effect of augmented gram-positive ac- control, including handwashing, in intensive care units has
fungal, mycobacterial, or viral tivity on infectious morbidity. Ann Intern Med 1996; 125: been reinforced by the increasing incidence of nosocomial
183–90. infections that are difficult to treat such as those due to
The routine use of colony-stimulating factors as an adjunct
to antibacterial treatment is not generally recommended4 vancomycin-resistant enterococci and Acinetobacter. In
but may be indicated in febrile neutropenic patients at high Intensive care one such outbreak due to A. baumannii some strains were
risk of serious infections or infection-related complica- Like immunocompromised patients (above), those in in- resistant to imipenem and all other antibacterials except
tions; examples include some patients with malignant tensive care units are often very susceptible to endogenous polymyxin B and sulbactam.35 Intensive infection control
neoplasms6,7 and those with persistent severe neutropenia infections, especially respiratory and urinary-tract infec- measures and irrigation of all open wounds with polymyx-
and infections that are not responsive to antibacterials tions, arising from gastrointestinal colonisation by aerobic in B solution were used to eliminate infection and coloni-
alone.4 A systematic review8 of the use of colony-stimulat- Gram-negative bacilli acquired in hospital. Selective di- sation.
ing factors in patients with febrile neutropenia due to can- gestive tract decontamination (SDD), using oral non-ab- 1. Kollef MH. The prevention of ventilator-associated pneumonia.
N Engl J Med 1999; 340: 627–34. Correction. ibid.; 341: 294.
cer chemotherapy concluded that their use did not affect sorbable antibacterial regimens, and selective parenteral 2. CDC. Guidelines for prevention of nosocomial pneumonia.
overall mortality but did reduce time spent in hospital and and enteral antisepsis regimens (SPEAR), incorporating MMWR 1997; 46 (RR-1): 1–79. Also available at: http://
the neutrophil recovery time. selective decontamination with systemic antibacterial www.cdc.gov/mmwr/PDF/rr/rr4601.pdf (accessed 19/05/04)
prophylaxis, have been used in an attempt to prevent colo- 3. American Thoracic Society; Infectious Diseases Society of Amer-
PROPHYLAXIS. Most infections in immunocompromised ica. Guidelines for the management of adults with hospital-ac-
patients are caused by organisms from their own alimenta- nisation and infection in these high-risk patients, although quired, ventilator-associated, and healthcare-associated pneumo-
ry tract and in cancer patients, for example, may follow their effectiveness is debated. SDD has generally not been nia. Am J Respir Crit Care Med 2005; 171: 388–416. Also
widely adopted in the USA1 particularly in relation to pre- available at: http://www.thoracic.org/sections/publications/
chemotherapy-induced mucosal damage to the tract. Al- statements/pages/mtpi/guide1-29.html (accessed 25/05/06)
though antibacterial prophylaxis may be effective in afe- vention of nosocomial pneumonia,2 although benefit of 4. Nathens AB, Marshall JC. Selective decontamination of the di-
brile patients likely to be neutropenic, the efficacy of em- short-term use may be seen in some patient groups.3 It may gestive tract in surgical patients: a systematic review of the ev-
pirical treatment means that prophylaxis is less widely be more effective in surgical patients.4 idence. Arch Surg 1999; 134: 170–6.
5. van Saene HKF, Stoutenbeek CP. Selective decontamination. J
used9 and the Infectious Diseases Society of America4 dis- Selective decontamination is achieved by elimination of Antimicrob Chemother 1987; 20: 462–5.
courages routine use; reasons include toxicity of the anti- aerobic, potentially pathogenic, organisms from the throat 6. Krueger WA, Unertl KE. Selective decontamination of the di-
bacterial, potential fungal overgrowth, and problems of and intestines while preserving the indigenous, mostly gestive tract. Curr Opin Crit Care 2002; 8: 139–44.
7. Rodriguez-Roldan JM, et al. Prevention of nosocomial lung in-
bacterial resistance (see below). Most experience with anaerobic, flora.5,6 Regimens commonly include two or fection in ventilated patients: use of an antimicrobial pharyngeal
prophylaxis has been in patients with leukaemia. Possible three non-absorbable or poorly absorbed antibacterial nonabsorbable paste. Crit Care Med 1990; 18: 1239–42.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
176 Antibacterials
8. Pugin J, et al. Oropharyngeal decontamination decreases inci- compromised patients, although this may be of little fur- pentoxifylline5,10 and infliximab.11 Chloroquine has
dence of ventilator-associated pneumonia: a randomized, place-
bo-controlled, double-blind clinical trial. JAMA 1991; 265: ther benefit.3 also been used with limited effect.1 Antileprotic drug
2704–10. 1. Diederen BMW. Legionella spp. and Legionnaires’ disease. J In- therapy is generally continued during lepra reactions.
9. Ledingham IM, et al. Triple regimen of selective decontamina- fect 2008; 56: 1–12. Although measures to manage the consequences of nerve
tion of the digestive tract, systemic cefotaxime, and microbio-
logical surveillance for prevention of acquired infection in in- 2. Roig J, Rello J. Legionnaires’ disease: a rational approach to damage and lepra reactions are an important part of the
tensive care. Lancet 1988; i: 785–90. therapy. J Antimicrob Chemother 2003; 51: 1119–29. management of leprosy, curative antibacterial therapy is
10. Tetteroo GWM, et al. Selective decontamination to reduce 3. Amsden GW. Treatment of Legionnaires’ disease. Drugs 2005; the mainstay of treatment. Dapsone monotherapy, long
gram-negative colonisation and infections after oesophageal re- 65: 605–14.
section. Lancet 1990; 335: 704–7. the basis of this, has been replaced since the 1980s with
4. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
11. Tetteroo GWM, et al. Bacteriology of selective decontamina-
book of antimicrobial therapy. 18th ed. New Rochelle NY: The multidrug oral regimens designed to overcome the devel-
tion: efficacy and rebound colonisation. J Antimicrob Chemoth-
er 1994; 34: 139–48. Medical Letter, 2008: 69. opment of resistance. Dapsone, rifampicin, and clofaz-
12. van Saene HKF, et al. Cefotaxime combined with selective de- imine form the elements of the standard combinations.5,12
contamination in long term intensive care unit patients: virtual Newer alternatives include clarithromycin, minocycline,
absence of emergence of resistance. Drugs 1988; 35 (suppl 2): Leprosy and fluoroquinolones such as ofloxacin and pefloxacin.
29–34.
13. Bonten MJM, et al. Colonization and infection with Enterococ- Leprosy (Hansen’s disease) is a chronic disease caused by These may be used as second-line therapy for patients un-
cus faecalis in intensive care units: the role of antimicrobial the bacillus, Mycobacterium leprae; it has a prolonged in- able to tolerate dapsone or clofazimine. Ethionamide or
agents. Antimicrob Agents Chemother 1995; 39: 2783–6. cubation period (years) and slow onset of symptoms. Dis-
14. Aerdts SJA, et al. Prevention of bacterial colonization of the protionamide have been used in light-skinned patients to
respiratory tract and stomach of mechanically ventilated pa- ease results from bacillary infiltration of the peripheral avoid clofazimine’s tendency to pigment the skin, but are
tients by a novel regimen of selective decontamination in com- nervous system, skin, eyes, respiratory mucosa, bones, and no longer recommended because of their risk of hepato-
bination with initial systemic cefotaxime. J Antimicrob Chem- testes. It is not highly infectious and transmission requires
other 1990; 26 (suppl A): 59–76. toxicity.
15. Loirat P, et al. Selective digestive decontamination in intensive both prolonged close contact with an infected patient and The most widely used multidrug regimens are those rec-
care unit patients. Intensive Care Med 1992; 18: 182–8. an inherent immunological susceptibility to the disease in ommended by WHO3 and in these the choice of drugs and
16. Vandenbroucke-Grauls CMJE, Vandenbroucke JP. Effect of se- the exposed person. Clinical leprosy may be regarded as a
lective decontamination of the digestive tract on respiratory length of treatment are based on the clinical classification
tract infections and mortality in the intensive care unit. Lancet consequence of deficient cell-mediated immunity in sus- outlined above.
1991; 338: 859–62. ceptible individuals; most individuals are naturally im-
17. van Saene HKF, et al. Selective decontamination of the diges- mune, and symptoms are suppressed. The clinical mani- • MULTIBACILLARY LEPROSY
tive tract in the intensive care unit: current status and future The standard regimen recommended by WHO for
prospects. Crit Care Med 1992; 20: 691–703. festations depend on the bacillary load and the host’s
18. Selective Decontamination of the Digestive Tract Trialists’ Col- immune response to the mycobacterium. Patients with lep- multibacillary leprosy3,4 is rifampicin 600 mg and
laborative Group. Meta-analysis of randomised controlled trials rosy may be classified as having: clofazimine 300 mg both given once a month, with
of selective decontamination of the digestive tract. BMJ 1993; clofazimine 50 mg and dapsone 100 mg both daily.
307: 525–32. • Multibacillary (or lepromatous) leprosy, which occurs
19. Liberati A, et al. Antibiotic prophylaxis to reduce respiratory Treatment is continued for 12 months.4
tract infections and mortality in adults receiving intensive care. when cellular immunity is largely deficient, and in-
A 2-year treatment duration was chosen originally be-
Available in The Cochrane Database of Systematic Reviews; Is- cludes the sub-groups lepromatous (LL), borderline lep-
sue 1. Chichester: John Wiley; 2004 (accessed 16/05/05). cause it is highly effective in the majority of cases and
romatous (BL), and midborderline leprosy (BB), as well
20. D’Amico R, et al. Effectiveness of antibiotic prophylaxis in crit- avoids the need to assess response with skin smears.
ically ill adult patients: systematic review of randomised con- as any other types giving a positive skin smear for acid-
However, such a long treatment duration is an obstacle
trolled trials. BMJ 1998; 316: 1275–85. fast bacilli. Generally the lepromin test (p.2333) is neg-
21. Kollef MH. The prevention of ventilator-associated pneumonia. to implementing treatment programmes in areas where
ative.
N Engl J Med 1999; 341: 294. healthcare is inaccessible or the infrastructure is poor.
22. Atkinson SW, Bihari DJ. Selective decontamination of the gut. • Paucibacillary (or tuberculoid) leprosy, which results Ongoing clinical studies and experience with patients
BMJ 1993; 306: 286–7.
23. Koeman M, et al. Oral decontamination with chlorhexidine re- when cellular immunity is only partially deficient, and defaulting from treatment have encouraged WHO to
duces the incidence of ventilator-associated pneumonia. Am J includes the sub-groups borderline tuberculoid (BT), tu- now recommend that treatment for 12 months is ade-
Respir Crit Care Med 2006; 173: 1348–55. berculoid (TT), and indeterminate leprosy (I) when the quate.4 Early hopes that reducing duration of treatment
24. Elliott TSJ. Line-associated bacteraemias. Commun Dis Rep
1993; 3: R91–R96. skin smear is negative. Generally the lepromin test is to as little as one month would be possible have not been
25. Raad I. Intravascular-catheter-related infections. Lancet 1998; positive. supported by a study using daily rifampicin and
351: 893–8. ofloxacin.13
26. Maki DG, et al. The risk of bloodstream infection in adults with For the purpose of treatment, WHO classifies patients with
different intravascular devices: a systematic review of 200 pub- more than 5 skin lesions as having multibacillary leprosy, In patients for whom rifampicin is unsuitable because of
lished prospective studies. Mayo Clin Proc 2006; 81: 1159–71.
and those with 1 to 5 skin lesions as having paucibacillary resistance or intolerance, WHO recommends3 daily
27. Eggimann P. Prevention of intravascular catheter infection.
Curr Opin Infect Dis 2007; 20: 360–9. leprosy. The use of this clinical classification avoids the treatment with clofazimine 50 mg, ofloxacin 400 mg,
28. O’Grady NP, et al. Guidelines for the prevention of intravascular necessity to provide facilities for bacteriological examina- and minocycline 100 mg for the first 6 months; treat-
catheter-related infections. MMWR 2002; 51(RR-10): 1–29. Cor- ment is then continued for at least a further 18 months
rection. ibid.; 51: 711. Also available at: http://www.cdc.gov/ tion of skin smears.
mmwr/PDF/rr/rr5110.pdf (accessed 12/07/04) with clofazimine together with either minocycline or
Changes in the hosts immune response to the mycobacte-
29. McGee DC, Gould MK. Preventing complications of central ve- ofloxacin.
nous catheterization. N Engl J Med 2003; 348: 1123–33. ria may result in lepra reactions and unless treated these
30. Yassien M, et al. Modulation of biofilms of Pseudomonas aeru- may lead to severe nerve and tissue damage.1 Most reac- When clofazimine cannot be given ofloxacin 400 mg
ginosa by quinolones. Antimicrob Agents Chemother 1995; 39: tions belong to one of two main types: daily or minocycline 100 mg daily may be substituted in
2262–8. the standard regimen.14
31. Raad I, et al. Antibiotics and prevention of microbial coloniza- • Type 1 lepra reactions, or reversal reactions, are caused
tion of catheters. Antimicrob Agents Chemother 1995; 39: Rifampicin 600 mg, ofloxacin 400 mg, and minocy-
2397–2400. by spontaneous increases in T-cell reactivity to myco- cline 100 mg (ROM) given once a month for 24 months
32. Appelgren P, et al. Does surface heparinisation reduce bacterial bacterial antigens (type IV hypersensitivity) and occur was found to be as effective as the WHO standard regi-
colonisation of central venous catheters? Lancet 1995; 345: in patients with borderline forms of leprosy. These reac-
130. men given for 24 months15 and has been suggested as an
33. Raad I, et al. Central venous catheters coated with minocycline tions are characterised by erythema and oedema of the alternative regimen.3
and rifampin for the prevention of catheter-related colonization skin and tenderness of peripheral nerves. Prompt treat-
and bloodstream infections: a randomized, double-blind trial. ment with corticosteroids is necessary to prevent perma- • PAUCIBACILLARY LEPROSY
Ann Intern Med 1997; 127: 267–74.
nent nerve damage.2-5 Treatment is usually continued The WHO recommended regimen3,4 for paucibacillary
34. Darouiche RO, et al. A comparison of two antimicrobial-im-
pregnated central venous catheters. N Engl J Med 1999; 340: for 3 to 6 months. Adding azathioprine may permit the leprosy is rifampicin 600 mg monthly and dapsone
1–8. use of lower cumulative doses of corticosteroid.6 Meth- 100 mg daily. Treatment is continued for 6 months. If
35. Go ES, et al. Clinical and molecular epidemiology of acineto- there are severe toxic effects with dapsone it should be
bacter infections sensitive only to polymyxin B and sulbactam. otrexate was found to be effective in treating a patient
Lancet 1994; 344: 1329–32. intolerant to corticosteroids,7 while ciclosporin is con- substituted with clofazimine.14
sidered to be effective for chronic neuritis.2,8 Prophylac- On the basis of a clinical study16 showing that a single
Legionnaires’ disease tic use of low-dose corticosteroids during the first 4 dose each of rifampicin 600 mg, ofloxacin 400 mg, and
Legionnaires’ disease1 is a legionella pneumonia caused months of standard multidrug treatment for leprosy has minocycline 100 mg given in combination is only
by the Gram-negative bacterium Legionella pneumophila. also been investigated, and found to decrease the slightly less effective than standard multidrug treatment,
Serious outbreaks have been associated with infected air- number of reactional episodes by 75%; but the protec- WHO has suggested that this is a suitable alternative for
conditioning systems or water supplies. Pontiac fever is a tive effect was lost by the end of 12 months.9 patients with single-lesion paucibacillary leprosy.3
milder, usually self-limiting, flu-like illness also caused by However, reservations have been expressed about the
• Type 2 lepra reactions, also known as erythema nodo- study, including concerns regarding the short follow-
L. pneumophila as well as by other Legionella spp. Le- sum leprosum (ENL), represent a systemic inflammato-
gionellosis has been suggested as a broad term to cover up17 and poor microbiological rationale.18
ry response (type III hypersensitivity) to dead bacteria
pneumonic and non-pneumonic clinical syndromes and are accompanied by high levels of circulating tu- • RELAPSE
caused by any Legionella spp., which may include L. boze- mour necrosis factor alpha (TNFα). This reaction oc- Relapse after a recommended course of multidrug ther-
manii, L. micdadei (Pittsburgh pneumonia agent), and L. curs only in patients with borderline lepromatous or lep- apy for multibacillary or paucibacillary leprosy can oc-
wadsworthii. romatous leprosy. Mild type 2 reactions may be treated cur and WHO recommends re-treatment with the initial
The usual treatment for Legionella infections is with a with anti-inflammatories but moderate or severe reac- regimen.3,4 Although the relapse rate after standard
macrolide, with erythromycin now increasingly replaced tions should be treated with corticosteroids or thalido- multidrug therapy for multibacillary leprosy is generally
by azithromycin;2,3 clarithromycin, roxithromycin, or tel- mide (in males and post menopausal women).2-4 The in- low,3,19 there is insufficient information on the long-
ithromycin may be further acceptable alternative mac- cidence and severity of ENL has decreased since the term efficacy of shorter treatment courses.13
rolides.2,3 Fluoroquinolones are also increasingly recom- inclusion of clofazimine in multidrug regimens, proba- • PREGNANCY
mended as alternatives to the macrolides.1-3 Doxycycline bly owing to the drug’s anti-inflammatory action.2 Standard multidrug therapy is safe during pregnancy.4,5
or co-trimoxazole are further alternatives.4 Rifampicin has Clofazimine does not act as rapidly as either corticoster- Leprosy patients who are pregnant or breast feeding
been given in addition to fluoroquinolones or doxycycline, oids or thalidomide, nor is it as effective.2,3 Other TNFα may experience clinical deterioration and, in general,
especially in severe or deteriorating illness or in immuno- inhibiting drugs that have been tried include antileprotic therapy is continued in such patients.
 Antibacterials 177
• PROPHYLAXIS Leptospira are widely distributed in wild and domestic an- The treatment of choice is generally ampicillin with gen-
Leprosy is spread from person to person through respi- imals, including cattle. Rats are a common source of infec- tamicin,1,2,4,5 although some have advocated ampicillin
ratory droplets, so household contacts may become in- tion in man and transmission is often by contact with water alone;6 synergy has been reported in vitro. Ampicillin or
fected. A systematic review and meta-analysis20 has or soil contaminated with infected urine. The main occu- amoxicillin alone may be used in pregnant women.7 In
concluded that prophylaxis, usually with dapsone, in pational group at risk in the UK has been farmers and ag- penicillin-allergic patients co-trimoxazole, vancomycin or
some household contacts may prevent disease in this ricultural workers, although there have been outbreaks teicoplanin, erythromycin, and tetracycline are alterna-
high-risk group. A large randomised placebo-controlled elsewhere among recreational water users such as canoe- tives,1,3 but the choice of treatment in these patients is
study21 found that a single dose of rifampicin given to ists.3 The majority of symptomatic patients have no more more difficult. Gentamicin with chloramphenicol or with
contacts of new patients with leprosy significantly re- than a mild flu-like illness, although a small proportion de- vancomycin has been used4 as has erythromycin plus gen-
duced the incidence of developing leprosy in the first 2 velop Weil’s disease with haemorrhagic complications and tamicin.8 According to some,4 tetracycline should not be
years but no difference was noted beyond 2 years. severe hepatic and renal impairment. used to treat listeriosis in the UK because of bacterial re-
WHO3 suggests that contacts of newly diagnosed cases The use of antibacterials is controversial since many pa- sistance. Others3 recommend against use of cepha-
should be examined for evidence of leprosy and then ad- tients recover without treatment. There is insufficient evi- losporins.
vised how to watch for early signs of the disease; proph- dence to conclude whether treatment with antibacterials is Further details specifically concerning neonatal listerial
ylaxis with rifampicin or other antileprotics is not rec- worthwhile.4 However, treatment for suspected leptospiro- meningitis and its treatment can be found under Meningi-
ommended in leprosy control programmes. BCG sis within 4 to 7 days has been recommended to prevent tis, p.178.
vaccine appears to be protective. Vaccines specifically complications.5,6 The intravenous use of either benzylpen- 1. Gellin BG, Broome CV. Listeriosis. JAMA 1989; 261: 1313–20.
against leprosy are under investigation. icillin 900 mg, ampicillin 1 g, or erythromycin 500 mg 2. Schlech WF. Foodborne listeriosis. Clin Infect Dis 2000; 31:
• ELIMINATION every 6 hours, or the oral use of amoxicillin 500 mg every 770–5. Correction. ibid. 2001; 32: 1518–19.
8 hours or doxycycline 100 mg twice daily has been sug- 3. Swaminathan B, Gerner-Smidt P. The epidemiology of human
The multidrug therapy regimens recommended by listeriosis. Microbes Infect 2007; 9: 1236–43.
WHO have been widely implemented in recent years gested;6 treatment is continued for 7 days. Benzylpenicil- 4. MacGowan AP. Listeriosis—the therapeutic options. J Antimi-
raising the possibility of eliminating leprosy as a public lin has been given intravenously in higher doses for severe crob Chemother 1990; 26: 721–2.
health problem: that is, reducing the prevalence to less leptospirosis; 7.2 to 9.6 g daily for 5 days followed by 5. Temple ME, Nahata MC. Treatment of listeriosis. Ann Pharma-
than 1 case per 10 000 population in endemic areas. 1.44 g daily for a further 5 days has been advocated.7 cother 2000; 34: 656–61.
However, intravenous doses of 900 mg every 6 hours for 7 6. Kessler SL, Dajani AS. Listeria meningitis in infants and chil-
Considerable progress towards this target has been dren. Pediatr Infect Dis J 1990; 9: 61–3.
made, and it was announced in 2001 that the global level days have proved successful even when given late in the 7. Wilkinson P. Uncommon infections 2: listeriosis. Prescribers’ J
of leprosy had decreased by over 90%. Full control of course of illness.8 Intravenous ceftriaxone 1 g daily,9 intra- 1992; 32: 26–31.
leprosy, however, has still not been attained in several venous cefotaxime 1 g every 6 hours (followed by a switch 8. MacGowan AP, et al. Maternal listeriosis in pregnancy without
countries and continued efforts are necessary. WHO has to oral amoxicillin),10 and intravenous doxycycline given fetal or neonatal infection. J Infect 1991; 22: 53–7.
since developed a global strategy for the further reduc- as an initial dose of 200 mg, then 100 mg every 12 hours
tion of the leprosy burden and sustained leprosy con- (followed by a switch to oral doxycycline),10 each regimen Lyme disease
trol.22 given for a total of 7 days, have also been found to be ef- Lyme disease is a seasonal infectious disease caused by the
1. Walker SL, Lockwood DNJ. The clinical and immunological fective for treatment of severe leptospirosis. In severe in- spirochaete Borrelia burgdorferi and transmitted primarily
features of leprosy. Br Med Bull 2006; 77–78: 103–21. fections, supportive therapy with analgesics and antiemet- by Ixodes ticks. I. scapularis, one of the species of ticks
2. Britton WJ, Lockwood DNJ. Leprosy reactions: current and fu- ics may be required. Renal function should be monitored
ture approaches to management. Baillieres Clin Infect Dis 1997; that may cause Lyme disease, may also be infected with,
4: 1–23. and dialysis instigated if necessary, and blood products and transmit, Anaplasma phagocytophilum and/or Babe-
3. WHO. WHO expert committee on leprosy. WHO Tech Rep Ser may be necessary to control haemorrhagic complications.5 sia microti and therefore the bite from this tick may lead to
874 1998. Also available at: http://libdoc.who.int/trs/
WHO_TRS_874.pdf (accessed 13/07/07) The incidence of leptospirosis in US soldiers in Panama Lyme disease, human granulocytic anaplasmosis (see Ehr-
4. WHO. Guide to eliminate leprosy as a public health problem. 1st was reduced when they were given prophylaxis with oral lichiosis, p.168), or babesiosis (p.823) as a single infection
ed. Geneva: WHO, 2000. Also available at: http://www.who.int/
lep/resources/Guide_Int_E.pdf (accessed 28/06/07) doxycycline 200 mg weekly throughout the period of ex- or as a co-infection.1 Lyme disease was first recognised in
5. Britton WJ, Lockwood DNJ. Leprosy. Lancet 2004; 363: posure.11 Leptospirosis vaccines are available in some the 1970s in Lyme, Connecticut, but when the spirochaete
1209–19. countries. responsible was later identified, it was found to occur
6. Marlowe SNS, et al. Clinical outcomes in a randomized control-
led study comparing azathioprine and prednisolone versus pred- 1. WHO, International Leptospirosis Society. Human leptospiro- worldwide with regional variations. Lyme disease is a
nisolone alone in the treatment of severe leprosy type 1 reac- sis: guidance for diagnosis, surveillance and control. Geneva: multisystem disease characterised by inflammatory reac-
tions in Nepal. Trans R Soc Trop Med Hyg 2004; 98: 602–9. WHO, 2003.
7. Biosca G, et al. Methotrexate treatment for type 1 (reversal) lep- 2. Ferguson IR. Leptospirosis update. BMJ 1991; 302 128–9. tions that principally affects the skin, nervous system,
rosy reactions. Clin Infect Dis 2007; 45: e7–e9. 3. CDC. Outbreak of leptospirosis among white-water rafters— heart, and joints, and can be divided into 3 stages. In the
8. De Sena CBC, et al. Cyclosporine A treatment of leprosy pa- Costa Rica, 1996. MMWR 1997; 46: 577–9. early stage a characteristic skin lesion (erythema migrans)
tients with chronic neuritis is associated with pain control and 4. Guidugli F, et al. Antibiotics for leptospirosis. Available in The occurs at the site of the tick bite and may be accompanied
reduction in antibodies against nerve growth factor. Lepr Rev Cochrane Database of Systematic Reviews; Issue 4. Chichester:
2006; 77: 121–9. John Wiley; 2000 (accessed 16/05/05). by flu-like or meningitis-like symptoms. This may be fol-
9. Smith WCS, et al. Steroid prophylaxis for prevention of nerve 5. Ferguson I. Uncommon infections I: leptospirosis. Prescribers’ lowed weeks or months later by signs of disseminated in-
function impairment in leprosy: randomised placebo controlled J 1991; 31: 185–9. fection, including neurological and cardiac abnormalities,
trial (TRIPOD 1). BMJ 2004; 328: 1459–62.
6. Ferguson IR. Leptospirosis surveillance: 1990-1992. Commun and even years later by chronic arthritis and the late skin
10. Moreira AL, et al. Comparison of pentoxifylline, thalidomide Dis Rep 1993; 3: R47–R48.
and prednisone in the treatment of ENL. Int J Lepr Other Myco-
7. Anonymous. Leptospira outbreak in cattle and man. J R Coll
manifestation acrodermatitis chronica atrophicans, both
bact Dis 1998; 66: 61–5.
11. Faber WR, et al. Treatment of recurrent erythema nodosum lep- Gen Pract 1985; 35: 36. signs of persistent infection.
rosum with infliximab. N Engl J Med 2006; 355: 739. 8. Watt G, et al. Placebo-controlled trial of intravenous penicillin Appropriate treatment should prove curative, especially
12. Sansarricq H, ed. Multidrug therapy against leprosy: develop- for severe and late leptospirosis. Lancet 1988; i: 433–5.
ment and implementation over the past 25 years. Geneva: 9. Panaphut T, et al. Ceftriaxone compared with sodium penicillin in the early stages. Recommendations for treatment1-4 give
WHO, 2004. Available at: http://www.who.int/lep/resources/ G for treatment of severe leptospirosis. Clin Infect Dis 2003; 36: oral tetracyclines (doxycycline or tetracycline) and the
MDT_Full.pdf (accessed 28/06/07) 1507–13. beta-lactam antibacterials (amoxicillin, phenoxymethyl-
13. Ji B, et al. High relapse rate among lepromatous leprosy patients 10. Suputtamongkol Y, et al. An open, randomized, controlled trial
treated with rifampin plus ofloxacin daily for 4 weeks. Antimi- of penicillin, doxycycline, and cefotaxime for patients with se-
penicillin, or cefuroxime) as the antibacterials of choice
crob Agents Chemother 1997; 41: 1953–6. vere leptospirosis. Clin Infect Dis 2004; 39: 1417–24. for early Lyme disease in the absence of neurological
14. WHO. Chemotherapy of leprosy. WHO Tech Rep Ser 847 1994. 11. Takafuji ET, et al. An efficacy trial of doxycycline chemoproph- symptoms or advanced AV block. Treatment is usually for
Also available at: http://libdoc.who.int/trs/WHO_TRS_847.pdf ylaxis against leptospirosis. N Engl J Med 1984; 310: 497–500.
(accessed 13/07/07) 14 days (range 10 to 21 days for doxycycline and 14 to 21
15. Villahermosa LG, et al. Parallel assessment of 24 monthly doses days for amoxicillin or cefuroxime). The macrolides (azi-
of rifampin, ofloxacin, and minocycline versus two years of thromycin, clarithromycin, erythromycin, and roxithro-
World Health Organization multi-drug therapy for multi-bacil- Listeriosis
lary leprosy. Am J Trop Med Hyg 2004; 70: 197–200. Listeriosis is caused by Listeria monocytogenes, a Gram- mycin) are less effective and should only be used in pa-
16. Single-lesion Multicentre Trial Group. Efficacy of single-dose positive bacterium widespread in the environment and ca- tients allergic to, or who cannot be given, the first-line
multidrug therapy for the treatment of single-lesion paucibacil-
pable of growing at low temperatures. Increased aware- agents.2,3 Young children (usually specified as below 8
lary leprosy. Lepr Rev 1997; 68: 341–9.
17. Lockwood DNJ. Rifampicin/minocycline and ofloxacin (ROM) ness of L. monocytogenes as a human pathogen has fol- years of age in the US and below 12 years in the UK) may
for single lesions—what is the evidence? Lepr Rev. 1997; 68: lowed epidemics of listeriosis associated with the be given amoxicillin or cefuroxime.1,3 Pregnant women
299–300. should avoid tetracyclines but may be given any of the oth-
18. Katoch VM. Is there a microbiological rationale for single-dose consumption of contaminated food products including soft
treatment of leprosy? Lepr Rev 1998; 69: 2–5. cheeses, coleslaw, and milk. L. monocytogenes has since er oral regimens.1,3
19. World Health Organisation Leprosy Unit. Risk of relapse in lep- been detected in many types of food, especially uncooked Adults and children presenting with neurological symp-
rosy. Indian J Lepr 1995; 67: 13–26.
20. Smith CM, Smith WCS. Chemoprophylaxis is effective in the hot dogs, undercooked chicken, and pâté. It has been toms, either early or late, should be treated with intrave-
prevention of leprosy in endemic countries: a systematic review acknowledged1-3 that it is a relatively rare infection and nous ceftriaxone, cefotaxime, or benzylpenicillin for 14 to
and meta-analysis. J Infect 2000; 41: 137–42. that despite epidemics associated with identified food 28 days. Patients allergic to cephalosporins or penicillins
21. Moet FJ, et al. COLEP Study Group. Effectiveness of single
dose rifampicin in preventing leprosy in close contacts of pa- products it typically occurs sporadically and the source is may be given oral doxycycline 200 to 400 mg daily in 2
tients with newly diagnosed leprosy: cluster randomised con- usually not certain. Infection occurs primarily in pregnant divided doses.1,3 Early Lyme disease with cardiac compli-
trolled trial. BMJ 2008; 336: 761–4. women, neonates, the elderly, and immunocompromised cations may be treated with either an oral or intravenous
22. WHO. Global strategy for further reducing the leprosy burden
and sustaining leprosy control activities (plan period: 2006— patients. Clinical manifestations vary. Pregnant women antibacterial for 14 to 21 days. Lyme arthritis can general-
2010). Geneva: WHO, 2005. Available at: http://www.who.int/ may have relatively mild flu-like symptoms, but infection ly be effectively treated with one of the oral regimens giv-
lep/resources/GlobalStrategy.pdf (accessed 13/12/06) may result in spontaneous abortion, fetal death, or perina- en for 28 days. Patients with ongoing or recurrent joint
tal sepsis or meningitis in the neonate. Non-perinatal liste- pain after the initial treatment course may be re-treated
Leptospirosis riosis may cause sepsis but commonly presents as menin- with either another 4-week course of oral antibacterials or
Leptospirosis1 is an infectious disease caused by serovars gitis. Endocarditis has occurred in patients with cardiac with intravenous ceftriaxone for 2 to 4 weeks. Acroderma-
of the spirochaete Leptospira interrogans, the commonest lesions. Focal infections after initial bacteraemia occur titis chronica atrophicans may be treated with an oral an-
in the UK being L. hardjo and L. icterohaemorrhagiae.2 mainly in immunocompromised patients. tibacterial for 21 days.3
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
178 Antibacterials
A small percentage of patients continue to experience non- on anecdotal regimens until, in a study from Thailand,4 in- festations of meningitis in older children and adults, in-
specific symptoms after appropriate treatment of Lyme travenous ceftazidime halved the mortality of severe cluding fever, headache, neck stiffness, photophobia, con-
disease; there is some controversy over whether prolonged melioidosis when compared with conventional parenteral fusion, and vomiting, are rarely present in infants. In
treatment is effective in these patients and studies have treatment with high doses of chloramphenicol intrave- general, the younger the patient, the more subtle and atyp-
suggested otherwise.5-7 The use of antibacterials in pa- nously, doxycycline, and co-trimoxazole. As a result ical are the signs and symptoms. Fatality rates can be as
tients with chronic (more than 6 months) subjective symp- ceftazidime came to be considered the treatment of choice low as 2% in infants and children, and as high as 20 to 30%
toms after recommended treatment is hotly debated8,9 but for septicaemic melioidosis.2 A systematic review5 of in neonates and adults depending on the causative bacteria
the Infectious Diseases Society of America (IDSA) does treatment of acute melioidosis has also concluded that reg- and patient’s age. Brain damage, transient or permanent
not support such therapy.3 imens should contain ceftazidime or imipenem parenteral- deafness, or learning disability may occur in up to one-
Adults and older children co-infected with A. phagocy- ly. Parenteral treatment for a minimum of 7 days is fol- third of survivors.1,2 A less common but more severe (of-
tophilum should be treated with doxycycline for 10 days. lowed by oral maintenance therapy with amoxicillin- ten fatal) form of meningococcal disease is meningococcal
In the US, recommended treatment for severely ill children clavulanic acid or the conventional regimen (chloram- septicaemia which is characterised by a widespread haem-
less than 8 years of age is doxycycline for 4 to 5 days fol- phenicol, doxycycline, and co-trimoxazole);1,4 amoxicil- orrhagic rash, acute adrenal insufficiency, and rapid circu-
lowed by amoxicillin or cefuroxime to complete a 14-day lin-clavulanic acid has shown promise4 and appears to be latory collapse.1 (For further information see Meningococ-
course. Patients with mild illness and who cannot be given a safe alternative to the conventional regimen for the oral cal Infections, below p.179.)
a tetracycline may be given rifampicin 300 mg twice daily treatment of melioidosis.6 However, resistance to ceftazi-
for 7 to 10 days plus amoxicillin or cefuroxime.3 dime and amoxicillin-clavulanic acid has been reported,7 Choice of treatment. Bacterial meningitis is a medical
Preventive measures against Lyme disease include the use emphasising the importance of careful monitoring for the emergency and almost universally requires hospitalisa-
of tick repellents, physical protection,3,10,11 and prompt re- emergence of resistance during treatment. Ceftazidime tion. Death may occur in a matter of hours if left untreated.
moval of attached ticks.3 Most guidelines3,10 do not sup- plus co-trimoxazole, both given intravenously, has been Outcome is worse if treatment is delayed and therefore
port the use of empirical antibacterial therapy or serologic advocated by some for severe melioidosis, especially in doctors in the UK are advised3,4 to give emergency treat-
testing after tick bites as generally the risk of infection is patients with septicaemia.8 ment with parenteral benzylpenicillin in all suspected cas-
low,12 particularly if the tick is removed promptly. The risk B. pseudomallei has the potential for prolonged latency as es of meningitis before transfer to hospital. Alternative an-
of infection may, however, be greater if the tick has fed to demonstrated by a Vietnam war veteran who presented tibacterials include a third generation cephalosporin or
repletion.13 A study14 has shown that empirical treatment with melioidosis of the bone 18 years after exposure to the chloramphenicol.3,5 Patients with suspected or confirmed
with a single dose of doxycycline given within 72 hours of organism.9 He was treated with ceftriaxone intravenously bacterial meningitis should have blood and/or CSF sam-
a tick bite may be warranted in endemic areas where the for 8 weeks followed by oral ciprofloxacin. ples taken for culture and receive empirical therapy until
probability of infection is high. Although routine antibac- 1. White NJ. Melioidosis. Lancet 2003; 361: 1715–22. the causative organism has been identified and susceptibil-
terial prophylaxis is not recommended by the IDSA,3 they 2. Dance DAB. Pseudomonas pseudomallei: danger in the paddy ity patterns have become available.4,6,7 Empiric antibacte-
fields. Trans R Soc Trop Med Hyg 1991; 85: 1–3. rials are given intravenously in relatively high doses, and
recommend that a single dose of doxycycline may be giv- 3. Guard RW, et al. Melioidosis in far north Queensland: a clinical
en provided that the tick has been attached for 36 hours or and epidemiological review of twenty cases. Am J Trop Med Hyg
treatment should be targeted at specific organisms as soon
more, prophylaxis can be started within 72 hours of the 1984; 33: 467–73. as the results of blood and/or CSF cultures are known. The
time of tick removal, and the tick species can be identified 4. White NJ, et al. Halving of mortality of severe melioidosis by choice of empirical therapy depends on the bacterial path-
ceftazidime. Lancet 1989; ii: 697–701. ogens (and their antibacterial susceptibility patterns) that
as I. scapularis. Lyme disease vaccines are available in 5. Samuel M, Ti TY. Interventions for treating melioidosis. Availa-
some countries. ble in The Cochrane Database of Systematic Reviews; Issue 4. are most likely to have caused meningitis and varies with
1. Steere AC. Lyme disease. N Engl J Med 2001; 345: 115–25. Chichester: John Wiley; 2002 (accessed 16/05/05). age and the presence of predisposing factors such as trau-
2. Loewen PS, et al. Systematic review of the treatment of early 6. Rajchanuvong A, et al. A prospective comparison of co-amoxi- ma or neurosurgery. Guidelines have been published for
Lyme disease. Drugs 1999; 57: 157–73. clav and the combination of chloramphenicol, doxycycline, and the UK4,6,8 and the USA,7 and country specific guidelines
3. Wormser GP, et al. The clinical assessment, treatment, and pre- co-trimoxazole for the oral maintenance treatment of melioido-
vention of Lyme disease, human granulocytic anaplasmosis, and sis. Trans R Soc Trop Med Hyg 1995; 89: 546–9. should be consulted where available. In most countries, a
babesiosis: clinical practice guidelines by the Infectious Diseas- 7. Dance DAB, et al. Development of resistance to ceftazidime and third generation cephalosporin (high-dose ceftriaxone or
es Society of America. Clin Infect Dis 2006; 43: 1089–1134. co-amoxiclav in Pseudomonas pseudomallei. J Antimicrob cefotaxime) is recommended as empirical treatment for
Also available at: http://www.journals.uchicago.edu/ Chemother 1991; 28: 321–4.
doi/pdf/10.1086/508667 (accessed 18/08/08) 8. Sookpranee M, et al. Multicenter prospective randomized trial
bacterial meningitis in adults and children. These drugs are
4. Wormser GP. Early Lyme disease. N Engl J Med 2006; 354: comparing ceftazidime plus co-trimoxazole with chlorampheni- active against N. meningitidis, most Str. pneumoniae
2794–2801. col plus doxycycline and co-trimoxazole for treatment of severe strains, and H. influenzae, and penetrate CSF well. How-
5. Klempner MS, et al. Two controlled trials of antibiotic treat- melioidosis. Antimicrob Agents Chemother 1992; 36: 158–62.
ment in patients with persistent symptoms and a history of Lyme ever, in situations where ceftriaxone or cefotaxime are not
9. Koponen MA, et al. Melioidosis: forgotten but not gone. Arch
disease. N Engl J Med 2001; 345: 85–92. Intern Med 1991; 151: 605–8. available or are unaffordable, a combination of ampicillin
6. Kaplan RF, et al. Cognitive function in post-treatment Lyme and chloramphenicol or chloramphenicol alone may be
disease: do additional antibiotics help? Neurology 2003; 60:
1916–22. used as an alternative.9 For those patients allergic to both
7. Krupp LB, et al. Study and treatment of post Lyme disease
Meningitis penicillins and cephalosporins, a combination of vanco-
(STOP-LD): a randomized double masked clinical trial. Neurol- Meningitis refers to infection of the subarachnoid space mycin and chloramphenicol may be given.4 In patients
ogy 2003; 60: 1923–30. and meninges, which may be caused by viruses, bacteria, over 55 years ampicillin should be added to cover Liste-
8. Auwaerter PG. Point: antibiotic therapy is not the answer for protozoa, or fungi. The symptoms and signs of meningitis
patients with persisting symptoms attributable to lyme disease. ria.6 Empirical treatment in neonates may include cefotax-
Clin Infect Dis 2007; 45: 143–8. result from the host inflammatory response to infection. ime, ampicillin to cover Listeria, and an aminoglycoside to
9. Stricker RB. Counterpoint: long-term antibiotic therapy im- Whereas viruses cause the majority of generally mild cas- cover Gram-negative organisms.7,10 In the USA and other
proves persistent symptoms associated with lyme disease. Clin es of infectious meningitis, bacterial meningitis is usually
Infect Dis 2007; 45: 149–57. areas where penicillin and cephalosporin-resistant pneu-
10. American Academy of Pediatrics Committee on Infectious Dis- a more serious condition. Meningitis may occasionally be mococci or meticillin-resistant staphylococci are encoun-
eases. Prevention of Lyme disease. Pediatrics 2000; 105: a manifestation of non-infectious (auto-immune or neo- tered, vancomycin (with or without rifampicin) should be
142–7. plastic) disease. This section discusses bacterial meningitis
11. Hayes EB, Piesman J. How can we prevent Lyme disease? N given with a third-generation cephalosporin to children or
Engl J Med 2003; 348: 2424–30. and its management. For reference to fungal meningitis, adults with bacterial meningitis.4,6-8 Vancomycin together
12. Shapiro ED, et al. A controlled trial of antimicrobial prophylax- see p.520. with ceftazidime (or/cefepime or meropenem) should be
is for Lyme disease after deer-tick bites. N Engl J Med 1992;
327: 1769–73. The bacteria most often encountered in adult or childhood given to patients with meningitis complicating neurosur-
13. Matuschka F-R, Spielman A. Risk of infection from and treat- meningitis are Neisseria meningitidis (meningococci) and gery, head trauma, or CSF shunts. Because of concern of
ment of tick bite. Lancet 1993; 342: 529–30. Streptococcus pneumoniae (pneumococci). N. meningi-
14. Nadelman RB, et al. Prophylaxis with single-dose doxycycline
suboptimal CSF penetration, vancomycin should not be
for the prevention of Lyme disease after an Ixodes scapularis tidis A, C, and W135 are the main subtypes involved in used alone in patients with meningitis due to resistant
tick bite. N Engl J Med 2001; 345: 79–84. epidemics in the African meningitis belt, whereas B and C pneumococci or staphylococci, especially when dexame-
subtypes are responsible for outbreaks in Europe and thasone is given as well. The duration of antibacterial treat-
North America. In neonates, infants, pregnant women, im- ment depends on the organism isolated. For Str. pneumoni-
Lymphogranuloma venereum
munocompromised patients, and the elderly, Listeria ae 10 to 14 days of treatment is recommended and for H.
See under Sexually Transmitted Diseases, p.192.
monocytogenes and Gram-negative bacilli may also be en- influenzae 7 to 14 days. For N. meningitidis 7 days, treat-
countered, and Str. agalactiae may cause meningitis in ne- ment is sufficient. In L. monocytogenes and group B strep-
Melioidosis onates and infants. Haemophilus influenzae meningitis tococcal meningitis, antibacterials should be given for a
Melioidosis is caused by the Gram-negative aerobic bacte- was a common cause of meningitis in infants and young minimum of 14 to 21 days while Gram-negative bacilli
rium Burkholderia pseudomallei (Pseudomonas pseu- children before the availability of H. influenzae type b should be treated for a minimum of 3 weeks.7,11
domallei), and has been found mainly in south-east Asia vaccine, and this pathogen is still encountered in non-
and northern Australia.1 Its true incidence and distribution vaccinated young children, particularly in resource-poor Chloramphenicol is effective for the treatment of epidemic
may be much wider than originally thought;2 diagnosis is countries. Meningitis after head trauma, neurosurgery, or meningococcal meningitis and is the drug of choice for pa-
difficult because of the broad spectrum of clinical manifes- in the presence of CSF shunts is not infrequently caused by tients over 1 year of age in areas with limited health facil-
tations. Pulmonary melioidosis is probably the commonest staphylococci (both Staphylococcus aureus and coagulase- ities.1,12 An intramuscular dose of ceftriaxone (100 mg/kg
form and has been treated with doxycycline for 3 to 6 negative staphylococci) or Gram-negative bacilli. to a maximum of 4 g) was found to be as effective as an
months.3 Chronic or subacute non-bacteraemic melioido- The bacteria are transmitted from person to person through intramuscular dose of oily chloramphenicol (100 mg/kg to
sis has also been treated long term with tetracycline or co- droplets of respiratory or throat secretions. Infection is a maximum of 3 g) for the treatment of meningococcal
trimoxazole.3 spread by prolonged close contact (such as kissing, sneez- meningitis during epidemics in resource-poor settings.13
Septicaemic melioidosis is an important cause of death in ing and coughing, living in close quarters or dormitories, For children under 2 months, intravenous ampicillin for 7
Thailand. Because B. pseudomallei is intrinsically resist- and sharing eating or drinking utensils). The average incu- days is recommended to cover Listeria, while for children
ant to many antibacterials, including aminoglycosides and bation period is 4 days, ranging between 2 and 10 days. aged between 2 months and 1 year, intramuscular ceftriax-
the early beta lactams, it has been unresponsive to many The clinical presentation of acute bacterial meningitis is one for 5 days or intravenous ampicillin for 7 days may be
empirical regimens for septicaemia.2 Treatment was based largely dependent on the patient’s age. The classic mani- used.12
 Antibacterials 179
Prophylaxis. Immunisation is the most effective way of is estimated that a mass immunisation campaign, promptly 14. Fraser A, et al. Antibiotics for preventing meningococcal infec-
tions. Available in The Cochrane Database of Systematic Re-
preventing bacterial meningitis in children. Vaccination is implemented, can avoid 70% of cases.1 views; Issue 4. Chichester: John Wiley; 2006 (accessed
also recommended for travellers to areas affected by Adjunctive treatment. Mortality and morbidity, includ- 29/07/08).
meningococcal outbreaks and is compulsory for pilgrims 15. van de Beek D, et al. Corticosteroids for acute bacterial menin-
ing deafness in children, remain high in meningitis despite gitis. Available in The Cochrane Database of Systematic Re-
going to Saudi Arabia. Several vaccines are available to effective antibacterial therapy. Endotoxins and other mi- views; Issue 1. Chichester: John Wiley; 2007 (accessed
prevent bacterial meningitis. Unconjugated polysaccha- crobial products, released from bacteria after antibacterial 20/08/07).
ride vaccines against N. meningitidis subtypes A, C, Y, 16. Scarborough M, et al. Corticosteroids for bacterial meningitis in
treatment, are able to elicit a severe inflammatory re- adults in sub-Saharan Africa. N Engl J Med 2007; 357:
and/ or W135, in various combinations, have been availa- sponse, suggesting that anti-inflammatory drugs may be of 2441–50.
ble for many years and are recommended for children old- benefit. A systematic review15 of adjunctive corticosteroid 17. Nguyen THM, et al. Dexamethasone in Vietnamese adolescents
er than 2 years who are at high risk of infection, such as and adults with bacterial meningitis. N Engl J Med 2007; 357:
therapy concluded that corticosteroids reduce mortality, 2431–40.
those with asplenia and with terminal complement defi- neurological sequelae, and especially the risk of severe 18. Oates-Whitehead RM, et al. Fluid therapy for acute bacterial
ciencies, and students living in dormitories. A newer con- hearing loss in both children and adults. This systematic meningitis. Available in The Cochrane Database of Systematic
jugated tetravalent ACWY meningococcal vaccine pro- Reviews; Issue 3. Chichester: John Wiley; 2005 (accessed
review concludes that corticosteroids should be given be- 16/03/06).
tects against A, C, W135 and Y meningococcal subtypes fore, or with the first dose of antibacterial in adults; the 19. Yogev R, Guzman-Cottrill J. Bacterial meningitis in children:
and is now a visa requirement for pilgrims to Saudi Arabia. same recommendations apply to children living in high- critical review of current concepts. Drugs 2005; 65: 1097–112.
A monovalent conjugate vaccine against N. meningitidis income countries. However, results from a study in sub-
subtype C has recently been licensed in developed coun- Saharan Africa16 did not support the routine use of adjunc- Meningococcal infections
tries for use in children and adolescents. This conjugate tive corticosteroids in the treatment of adults with bacterial Meningococcal disease1-3 refers to systemic infection with
vaccine produces better protection than unconjugated meningitis in resource-poor countries where Strep. pneu- Neisseria meningitidis and may present clinically either as
polysaccharide vaccine, in children under 2 years of age.1,3 moniae is the main pathogen and where a large number of meningitis or septicaemia, or both. Less common forms of
For further information on meningococcal vaccines see, patients are also likely to have advanced HIV disease. An- metastatic meningococcal infection include polyarthritis,
p.2224. The newer conjugate Haemophilus vaccines (see other study17 of dexamethasone in Vietnamese patients pericarditis, pneumonitis, and genito-urinary-tract infec-
p.2213) are similarly more immunogenic than the polysac- over 14 years of age with suspected bacterial meningitis tions. N. meningitidis is a Gram-negative bacterium, oc-
charide vaccine, and universal immunisation of infants reported that dexamethasone did not improve survival in curring worldwide, and is classified into several serotypes.
with these conjugate vaccines has been associated with all patients; significant benefit was only seen in patients Serotypes A, C, and W135 are responsible for epidemic
more than 99% reduction in invasive H. influenzae type b with proven bacterial meningitis, including those given meningitis in sub-Saharan Africa, while serotypes B and C
diseases in developed countries.2 In 2000, a conjugate vac- prior treatment with antibacterials. This finding was are the cause of outbreaks in Europe and North America.
cine, directed against the seven most prevalent invasive thought to be due to patients with tuberculosis meningitis The number of cases of meningococcal disease due to se-
pneumococcal strains in the USA, was approved for rou- in the treatment group. rotype C has decreased significantly after the introduction
tine childhood immunisation. Three doses of this vaccine, of vaccination in developed countries.
given at 2, 4, and 6 months of age, were associated with a Careful management of fluid and electrolyte balance may
be important in the treatment of meningitis and fluid re- Infections are more common in young children under 5
reduction of more than 90% in invasive pneumococcal in- years of age and in adolescents. N. meningitidis only in-
fections, including sepsis and meningitis.2 For further in- striction to prevent cerebral oedema has been widely advo-
cated and used in children.18,19 This practice was based on fects humans and about 10 to 25% of the population may
formation on pneumococcal vaccines see, p.2231. be carriers of the organism. The bacteria are carried in the
reports of hyponatraemia which were attributed to inap-
Close contacts of patients infected with meningococcus A, propriately increased concentrations of antidiuretic hor- pharynx and may sometimes penetrate the mucosa and
C, Y, or W135 and aged over 2 years should be offered mone. However, subsequent studies have suggested that spread through the bloodstream causing systemic disease
tetravalent meningococcal vaccine.2-4,11 Those over 3 the raised concentration of antidiuretic hormone may be an that may rapidly progress to shock and death. Patients with
months and exposed to serogroup A infection may also be appropriate host response to hypovolaemia, and that more meningococcal disease and asymptomatic nasopharyngeal
given a tetravalent meningococcal vaccine, while those liberal use of parenteral fluids may be beneficial.2 A sys- carriers may spread meningococcal infection via respirato-
over 2 months of age and exposed to serogroup C infection tematic review18 concluded that there is some evidence to ry droplets or throat secretions. Close and prolonged con-
who are unimmunised or incompletely immunised may be support the use of intravenous fluids, in preference to re- tact such as kissing, sneezing and coughing, living in close
vaccinated with a meningococcal C vaccine. Those who stricted fluid intake, particularly in the first 48 hours in set- quarters, and sharing eating or drinking utensils are estab-
completed a course more than one year before should be tings with high mortality rates. However, where children lished risk factors.1,2,4 Symptoms and signs during the ear-
offered a booster.3 All unimmunised index cases under the present early and mortality rates are lower, there is proba- ly stage of meningococcal disease are non-specific and in-
age of 25 years should also be offered a meningococcal C bly little benefit and insufficient evidence to guide prac- clude fever, vomiting, malaise, and lethargy. Most patients
vaccine. Cases of confirmed serogroup C disease who tice; it has been suggested that fluids should not be restrict- with meningococcal septicaemia develop a vasculitic rash
have previously been immunised with meningococcal C ed in children.11 The British Infection Society working (petechiae or purpura) which is often scant or absent in pa-
or tetravalent vaccines should be offered a meningococcal party4,6 recommends that adult patients with meningitis tients with meningitis. Purpuric rash, drowsiness or im-
C vaccine before discharge from hospital.3 should not be fluid restricted in an attempt to reduce cere- paired consciousness, and shock are late presentations and
bral oedema. associated with high mortality rates, which may be up to
Antibacterial treatment does not eliminate nasopharyngeal 1. WHO. Meningococcal meningitis. Fact sheet No. 141 2003.
50% in severe forms. Meningococcal meningitis usually
carriage of N. meningitidis and chemoprophylaxis should Available at: http://www.who.int/mediacentre/factsheets/ presents with headache, neck stiffness, photophobia, and
be given to close contacts of the index case (irrespective of fs141/en (accessed 16/03/06) drowsiness. Mortality from meningococcal meningitis is
vaccination status) to reduce the risk of invasive disease.3 2. Sáez-Llorens X, McCracken GH. Bacterial meningitis in chil- less than in septicaemia and may be below 5% with
dren. Lancet 2003; 361: 2139–48.
A systematic review14 found that ceftriaxone, cipro- 3. Health Protection Agency. Guidance for public health manage-
prompt treatment.1,2,5
floxacin, and rifampicin were all effective at eradicating ment of meningococcal disease in the UK (issued August 2006). Guidelines for prevention and control of meningococcal
carriage for up to 2 weeks although resistance to ri- Available at: http://www.hpa.org.uk/web/HPAwebFile/ disease have been developed for the UK6 and the USA.7,8
fampicin may occur after prophylactic treatment; penicil- HPAweb_C/1194947389261 (accessed 28/07/08)
4. Begg N, et al. British Infection Society Working Party. Consen- Choice of treatment. Mortality is reduced by early recog-
lin was less effective. Oral rifampicin twice daily for 2 sus statement on diagnosis, investigation, treatment and preven- nition of the disease and prompt treatment with antibacte-
days (or a single oral dose of ciprofloxacin or a single dose tion of acute bacterial meningitis in immunocompetent adults. J rials. In the UK doctors are advised that if meningococcal
of intramuscular ceftriaxone) should be started in the close Infect 1999; 39: 1–15.
disease is suspected, benzylpenicillin should be given
contacts within 24 hours or as soon as possible after diag- 5. Sudarsanam T, et al. Pre-admission antibiotics for suspected
cases of meningococcal disease. Available in The Cochrane Da- parenterally, preferably intravenously, before transfer to
nosis of the index case. If further cases occur within a tabase of Systematic Reviews; Issue 1. Chichester: John Wiley; hospital.1,5,6 Alternative antibacterials include a third gen-
group of close contacts within 4 weeks of receiving proph- 2008 (accessed 29/07/08). eration cephalosporin or chloramphenicol.6 Both initial
ylaxis with rifampicin, then repeat prophylaxis should be 6. British Infection Society. Early management of suspected bac- empiric and later treatment may be with benzylpenicillin,
terial meningitis and meningococcal septicaemia in immuno-
with either ciprofloxacin or ceftriaxone. Index cases (ex- competent adults—second edition (12/04). Available at: ampicillin, chloramphenicol, or third-generation cepha-
cept those whose disease was treated with ceftriaxone) h t t p : / / w w w. b r i t i s h i n f e c t i o n s o c i e t y. o r g / d o c u m e n t s / losporins such as cefotaxime or ceftriaxone. Oily chloram-
should be given antibacterial prophylaxis before discharge MeningitisAlgorithm03.pdf (accessed 18/08/08)
phenicol or ceftriaxone are used during epidemics in Afri-
from hospital.3 Chemoprophylaxis is also recommended 7. Tunkel AR, et al. Infectious Diseases Society of America. Prac-
tice guidelines for the management of bacterial meningitis. Clin ca and in areas with limited health facilities.
for health care workers whose mouth or nose is directly Infect Dis 2004; 39: 1267–84. Also available at: http:// Uncomplicated meningococcal disease usually requires 7
exposed to large particle droplets or secretions from the www.journals.uchicago.edu/doi/pdf/10.1086/425368 (accessed days of antibacterial treatment.4,5,9,10 For further details of
respiratory tract of a probable or confirmed index case of 18/08/08)
8. Heyderman RS; British Infection Society. Early management of
the treatment of meningococcal meningitis, including the
meningococcal disease during acute illness and until 24 suspected bacterial meningitis and meningococcal septicaemia treatment of close contacts, see Meningitis, above. Immu-
hours of systemic antibacterial treatment has been com- in immunocompetent adults—second edition. J Infect 2005; 50: nisation is the most effective way of preventing meningo-
pleted.3 Similarly, treatment of H. influenzae meningitis 373–4.
coccal meningitis and several vaccines are available (see
does not eliminate nasopharyngeal carriage of the organ- 9. Prasad K, et al. Third generation cephalosporins versus conven-
tional antibiotics for treating acute bacterial meningitis. Availa- Meningococcal Vaccines, p.2224).
ism and rifampicin should be given to index cases for 4 ble in The Cochrane Database of Systematic Reviews; Issue 4. 1. Welch SB, Nadel S. Treatment of meningococcal infection.
days before discharge from hospital. Anyone who has Chichester: John Wiley; 2007 (accessed 20/06/08). Arch Dis Child 2003; 88: 608–14.
been in direct or prolonged close contact with the infected 10. Heath PT, et al. Neonatal meningitis. Arch Dis Child Fetal Ne- 2. Singh J, Arrieta AC. Management of meningococcemia. Indian
onatal Ed 2003; 88: F173–F178. J Pediatr 2004; 71: 909–13.
persons should also be given rifampicin for 4 days. Unvac- 3. Stephens DS, et al. Epidemic meningitis, meningococcaemia,
11. El Bashir H, et al. Diagnosis and treatment of bacterial menin-
cinated children should be immunised. Chemoprophylaxis gitis. Arch Dis Child 2003; 88: 615–20. and Neisseria meningitidis. Lancet 2007; 369: 2196–2210.
4. WHO. Meningococcal meningitis. Fact sheet No. 141 2003.
is not normally indicated for close contacts of pneumococ- 12. Médecins Sans Frontières. Clinical guidelines: diagnosis and Available at: http://www.who.int/mediacentre/factsheets/fs141/
cal and other types of bacterial meningitis.4,11 treatment manual for curative programmes in hospitals and dis- en (accessed 20/03/06)
pensaries— seventh edition. Paris: MSF, 2006. 5. Meningitis Research Foundation. Meningococcal meningitis
The WHO recommendation for outbreak control is mass 13. Nathan N, et al. Ceftriaxone as effective as long-acting chlo- and septicaemia: diagnosis and treatment in general practice—
ramphenicol in short-course treatment of meningococcal men- fourth edition. Available at: http://www.meningitis.org/assets/
vaccination of persons residing in districts in the epidemic ingitis during epidemics: a randomised non-inferiority study. pdf/health_professionals/GP%20leaflet%2012.03.pdf (ac-
phase as well as surrounding districts in an alert phase. It Lancet 2005; 366: 308–13. cessed 18/08/08)

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
180 Antibacterials
6. Health Protection Agency. Guidance for public health manage- fungi (p.520) such as Madurella mycetomatis are called less threatening to sight than gonococcal infection, but
ment of meningococcal disease in the UK (issued August 2006).
Available at: http://www.hpa.org.uk/web/HPAwebFile/ eumycetomas and those caused by the filamentous bacte- may also infect the nasopharynx and can cause pneumo-
HPAweb_C/1194947389261 (accessed 28/07/08) ria, actinomycetes, are called actinomycetomas. Nocardia nia. Chlamydial conjunctivitis is more common than
7. CDC. Recommendations of the Advisory Committee on Immu- brasiliensis is the commonest actinomycete responsible; gonococcal conjunctivitis in developed countries. Both or-
nization Practices (ACIP): prevention and control of meningo-
coccal disease. MMWR 2005; 54 (RR-7): 1–21. Also available others include Actinomadura madurae, A. pelletieri, and ganisms are sexually transmitted and the infants of moth-
at: http://www.cdc.gov/mmwr/PDF/rr/rr5407.pdf (accessed Streptomyces somaliensis. For details of systemic infec- ers with such genital-tract infections are infected during
20/03/06) tions caused by Nocardia spp., see under Nocardiosis, their passage through the birth canal. Other less serious
8. American Academy of Pediatrics Committee on Infectious Dis-
eases. Prevention and control of meningococcal disease: recom- p.181. bacterial causes of neonatal conjunctivitis include Staphy-
mendations for use of meningococcal vaccines in pediatric pa- Various treatment regimens for actinomycetomas have lococcus aureus, Streptococcus pneumoniae, Haemophil-
tients. Pediatrics 2005; 116: 496–505. Full version: us spp., and Pseudomonas spp.; they are often hospital-ac-
http://pediatrics.aappublications.org/cgi/reprint/116/2/496.pdf been tried. Combined drug treatment is preferred so as to
(accessed 20/03/06) avoid resistance and eradicate residual infection.1 The quired.1
9. Meningitis Research Foundation. Early management of menin- most common regimen is streptomycin and dapsone; co- The management of gonococcal and chlamydial neonatal
gococcal disease in children—sixth edition 08/06. Available at:
http://www.meningitis.org/assets/x/50150 (accessed 18/08/08) trimoxazole may replace dapsone in patients who have not conjunctivitis varies from country to country depending on
10. British Infection Society. Early management of suspected bac- responded to initial treatment after a few months and in the prevalence of gonorrhoea and C. trachomatis infection
terial meningitis and meningococcal septicaemia in immuno- those who cannot tolerate dapsone. Successful treatment and on bacterial resistance.
competent adults—second edition 12/04. Available at:
h t t p : / / w w w. b r i t i s h i n f e c t i o n s o c i e t y. o rg / d o c u m e n t s / has been reported with amikacin, either as monotherapy or • PROPHYLAXIS
MeningitisAlgorithm03.pdf (accessed 18/08/08) with co-trimoxazole.1 Rifampicin, pyrimethamine-sulf- The ideal method of prophylaxis is to treat the infected
adoxine, and sulfonamides have also been tried in resistant mother during pregnancy, but this is not always possi-
Mouth infections infections and are considered suitable for second-line ther- ble. Where the risk of gonococcal infection is high, oc-
Infections of the mouth include those of dental origin such apy.1 Cures were achieved after treatment for 4 to 24 ular prophylaxis at birth is particularly important be-
as dental caries, abscesses, gingivitis, and periodontal in- months. In a study of antibacterial activity in vitro against cause of the rapid onset of conjunctivitis and its
fections, and those without a dental origin. Infections aris- strains of S. somaliensis isolated from mycetoma patients, potential seriousness and is preferable to early diagnosis
ing in the nasal cavity, middle ear, oropharynx, and para- rifampicin was the most effective followed in decreasing and treatment of the neonate.2 Cleansing of the ne-
nasal sinuses can also affect the oral cavity. Emphasis has order of activity by erythromycin, tobramycin, fusidic onate’s eyes immediately after birth followed by the
shifted from treatment to prevention of oral diseases.1 This acid, and streptomycin; all strains were resistant to trimeth- topical application of either tetracycline 1% eye oint-
discussion deals mainly with infections of dental origin. oprim.2 The successful use of hyperbaric oxygen in addi- ment,3,4 erythromycin 0.5% eye ointment,3 or silver ni-
The organisms most often encountered in oral infections tion to co-trimoxazole3 or of amoxicillin-clavulanic acid4 trate 1% eye drops is advised4 and is sometimes re-
are viridans streptococci, a variety of anaerobes, and facul- in the treatment of N. brasiliensis actinomycetoma previ- quired by law.3 Silver nitrate1 is active against all strains
tative streptococci.2 ously resistant to conventional therapy has been described. of N. gonorrhoeae regardless of their susceptibility to
1. Fahal AH. Mycetoma: a thorn in the flesh. Trans R Soc Trop Med antibacterials; it is inexpensive and widely available, but
Dental caries3 is caused by the erosion of tooth enamel Hyg 2004; 98: 3–11.
due to acid produced by bacteria (usually Streptococcus 2. Nasher MA, et al. In vitro studies of antibiotic sensitivities of may cause chemical conjunctivitis and has been ineffec-
mutans) in plaque. Fluoride in various forms is used in Streptomyces somaliensis—a cause of human actinomycetoma. tive in preventing chlamydial conjunctivitis (see below).
dental caries prophylaxis, where it may promote reminer- Trans R Soc Trop Med Hyg 1989; 83: 265–8. Tetracycline has been reported to be as effective as sil-
3. Walker RM, et al. Beneficial effects of hyperbaric oxygen ther- ver nitrate in protecting against gonococcal conjunctivi-
alisation or reduce acid production by plaque bacteria.1 apy in Nocardia brasiliensis soft-tissue infection. Med J Aust
Sugar-free chewing gum can help prevent caries by stimu- 1991; 155: 122–3. tis caused by multiresistant strains5 and WHO now lists
lating the production of saliva.4 Dental caries vaccines 4. Gomez A, et al. Amoxicillin and clavulanic acid in the treatment both drugs as the drugs of choice.4
of actinomycetoma. Int J Dermatol 1993; 32: 218–20. The value of prophylaxis against chlamydial neonatal
have also been investigated.
The term periodontal disease5 encompasses specific con- conjunctivitis is less certain. Tetracycline ointment has
ditions affecting the gingiva and the supporting connective Necrotising enterocolitis been reported to be less effective in preventing chlamy-
tissue and alveolar bone. Gingivitis is thought to be caused See p.173. dial infection than gonococcal infection5 and erythro-
by a non-specific bacterial plaque flora that gradually mycin ointment has also been unreliable.6 Silver nitrate
changes from predominantly Gram-positive to more is generally considered ineffective,1 despite an unex-
Necrotising fasciitis pected reduction in the incidence of chlamydial con-
Gram-negative. Gingivitis may or may not develop into Necrotising fasciitis is a severe soft-tissue infection result-
periodontitis, but periodontitis is always preceded by gin- junctivitis in one study.5 The CDC3 does not recom-
ing in necrosis of the subcutaneous tissue and adjacent fas- mend prophylactic antibacterial treatment for infants
givitis. Periodontitis is associated with a Gram-negative cia, together with severe systemic illness. It may be caused
anaerobic microflora. Most gingivitis and periodontitis born to mothers with untreated chlamydial infection.
by a mixture of aerobic and anaerobic organisms, but can Screening and treatment of pregnant women for C. tra-
can be prevented and treated by adequate oral hygiene and be due to group A streptococci or staphylococci alone and
plaque removal using mechanical means such as tooth- chomatis infection may be a more effective method of
may be associated with a toxic shock syndrome (p.196). control than ocular prophylaxis.5,7 This approach also
brushing. Mechanical removal of calculus is necessary
where the build up is significant. Antiseptics may also help Complete debridement of the infected tissue is considered tackles the more serious problem of pneumonia.8
to reduce plaque accumulation and several, but most nota- essential for treatment. Antibacterial therapy is given as an Neonatal conjunctivitis continues to cause blindness, es-
bly chlorhexidine, have been used.6,7 adjunct and should be continued until no further debride- pecially in developing countries. Povidone-iodine is less
ments are needed.1 Antibacterial treatment regimens expensive and perhaps more readily available in such
Penicillin has continued to be an effective drug in combat-
should cover Gram-positive, Gram-negative, and anaero- countries than silver nitrate or erythromycin. In a study
ing oral pathogens, and erythromycin or metronidazole are
bic organisms. The possibility of infection with group A in Kenya involving more than 3000 infants9 a 2.5% oph-
alternatives. In the UK, the BNF advises against the rou-
Streptococcus or Clostridium species should also be con- thalmic solution of povidone-iodine appeared to be a
tine use of clindamycin in oral infections, but notes that it
sidered. Possible treatment regimens include monotherapy more effective prophylactic than either a 1% ophthalmic
can be used for the treatment of dentoalveolar abscess that
with ertapenem, imipenem, meropenem, piperacillin-tazo- solution of silver nitrate or erythromycin 0.5% eye oint-
has not responded to penicillin or metronidazole. Fusiform
bactam, or tigecycline; multidrug regimens include high- ment. In particular, there were fewer cases of chlamy-
bacteria and spirochaetes have been linked with acute
dose benzylpenicillin and clindamycin plus a fluoroqui- dial conjunctivitis with povidone-iodine.
necrotising ulcerative gingivitis (also called Vincent’s in-
nolone or an aminoglycoside. Until meticillin-resistant
fection or trench mouth);8 systemic metronidazole is often • TREATMENT
staphylococcal infection has been ruled out, treatment reg-
the treatment of choice. Tinidazole has also been used. Tet- All cases of neonatal conjunctivitis should be treated for
imens should also include vancomycin, daptomycin, or
racyclines or metronidazole have been used for chronic both N. gonorrhoeae and C. trachomatis because of the
linezolid.1 Hyperbaric oxygen therapy has also been bene-
periodontal disease.9 Antibacterials and antiseptics deliv- possibility of mixed infection.4 Gonococcal neonatal
ficial although prospective controlled studies are lacking.2
ered locally to the periodontal pocket may be of value.7 conjunctivitis must be treated systemically. WHO4 rec-
Intravenous normal immunoglobulins have also been tried
1. WHO. Recent advances in oral health: report of a WHO expert
in patients with necrotising fasciitis caused by group A ommends ceftriaxone 50 mg/kg by intramuscular injec-
committee. WHO Tech Rep Ser 826 1992. Available at: http:// tion as a single dose (to a maximum of 125 mg) or, if
libdoc.who.int/trs/WHO_TRS_826.pdf (accessed 18/08/08) streptococcus.3
2. Guralnick W. Odontogenic infections. Br Dent J 1984; 156: 1. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diag-
ceftriaxone is not available, spectinomycin 25 mg/kg (to
440–7. nosis and management. Clin Infect Dis 2007; 44: 705–10. a maximum of 75 mg) or kanamycin 25 mg/kg (to a
3. Selwitz RH, et al. Dental caries. Lancet 2007; 369: 51–9. 2. Jallali N, et al. Hyperbaric oxygen as adjuvant therapy in the maximum of 75 mg) by intramuscular injection as a sin-
4. Edgar WM. Sugar substitutes, chewing gum and dental caries— management of necrotizing fasciitis. Am J Surg 2005; 189:
a review. Br Dent J 1998; 184: 29–32. gle dose.
462–6.
5. Pihlstrom BL, et al. Periodontal diseases. Lancet 2005; 366: 3. Kaul R, et al. Population-based surveillance for group A strepto- In the USA, CDC3 recommends a single intravenous or
1809–20. coccal necrotizing fasciitis: clinical features, prognostic indica- intramuscular injection of ceftriaxone 25 to 50 mg/kg
6. Eley BM. Antibacterial agents in the control of supragingival tors, and microbiologic analysis of seventy-seven cases. Am J
plaque—a review. Br Dent J 1999; 186: 286–96. (up to 125 mg) when there is no evidence of disseminat-
Med 1997; 103: 18–24.
7. Greenwell H, Bissada NF. Emerging concepts in periodontal ed infection.
therapy. Drugs 2002; 62: 2581–7.
8. Johnson BD, Engel D. Acute necrotizing ulcerative gingivitis: a
See also under Gonorrhoea (p.191) for the treatment of
review of diagnosis, etiology and treatment. J Periodontol 1986; Neonatal conjunctivitis infants exposed to gonorrhoea at birth or with estab-
57: 141–50. Conjunctivitis of the newborn, also known as ophthalmia lished gonococcal infection at any site.
9. Watts TLP. Periodontitis for medical practitioners. BMJ 1998; neonatorum, is defined as any conjunctivitis with dis-
316: 993–6. For nongonococcal neonatal conjunctivitis WHO4 and
charge occurring during the first 28 days of life.1 That due CDC3 recommend erythromycin 50 mg/kg daily in 4 di-
to Neisseria gonorrhoeae is the most serious; it usually ap- vided doses orally for 14 days; WHO4 recommend co-
Mycetoma pears by the third day after birth and can rapidly result in trimoxazole 240 mg twice daily for 14 days as an alter-
Mycetoma is a localised chronic infection seen especially blindness; systemic infections, especially severe septicae- native. There is no indication that topical therapy is of
in the tropics and subtropics and involving subcutaneous mia, may occur. Chlamydia trachomatis is another major additional benefit.3,4
tissue, bone, and skin. It has been termed Madura foot cause of neonatal conjunctivitis (inclusion conjunctivitis); 1. WHO. Conjunctivitis of the newborn: prevention and treatment
when affecting the sole of the foot. Mycetomas caused by it characteristically occurs 5 to 14 days after birth and is at the primary health care level. Geneva: WHO, 1986.
 Antibacterials 181
2. Laga M, et al. Epidemiology and control of gonococcal ophthal- granuloma), M. ulcerans (Buruli ulcer), M. chelonae (M. fection. There appears to be a tendency to delay starting
mia neonatorum. Bull WHO 1989; 67: 471–8.
3. CDC. Sexually transmitted diseases treatment guidelines 2006.
chelonei), M. abscessus (formerly M. chelonae subspe- prophylaxis until later in the disease process; the
MMWR 2006; 55(RR-11): 1–94. Also available at: http:// cies), or M. fortuitum. Ulcerated lesions due to M. haemo- guidelines5 from the US Public Health Service and the
www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/06/08) philum have been described mainly in immunocompro- Infectious Diseases Society of America (USPHS/ID-
4. WHO. Guidelines for the management of sexually transmitted mised patients. SA) recommend starting prophylaxis at a CD4+ count
in f e c tio ns . G e ne va : W HO , 20 03 . A l s o a v a i la b le a t :
http://whqlibdoc.who.int/publications/2003/9241546263.pdf Pulmonary disease may be clinically indistinguishable of less than 50 cells/microlitre with either azithromycin
(accessed 22/06/04) from pulmonary tuberculosis, and has most frequently or clarithromycin. If these drugs cannot be tolerated
5. Laga M, et al. Prophylaxis of gonococcal and chlamydial oph- been attributed to the M. avium complex (MAC), which then rifabutin may be given as an alternative. Combina-
thalmia neonatorum: a comparison of silver nitrate and tetracy- tion therapy with one of the macrolides and rifabutin is
cline. N Engl J Med 1988; 318: 653–7. includes M. avium and M. avium-intracellulare, or to M.
6. Black-Payne C, et al. Failure of erythromycin ointment for post kansasii, and to a lesser extent M. xenopi; less common not recommended. The US guidelines state that prophy-
natal ocular prophylaxis of chlamydial conjunctivitis. Pediatr causes include M. abscessus, M. asiaticum, M. celatum, laxis need not be lifelong in patients responding to
Infect Dis J 1989; 8: 491–5. HAART; specifically, primary prophylaxis may be
7. Hammerschlag MR, et al. Efficacy of neonatal ocular prophylax- M. chelonae, M. fortuitum, M. malmoense, M. scrofu-
is for the prevention of chlamydial and gonococcal conjunctivi- laceum, M. simiae, and M. szulgai. stopped in patients whose CD4+ count has increased to
tis. N Engl J Med 1989; 320: 769–72. Lymphadenitis, which is usually self-limiting and occurs more than 100 cells/microlitre for 3 months or more, but
8. Schachter J. Why we need a program for the control of Chlamy-
particularly in children under 5 years of age, may be should be restarted if the CD4+ count falls to below 50
dia trachomatis. N Engl J Med 1989; 320: 802–4. to 100 cells/microlitre again. Observational data from a
9. Isenberg SJ, et al. A controlled trial of povidone-iodine as proph- caused by many species but the great majority of cases are
ylaxis against ophthalmia neonatorum. N Engl J Med 1995; 332: due to M. avium complex, M. genavense, M. malmoense, large cohort of patients in the USA found no evidence of
562–6.
and M. scrofulaceum (sometimes collectively known as increased risk of MAC in patients who had stopped pri-
the MAIS complex). mary prophylaxis in accordance with the USPHS/IDSA
Nocardiosis guidelines.6
Dissemination of opportunistic mycobacterial infections
Nocardia spp. are Gram-positive aerobic branching bacte- may occur rapidly in immunocompromised patients. The The US guidelines5 also state that it may be possible to
ria that cause systemic or localised infection. The principal majority of cases have been attributed to the M. avium stop secondary prophylaxis (chronic maintenance ther-
pathogenic species in man is N. asteroides; others include complex; other species implicated include M. abscessus, apy) in HIV-infected patients who have completed at
N. brasiliensis, N. pseudobrasiliensis, and N. caviae. Lo- M. celatum, M. chelonae, M. genavense, M. haemophilum, least 12 months of treatment for MAC, who remain
calised chronic infection or actinomycetoma is described M. kansasii, M. malmoense, M. scrofulaceum, and M. sim- asymptomatic with respect to MAC, and who have a
under Mycetoma (p.180). Systemic nocardiosis is mainly iae. sustained response to HAART (CD4+ count greater
a lung infection and often involves abscess formation; it than 100 cells/microlitre). Secondary prophylaxis
The treatment depends on the site and nature of the infec- should be restarted if CD4+ count falls below 100
occurs especially in immunocompromised patients and tion and whether immunodeficiency is present. Both HIV-
may be disseminated with abscesses in the brain and sub- cells/microlitre.
negative and HIV-positive patients may be affected and
cutaneous tissues. In the UK, however, the British Thoracic Society guide-
the possibility of drug interactions should be borne in mind
The treatment of choice has been a sulfonamide such as lines note there is no general agreement about when
in patients receiving antiretroviral therapy. For further
sulfadiazine or co-trimoxazole,1-5 although a study in vitro prophylaxis should be used. If prophylaxis is to be given
information on drug interactions with antiretrovirals see
indicated that the fixed ratio of trimethoprim:sulfamethox- to patients with a CD4+ count below 50 cells/microlitre
Table 1, p.917, and Table 2, p.944, in Antivirals.
azole in co-trimoxazole might contain too little trimetho- the first drug of choice would be azithromycin; clari-
• MYCOBACTERIUM AVIUM COMPLEX (MAC). thromycin is an alternative and azithromycin with rifab-
prim for optimal activity.6 Sulfafurazole7 has been used
successfully. There have been reports of the effective treat- US guidelines1,2 produced by the CDC, National Insti- utin would be a third choice.3 The UK guidelines, partly
ment of nocardiosis with amikacin,8,9 linezolid,10 minocy- tutes of Health, HIV Medicine Association, and Infec- based on studies which predate the wide use of HAART,
cline,11,12 or ciprofloxacin with doxycycline.13 Other sug- tious Diseases Society of America recommend that the recommend that prophylaxis be continued indefinitely.3
gested alternatives include ceftriaxone, imipenem or treatment of HIV-positive patients with MAC should • MYCOBACTERIUM KANSASII INFECTION.
meropenem.14 Treatment needs to be prolonged and may consist of at least 2 antimycobacterial drugs. Clarithro- UK guidelines state that infections with M. kansasii
continue for 6 to 12 months. mycin is the preferred first drug (with azithromycin as may be treated with rifampicin (or rifabutin) and etham-
1. Abdi EA, et al. Nocardia infection in splenectomized patients: an alternative) and is given with ethambutol. Rifabutin butol.3 Pulmonary disease in HIV-negative patients is
case reports and a review of the literature. Postgrad Med J 1987; may be added as a third drug in patients with advanced usually treated for 9 months whereas HIV-positive pa-
63: 455–8. immunosuppression, high mycobacterial loads, or if the
2. Smego RA, et al. Treatment of systemic nocardiosis. Lancet tients should receive therapy for 2 years or until the spu-
1987; i: 456. patient is not taking effective HAART. The fluoroqui- tum has been negative for 12 months. For disseminated
3. Filice GA. Treatment of nocardiosis. Lancet 1987; i: 1261–2. nolones (ciprofloxacin or levofloxacin) or amikacin infection in HIV-positive patients, clarithromycin
4. Varghese GK, et al. Nocardia brasiliensis meningitis. Postgrad may be given when rifabutin is contra-indicated or not
Med J 1992; 68: 986. should be added and possibly also isoniazid. The place
5. Agterof MJ, et al. Nocardiosis: a case series and a mini review tolerated. In disseminated disease, patients who are not of macrolides and fluoroquinolones in pulmonary or
of clinical and microbiological features. Neth J Med 2007; 65: taking HAART should start antiretroviral treatment at disseminated M. kansasii infection remain to be estab-
199–202. the same time as starting treatment for MAC or at least
6. Bennett JE, Jennings AE. Factors influencing susceptibility of lished. In extrapulmonary disease in HIV-negative pa-
Nocardia species to trimethoprim-sulfamethoxazole. Antimi- 1 to 2 weeks thereafter. Those already on HAART tients, chemotherapy with rifampicin and ethambutol
crob Agents Chemother 1978; 13: 624–7. should continue this treatment. may be used before excision of an infected lymph node.
7. Poland GA, et al. Nocardia asteroides pericarditis: report of a UK guidelines from the British Thoracic Society
case and review of the literature. Mayo Clin Proc 1990; 65: In other extrapulmonary disease the guidelines state that
819–24. (1999)3 for treatment of HIV-positive patients with the data are insufficient to make recommendations, but
8. Goldstein FW, et al. Amikacin-containing regimens for treat- MAC broadly concur with the US recommendations. consider that rifampicin and ethambutol for 9 months
ment of nocardiosis in immunocompromized patients. Eur J
Clin Microbiol 1987; 6: 198–200. Rifampicin or rifabutin, ethambutol, and clarithromycin appears sensible with the addition of protionamide and
9. Meier B, et al. Successful treatment of a pancreatic Nocardia or azithromycin are recommended. A fluoroquinolone streptomycin and/or a macrolide if the condition is not
asteroides abscess with amikacin and surgical drainage. Antimi- such as ciprofloxacin, or even amikacin, may be added responding.3
crob Agents Chemother 1986; 29: 150–1.
10. Moylett EH, et al. Clinical experience with linezolid for the
for patients who are intolerant of first-line drugs or who • OTHER OPPORTUNISTIC MYCOBACTERIA.
treatment of Nocardia infection. Clin Infect Dis 2003; 36: fail to respond. UK guidelines recommend lifelong In M. malmoense and M. xenopi pulmonary disease,
313–18. treatment; the US considers that treatment may be
11. Petersen EA, et al. Minocycline treatment of pulmonary nocar- the UK guidelines recommend that rifampicin and
diosis. JAMA 1983; 250: 930–2. stopped in selected patients (see Chemoprophylaxis, be- ethambutol should be given for 2 years in HIV-negative
12. Naka W, et al. Unusually located lymphocutaneous nocardiosis low). In disseminated disease, the same treatment patients. Extrapulmonary M. malmoense infections
caused by Nocardia brasiliensis. Br J Dermatol 1995; 132: should be given and continued indefinitely. should be treated in the same manner as extrapulmonary
609–13.
13. Bath PMW, et al. Treatment of multiple subcutaneous Nocardia A prospective, randomised study4 undertaken to com- MAC or M. kansasii infections. M. malmoense infection
asteroides abscesses with ciprofloxacin and doxycycline. Post- pare 3 regimens (clarithromycin and ethambutol, clari- rarely occurs in AIDS patients, but if necessary, treat-
grad Med J 1989; 65: 190–1. thromycin and rifabutin, and all 3 drugs) for the treat-
14. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand- ment with rifampicin, ethambutol, and clarithromycin,
book of antimicrobial therapy. 18th ed. New Rochelle NY: The ment of disseminated MAC in patients with AIDS and possibly isoniazid should be used. For M. xenopi in
Medical Letter, 2008: 72. found that all regimens appeared to provide effective HIV-positive patients the guidelines state that there is no
treatment and the differences were not statistically sig- evidence on which to base recommendations; treatment
Nontuberculous mycobacterial infections nificant. However, patients taking the 3-drug regimen as for pulmonary or disseminated MAC infection is sug-
Environmental mycobacteria are widespread, and a had greater overall clinical efficacy, a lower relapse rate, gested.3
number of species other than those responsible for leprosy and a lower risk of death. For pulmonary disease due to rapidly growing bacteria
(p.176) and tuberculosis (p.196) are facultative parasites The British Thoracic Society guidelines (1999)3 state (M. abcessus, M. chelonae, M. fortuitum, and M. gor-
capable of producing disease in man. These organisms, that treatment for HIV-negative patients with MAC donae) and other species (M. genavense, M. haemophil-
which have been referred to as atypical, nontuberculous pulmonary disease should consist of rifampicin and um, M. simiae, M. szulgai, and M. ulcerans) surgery
(NTM), tuberculoid, opportunistic, or MOTT (mycobacte- ethambutol for 24 months, with or without isoniazid. In should be used if possible. Drug therapy should proba-
ria other than tuberculous), are rarely, if ever, transmitted extrapulmonary disease affecting lymph nodes, surgical bly include rifampicin, ethambutol, and clarithromycin.
from person to person but are acquired from the environ- excision of the nodes should be undertaken; chemother- Amikacin, cefoxitin, imipenem, quinolones, and sulfon-
ment. Symptomatic infections are usually associated with apy with rifampicin, ethambutol, and clarithromycin for amides may have a place in treatment. For extrapulmo-
focal or generalised defects in the host’s immune system. up to 2 years should be considered if disease recurs or nary disease due to these organisms, there have been
The diseases produced include localised skin and soft tis- where the excision is incomplete or impossible. In sites several anecdotal reports outlining treatment but there is
sue lesions, pulmonary infections, lymphadenitis, and dis- other than lymph nodes, chemotherapy should be given no evidence from controlled clinical studies.3 Success-
seminated infections. for 18 to 24 months. ful treatment of M. simiae infection in patients with
Cutaneous disease may follow traumatic inoculation with Prophylactic treatment is used to reduce the incidence AIDS was reported with clarithromycin, ethambutol,
Mycobacterium marinum (‘swimming pool’ or ‘fish-tank’ of disseminated MAC disease in patients with HIV in- and ciprofloxacin.7 Surgical treatment and intensive
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
182 Antibacterials
antibacterial regimens have been used for M. scrofu- 12. Laing RBS, et al. Antimicrobial treatment of fish tank granulo- acetic acid) and antibacterials such as aminoglycosides,
ma. J Hand Surg (Br) 1997; 22B: 135–7.
laceum infections.8 Symptomatic improvement was 13. Gray SF, et al. Fish tank granuloma. BMJ 1990; 300: 1069–70. fluoroquinolones (ciprofloxacin and ofloxacin), chloram-
achieved in an AIDS patient with M. celatum infection 14. Laing RBS, et al. New antimicrobials against Mycobacterium phenicol, or polymyxin B, with or without corticosteroids
with a regimen of isoniazid, rifampicin, and ethambu- marinum infection. Br J Dermatol 1994; 131: 914. such as dexamethasone.1,3 Antifungals may sometimes be
15. American Thoracic Society. Diagnosis and treatment of disease
tol.9 caused by nontuberculous mycobacteria. Am J Respir Crit Care required. A wick may be used if instillation proves diffi-
For cutaneous infections due to M. marinum (swim- M e d 1 99 7; 1 5 6 : S 1 – S 2 5 . A l s o a v a i l a b l e a t : h t t p : / / cult.1 Systemic antibacterials may be necessary in severe
ming-pool granuloma or fish-tank granuloma) numer- www.thoracic.org/sections/publications/statements/pages/mtpi/ cases of otitis externa.1,3
nontuberc1-27.html (accessed 18/08/08)
ous antibacterial regimens have been used,10 including 16. Sizaire V, et al. Mycobacterium ulcerans infection: control, di- Chronic otitis externa is treated similarly, although the top-
rifampicin with ethambutol11 or isoniazid, rifabutin with agnosis, and treatment. Lancet Infect Dis 2006; 6: 288–96. ical antibacterials and corticosteroids used should not be
17. Etuaful S, et al. Efficacy of the combination rifampin-strepto-
ciprofloxacin,12 minocycline with co-trimoxazole,13 mycin in preventing growth of Mycobacterium ulcerans in early
the same as those used previously for the treatment of
clarithromycin with rifabutin14 or ciprofloxacin12 or lesions of Buruli ulcer in humans. Antimicrob Agents Chemoth- acute disease.1
ethambutol.12 Monotherapy with clarithromycin, mino- er 2005; 49: 3182–6. Necrotising (malignant) otitis externa, due to fulminating
18. WHO. Provisional guidance on the role of specific antibiotics in
cycline, doxycycline, or co-trimoxazole15 have each the management of Mycobacterium ulcerans disease (Buruli ul- infection, especially with Pseudomonas, is uncommon but
been tried, mainly in small series of patients. cer). Geneva: WHO, 2004. Available at: http://whqlibdoc.who.int/ can occur in susceptible patients. Topical antibacterials are
hq/2004/WHO_CDS_CPE_GBUI_2004.10.pdf (accessed not effective and systemic treatment with antipseudomon-
Buruli ulcer, due to M. ulcerans, is difficult to treat and 13/12/06)
usually requires surgery; responses to antimycobacterial 19. Johnson PD, et al. Consensus recommendations for the diagno- al drugs such as gentamicin, ceftazidime, a carbapenem, or
monotherapies have been generally disappointing. sis, treatment and control of Mycobacterium ulcerans infection a fluoroquinolone is needed for about 4 to 8 weeks.1,3
(Bairnsdale or Buruli ulcer) in Victoria, Australia. Med J Aust However, resistance to ciprofloxacin has been reported.5
However, recent evidence suggests that combination 2007; 186: 64–8.
antibacterial therapy may reduce the healing time and 20. Phillips R, et al. Pilot randomized double-blind trial of treat- Combination treatment with an aminoglycoside and an-
recurrence rates of ulcers, and minimise or avoid the ment of Mycobacterium ulcerans disease (Buruli ulcer) with other antipseudomonal drug or a penicillin (such as azlo-
topical nitrogen oxides. Antimicrob Agents Chemother 2004;
need for surgery.16 Treatment of nodules and plaques of 48: 2866–70. cillin, piperacillin, or ticarcillin) may also be used.1,3
early Buruli ulcers with rifampicin and streptomycin for 21. Adjei O, et al. Phenytoin in the treatment of Buruli ulcer. Trans 1. Brook I. Treatment of otitis externa in children. Paediatr Drugs
R Soc Trop Med Hyg 1998; 92: 108–9. 1999; 1: 283–9.
up to 12 weeks, showed inhibition of growth 4 weeks 22. Elsayed S, Read R. Mycobacterium haemophilum osteomyeli- 2. Hughes E, Lee JH. Otitis externa. Pediatr Rev 2001; 22: 191–7.
after starting treatment.17 Furthermore, no lesions en- tis: case report and review of the literature. BMC Infect Dis 3. Ong YK, Chee G. Infections of the external ear. Ann Acad Med
larged during the treatment period. WHO therefore rec- 2006; 6: 70. Available at: http://www.biomedcentral.com/ Singapore 2005; 34: 330–34.
ommends the use of rifampicin and streptomycin or content/pdf/1471-2334-6-70.pdf (accessed 13/12/06) 4. Osguthorpe JD, Nielsen DR. Otitis externa: review and clinical
23. Kyle SD, Porter WM. Mycobacterium chelonae infection suc- update. Am Fam Physician 2006; 74: 1510–16.
amikacin for 8 weeks.18 Consensus recommendations cessfully treated with oral clarithromycin and linezolid. Br J 5. Cooper MA, et al. Ciprofloxacin resistance developing during
issued by practitioners in Victoria, Australia19 consider Dermatol 2004; 151: 1101. treatment of malignant otitis externa. J Antimicrob Chemother
surgery to be the best treatment for Buruli ulcer, with 1993; 32: 163–4.
antibacterial therapy being indicated for more extensive Obstetric disorders
disease. Use of antibacterial may also possibly allow See under: Endometritis (the prophylaxis and treatment of Otitis media
more conservative resection and reduce the risk of re- postpartum endometritis), p.170; Premature Labour, Otitis media is a general term used to describe inflamma-
lapse. The recommended oral regimens were: at least 3 p.188; and Urinary-Tract Infections in Pregnancy, p.199. tion of the middle ear that usually results from dysfunction
months of rifampicin given with clarithromycin, cipro- See also Neonatal Conjunctivitis, p.180, and Perinatal of the Eustachian tube after a viral infection of the naso-
floxacin, or moxifloxacin. For more severe or extensive Streptococcal Infections, p.184. pharynx. It is one of the most frequent childhood illnesses
disease patients may also require intravenous amikacin seen in general practice. Subtypes of otitis media may be
for 4 to 8 weeks in addition to oral therapy. Reports of classified as follows:
other therapies include a beneficial response with topi- Osteomyelitis
• acute otitis media (AOM) is seen especially in young
cal nitrogen oxides in a small pilot study of 37 patients See under Bone and Joint Infections, p.164.
children and is often due to bacterial and/or viral infec-
with Buruli ulcer,20 and healing after local application of tion and is sometimes associated with upper respiratory-
phenytoin.21 Otitis externa tract infection. It is characterised by rapid onset, ear dis-
Cutaneous disease due to M. haemophilum infection has Otitis externa is a general term used to describe inflamma- comfort, and pain. Common bacterial pathogens include
been treated with an initial treatment course of rifabutin, tion of the skin of the external auditory canal that may be Streptococcus pneumoniae, Haemophilus influenzae,
ciprofloxacin, and clarithromycin, followed by clari- due to infection with bacteria, viruses, or fungi or second- and Moraxella catarrhalis (Branhamella catarrhalis)
thromycin for 2 years.22 M. chelonae was successfully ary to skin disorders such as eczema. Otitis externa is as- • recurrent acute otitis media refers to frequent episodes
treated with clarithromycin and linezolid for one month, sociated with high humidity, warmer temperatures, swim- of AOM (3 or more episodes within 6 months or 4 epi-
followed by a further 5 months of treatment with clari- ming, local trauma, or obstruction of the ear canal. sodes within 12 months) and may be due to relapse or
thromycin.23 Subtypes include acute localised otitis externa, acute dif- re-infection
1. CDC. Treating opportunistic infections among HIV-exposed fuse otitis externa (swimmer’s ear), chronic otitis externa, • otitis media with effusion (OME) or serous otitis media,
and infected children: recommendations from CDC, the Nation- and necrotising (malignant) otitis externa. Acute diffuse
al Institutes of Health, and the Infectious Diseases Society of commonly known as ‘glue ear’, is defined as the accu-
America. MMWR 2004; 53 (RR-14): 1–63. Also available at: disease is characterised by erythema, itching, pain, puru- mulation of fluid in the middle ear without local or sys-
http://www.cdc.gov/mmwr/PDF/RR/RR5314.pdf (accessed lent discharge, oedema, fullness, and deafness. If left un- temic illness. It may be associated with recurrent upper
26/06/07) treated or if treated inadequately it may progress to chronic
2. CDC. Treating opportunistic infections among HIV-infected respiratory-tract infection and is characterised by deaf-
adults and adolescents: recommendations from CDC, the Na- otitis externa. Chronic otitis externa may also result from ness although some episodes may be asymptomatic
tional Institutes of Health, and the HIV Medicine Associa- allergic contact dermatitis or other underlying skin condi- • chronic suppurative otitis media (CSOM) is often pre-
tion/Infectious Diseases Society of America. MMWR 2004; 53 tions, such as eczema. Malignant otitis externa is rare and
(RR-15): 1–112. Also available at: http://www.cdc.gov/mmwr/ ceded by one or more episodes of AOM and is associat-
PDF/RR/RR5315.pdf (accessed 26/06/07) Correction. MMWR occurs mainly in immunocompromised persons and in ed with perforation of the ear drum, and continued in-
2005; 54: 311. [dose of amphotericin B/flucytosine for C. neo- diabetics and can be life-threatening if temporal bone in- fection and inflammation in the middle ear causing
formans meningitis] Also available at: http://www.cdc.gov/ fections occur.
mmwr/preview/mmwrhtml/mm5412a10.htm (accessed persistent or recurrent discharge and deafness. The con-
26/06/07) The treatment of both acute and chronic otitis externa in- dition has been divided into inactive or active. Inactive
3. Subcommittee of the Joint Tuberculosis Committee of the British cludes thorough cleansing and the use of appropriate acid-
Thoracic Society. Management of opportunist mycobacterial infec- disease (tubo-tympanic disease) is typically character-
tions: Joint Tuberculosis Committee guidelines 1999. Thorax 2000; ifying and/or antibacterial ear drops, with or without a cor- ised by perforation of the ear drum, deafness, and a pro-
55: 210–18. Also available at: http://www.brit-thoracic.org.uk/ ticosteroid, even though some have doubted the value of fuse mucoid discharge associated with upper respirato-
Portals/0/Clinical%20Information/Opportunist%20Mycobacteria/ topical antibacterials. Ear drops containing aminoglyco-
Guidelines/OppMyco.pdf (accessed 18/08/08) ry-tract infection. In active disease (attico-antral
4. Benson CA, et al. A prospective, randomized trial examining sides, such as gentamicin, neomycin, or framycetin, or poly- disease) there may be cholesteatoma with bone involve-
the efficacy and safety of clarithromycin in combination with myxins should not be used when the ear drum is perforated ment. The commonest infecting organisms are Pseu-
ethambutol, rifabutin, or both for the treatment of disseminated because of the risk of ototoxicity.
Mycobacterium avium complex disease in persons with ac- domonas aeruginosa and anaerobes. Other common in-
quired immunodeficiency syndrome. Clin Infect Dis 2003; 37: The management of the various subtypes of otitis externa fecting aerobic organisms are diphtheroids,
1234–43. has been described.1-4 Staphylococcus aureus, and Klebsiella.1
5. CDC. Guidelines for preventing opportunistic infections among
HIV-infected persons—2002: recommendations of the US Pub- Acute localised otitis externa is an infection of the hair fol- TREATMENT Treatment of acute otitis media aims to re-
lic Health Service and the Infectious Diseases Society of Amer- licle (furunculosis), commonly due to Staphylococcus au- lieve symptoms, avoid complications, and prevent relapse,
ica. MMWR 2002; 51 (RR-8): 1–52. Also available at: http:// reus. It may cause severe pain, which may be treated with recurrence, and progression to the chronic state. Some-
www.cdc.gov/mmwr/PDF/rr/rr5108.pdf (accessed 26/06/07)
6. Brooks JT, et al. Discontinuation of primary prophylaxis against an analgesic such as paracetamol or ibuprofen. If the times an analgesic such as paracetamol may be all that is
Mycobacterium avium complex infection in HIV-infected per- furuncle is not pointing (ready to rupture spontaneously), required as long as frequent inspection is possible. Howev-
sons receiving antiretroviral therapy: observations from a large local heat application and systemic treatment with a peni- er, it is common practice to prescribe a systemic antibacte-
national cohort in the United States, 1992—2002. Clin Infect
Dis 2005; 41: 549–53. cillinase-resistant penicillin such as flucloxacillin or a rial as well as an analgesic,2 although the need for routine
7. Barzilai A, et al. Successful treatment of disseminated Myco- first-generation cephalosporin such as cefalexin may be antibacterial treatment is questionable.3-5 Systemic anti-
bacterium simiae infection in AIDS patients. Scand J Infect Dis used.1 Others have suggested application of topical anti- bacterial treatment aims to speed resolution and prevent
1998; 30: 143–6.
8. Bailey WC. Treatment of atypical mycobacterial disease. Chest bacterials using wicks which are left in the ear canal for 3 complications. However, meta-analyses and reviews have
1983; 84: 625–8. to 5 days.3 Pointed furuncles require incision and drainage shown only modest benefits from routine use of
9. Piersimoni C, et al. Disseminated infection due to Mycobacte- followed by a course of topical and/or oral antibacteri- antibacterials6-8 and experience from studies where anti-
rium celatum in patient with AIDS. Lancet 1994; 344: 332. als.1,3
10. Aubry A, et al. Sixty-three cases of Mycobacterium marinum bacterials are not given routinely for AOM suggested that
infection: clinical features, treatment, and antibiotic susceptibil- In acute diffuse otitis externa, Staphylococcus aureus, S. there is no consequent increase in complications.4,8,9 An-
ity of causative isolates. Arch Intern Med 2002; 162: 1746–52. epidermidis, and Pseudomonas spp. are often present. other meta-analysis10 to estimate the natural history of
11. Donta ST, et al. Therapy of Mycobacterium marinum infec-
tions: use of tetracyclines vs rifampin. Arch Intern Med 1986; Treatment includes thorough cleansing of the ear canal and AOM found that about 60% of children not initially treated
146: 902–4. instillation of ear drops including acidifying agents (2% with an antibacterial showed symptomatic improvement
 Antibacterials 183
within 24 hours, and that symptoms resolved within 3 days sy over the use of ear drops containing aminoglycosides or 16. Foxlee R, et al. Topical analgesia for acute otitis media. Avail-
able in The Cochrane Database of Systematic Reviews; Issue 3.
in about 80% of these children. Suppurative complications polymyxins in the presence of a perforated ear drum, as Chichester: John Wiley; 2006 (accessed 22/05/07).
occurred in about 0.12% of children not immediately treat- they are potentially ototoxic. However, it is considered that 17. American Academy of Pediatrics. Clinical practice guideline:
ed with antibacterials and in 0.24% of those given imme- untreated disease is more likely to result in deafness than a diagnosis and management of acute otitis media. Pediatrics
2004; 113: 1451–65. Also available at:
diate treatment. A systematic review9 reported that clinical short course of these ear drops. A systematic review29 h t t p : / / a a p p o l i c y. a a p p u b l i c a t i o n s . o r g / c g i / r e p r i n t /
signs and symptoms resolved within 4 to 7 days in 78% of found that treatment with topical fluoroquinolone ear pediatrics;113/5/1451.pdf (accessed 22/05/07)
children not initially treated with an antibacterial. Howev- drops was more effective at drying the ear than no drug 18. Prodigy Guidance. Otitis media—acute (issued Jan 2007).
Available at: http://cks.library.nhs.uk/otitis_media_acute/
er, some clinicians have argued that although the benefit is treatment or topical antiseptics; effects of topical non-fluo- view_whole_topic (accessed 18/08/08)
modest, it is significant and therefore the routine use of an- roquinolone antibacterials when compared with no drug 19. Kozyrskyj AL, et al. Short course antibiotics for acute otitis me-
tibacterials is clinically justifiable.6 A later systematic treatment or topical antiseptics were less clear. Another dia. Available in The Cochrane Database of Systematic Re-
views; Issue 2. Chichester: John Wiley; 2000 (accessed
review11 concluded that antibacterials do provide a small systematic review30 found that ear drops containing fluor- 22/05/07).
benefit in very young children and a further meta- oquinolones were also more effective than systemic anti- 20. Klugman KP. Epidemiology, control and treatment of multire-
analysis12 reported that most benefit was seen in children bacterials at drying the ear. Effects of topical non-fluoro- sistant pneumococci. Drugs 1996; 52 (suppl 2): 42–6.
21. Rovers MM, et al. Otitis media. Lancet 2004; 363: 465–73. Cor-
under 2 years of age with bilateral AOM, and in children quinolone antibacterials or antiseptics were less clear and rection. ibid.; 1080.
with both AOM and discharge. Another suggested ap- no additional benefit was noted by adding a systemic anti- 22. Pelton SI. New concepts in the pathophysiology and manage-
proach has been to delay the start of antibacterials for 72 bacterial to topical antibacterial treatment. ment of middle ear disease in childhood. Drugs 1996; 52 (suppl
2): 62–7.
hours and to then only give them if the patient remains un- PREVENTION Long-term antibacterial prophylaxis has been 23. Jacobs MR. Prevention of otitis media: role of pneumococcal
well.8,13,14 No one antibacterial has been found to be supe- tried in children at high risk including those with recurrent conjugate vaccines in reducing incidence and antibiotic resist-
rior to another in the treatment of AOM.9 Adjunctive treat- acute otitis media,31,32 but the evidence for its benefit is ance. J Pediatr 2002; 141: 287–93.
24. American Academy of Family Physicians, American Academy
ment with topical and systemic decongestants and inconsistent. A meta-analysis33 on the use of antibacterials of Otolaryngology-Head and Neck Surgery, American Acade-
antihistamines has not been found to be beneficial15 and to prevent recurrent AOM concluded that they appeared to my of Pediatrics Subcommittee on Otitis Media With Effusion.
there is insufficient information to conclude whether there Otitis media with effusion. Pediatrics 2004; 113: 1412–29. Also
have limited benefit and that 9 children would need to be available at: http://pediatrics.aappublications.org/cgi/reprint/
is any benefit from the use of topical analgesics (including treated to show an improved outcome in one. A later meta- 113/5/1412 (accessed 26/01/07)
corticosteroids, local anaesthetics, and NSAIDs).16 analysis34 concluded that antibacterials reduced the proba- 25. UK National Library for Health. Clinical Knowledge Summa-
ries. Otitis media with effusion (issued March 2007). Available
The American Academy of Pediatrics has produced bility of disease recurring during the treatment period, but at: http://cks.library.nhs.uk/otitis_media_with_effusion/
guidelines17 for the diagnosis and management of uncom- that the long-term benefits of treatment were unclear and view_whole_topic (accessed 18/08/08)
plicated AOM in children from 2 months to 12 years of that 5 children would need to be treated to show an im- 26. Griffin GH, et al. Antihistamines and/or decongestants for otitis
media with effusion (OME) in children. Available in The Co-
age. They suggest that in a select group of children an ob- proved outcome in one. chrane Database of Systematic Reviews; Issue 4. Chichester:
servation period may be recommended depending on the The use of xylitol, which inhibits the growth of Str. pneu- John Wiley; 2006 (accessed 18/01/07).
27. Thomas CL, et al. Oral or topical nasal steroids for hearing loss
patient’s age, the diagnostic certainty, and the severity of moniae, as chewing gum35,36 or as syrup for very young associated with otitis media with effusion in children. Available
illness. These children should be given symptomatic treat- children36,37 has been reported to reduce the incidence of in The Cochrane Database of Systematic Reviews; Issue 3.
ment and observed for 48 to 72 hours; if the illness wors- AOM. Randomised studies35,36 with xylitol chewing gum Chichester: John Wiley; 2006 (accessed 18/01/07).
ens during the observation period or there is no improve- 28. Cantekin EI, McGuire TW. Antibiotics are not effective for oti-
reported a 40% reduction in the incidence of AOM in chil- tis media with effusion: reanalysis of meta-analyses. Otorhi-
ment then systemic antibacterials should be considered. dren with recurrent AOM. However, xylitol was found to nolaryngol Nova 1998; 8: 214–22.
Pain management is important, and appropriate analgesics be ineffective when it was used only during an acute respi- 29. Macfadyen CA, et al. Topical antibiotics without steroids for
chronically discharging ears with underlying eardrum perfora-
should be offered. If antibacterial treatment is given high- ratory-tract infection38 and the need for use 5 times a day tions. Available in The Cochrane Database of Systematic Re-
dose amoxicillin (80 to 90 mg/kg daily) is recommended may make this treatment impractical.35,36 views; Issue 4. Chichester: John Wiley; 2005 (accessed
for most children. In children with severe illness or those Vaccination against AOM with pneumococcal vaccines 18/01/07).
not responding to amoxicillin and thought to be infected 30. Macfadyen CA, et al. Systemic antibiotics versus topical treat-
has also been tried but unconjugated multivalent polysac- ments for chronically discharging ears with underlying eardrum
with H. influenzae or M. catarrhalis high-dose amoxicillin charide vaccines do not prevent AOM in children under 2 perforations. Available in The Cochrane Database of Systematic
with clavulanic acid should be given. Alternatives in pen- years of age23,39 and their benefit in older children is min- Reviews; Issue 1. Chichester: John Wiley; 2006 (accessed
18/01/07).
icillin-allergic children include cephalosporins, azithro- imal.39 A meta-analysis39 found that starting immunisation 31. Roark R, Berman S. Continuous twice daily or once daily amox-
mycin, or clarithromycin. Similar recommendations have with the 7-valent pneumococcal conjugate vaccine by 2 icillin prophylaxis compared with placebo for children with re-
been made for the treatment of AOM in the UK.18 months of age reduces the incidence of recurrent AOM. current acute otitis media. Pediatr Infect Dis J 1997; 16:
376–81.
Duration of therapy for AOM has varied from 5 to 10 or No benefit was noted in children with recurrent infections 32. Teele DW, et al. Antimicrobial prophylaxis for infants at risk for
more days. A systematic review19 of published clinical who received their first vaccination after 1 year of age. In recurrent acute otitis media. Vaccine 2001; 19 (suppl 1):
S140–S143.
studies suggests that a 5-day treatment course may be giv- a later study40 in children 2 to 8 years of age with recurrent 33. Williams RL, et al. Use of antibiotics in preventing recurrent
en to children with uncomplicated AOM. The American OME, vaccination with the 7-valent conjugated vaccine acute otitis media and in treating otitis media with effusion: a
Academy of Pediatrics recommends treatment with anti- before, and the 23-valent polysaccharide vaccine after, in- meta-analytic attempt to resolve the brouhaha. JAMA 1993;
270: 1344–51. Correction. ibid. 1994; 271: 430.
bacterials for 10 days in younger children (up to 6 years of sertion of a tympanostomy tube did not prevent recurrenc- 34. Leach AJ, Morris PS. Antibiotics for the prevention of acute and
age) and for children with severe disease; those aged 6 es. chronic suppurative otitis media in children. Available in The
years or older with mild to moderate disease may be given Vaccination may also have a role in reducing the incidence Cochrane Database of Systematic Reviews; Issue 4. Chichester:
John Wiley; 2006 (accessed 18/01/07).
treatment for 5 to 7 days.17 and in preventing the development of antibacterial 35. Uhari M, et al. Xylitol chewing gum in prevention of acute otitis
Penicillin-resistant strains of Str. pneumoniae have been resistance23 but use of conjugated pneumococcal vaccines media: double blind randomised trial. BMJ 1996; 313: 1180–4.
was found to cause a shift in the pathogens responsible for 36. Uhari M, et al. A novel use of xylitol sugar in preventing acute
reported in children with otitis media and are reported to otitis media. Pediatrics 1998; 102: 879–84.
be increasingly prevalent.20 About one-quarter of Str. AOM from vaccine-type pneumococci to nonvaccine-type 37. Uhari M, et al. Xylitol in preventing acute otitis media. Vaccine
pneumoniae isolates, one third of H. influenzae isolates, strains and to H. influenzae.23 2001; 19: S144–S147.
38. Tapiainen T, et al. Xylitol administered only during respiratory in-
and nearly all M. catarrhalis isolates are resistant to peni- 1. Wintermeyer SM, Nahata MC. Chronic suppurative otitis me-
fections failed to prevent acute otitis media. Abstract: Pediatrics
cillin and amoxicillin.2 However, resistance rates vary be- dia. Ann Pharmacother 1994; 28: 1089–99.
2002; 109: 302. Full version: http://pediatrics.aappublications.org/
2. Hendley JO. Otitis media. N Engl J Med 2002; 347: 1169–74.
tween countries21 and many penicillin-resistant strains re- 3. Browning GG. Childhood otalgia: acute otitis media 1. BMJ
cgi/content/full/109/2/e19 (accessed 22/05/07)
39. Straetemans M, et al. Pneumococcal vaccines for preventing
main sensitive in vivo to high-dose amoxicillin.20,22,23 1990; 300: 1005–6. otitis media. Available in The Cochrane Database of Systematic
4. Majeed A, Harris T. Acute otitis media in children. BMJ 1997; Reviews; Issue 1. Chichester: John Wiley; 2004 (accessed
Optimal treatment of otitis media with effusion is contro- 315: 321–2. 18/01/07).
versial and the majority of cases will resolve spontaneous- 5. Damoiseaux RAMJ, et al. Primary care based randomised, dou- 40. van Heerbeek N, et al. Effect of combined pneumococcal con-
ly within 3 months. Guidelines have been developed in the ble blind trial of amoxicillin versus placebo for acute otitis me- jugate and polysaccharide vaccination on recurrent otitis media
dia in children aged under 2 years. BMJ 2000; 320: 350–4.
USA24 for the diagnosis and management of uncomplicat- 6. Rosenfeld RM, et al. Clinical efficacy of antimicrobial drugs for
with effusion. Pediatrics 2006; 117: 603–8.
ed disease in children from 2 months to 12 years of age. acute otitis media: metaanalysis of 5400 children from thirty-
They suggest careful assessment and observation for at three randomized trials. J Pediatr 1994; 124: 355–67.
7. Del Mar C, et al. Are antibiotics indicated as initial treatment Pancreatitis
least 3 months before considering surgery. Those at in- for children with acute otitis media? A meta-analysis. BMJ The overall management of pancreatitis is discussed on
creased risk of developmental difficulties such as children 1997; 314: 1526–9. p.2361. Although there has been some uncertainty about
with cleft palate or Down’s syndrome should be referred to 8. Froom J, et al. Antimicrobials for acute otitis media? A review
from the International Primary Care Network. BMJ 1997; 315: the value of prophylactic antibacterials in acute pancreati-
a specialist. Similar recommendations have been made for 98–102. tis, a meta-analysis1 of 8 prospective studies showed a pos-
the treatment of OME in the UK.25 Antihistamines, decon- 9. Takata GS, et al. Evidence assessment of management of acute itive benefit in reducing mortality. The advantage was lim-
gestants, and mucolytics are ineffective.24-26 Oral or topi- otitis media: I— The role of antibiotics in treatment of uncom-
ited to patients with severe pancreatitis given broad-
plicated acute otitis media. Pediatrics 2001; 108: 239–47.
cal intranasal corticosteroids alone or with an antibacterial 10. Rosenfeld RM, Kay D. Natural history of untreated otitis media. spectrum drugs that achieved therapeutic levels in pancre-
have only short-term benefit27 and their use is not recom- Laryngoscope 2003; 113: 1645–57. atic tissue, such as imipenem or a fluoroquinolone. A ret-
mended as routine treatment.24,25 A meta-analysis28 on the 11. Glasziou PP, et al. Antibiotics for acute otitis media in children.
rospective study2 reported a reduction in the incidence, but
Available in The Cochrane Database of Systematic Reviews; Is-
use of antibacterials for the treatment of OME failed to sue 1. Chichester: John Wiley; 2004 (accessed 22/05/07). not in the time of onset, of infection in those given antibac-
find any benefit and their use cannot be justified.24,25 12. Rovers MM, et al. Antibiotics for acute otitis media: a meta- terial prophylaxis in severe disease. However, a systematic
analysis with individual patient data. Lancet 2006; 368:
Treatment of chronic suppurative otitis media aims to stop 1429–35. review3 of the value of antibacterial prophylaxis in patients
the discharge, eradicate the infection, heal the ear drum, 13. Little P, et al. Pragmatic randomised controlled trial of two pre- with severe acute necrotising pancreatitis concluded that,
and to prevent serious complications. Treatment options scribing strategies for childhood acute otitis media. BMJ 2001; despite variations in drugs used (cefuroxime, imipenem, or
322: 336–42.
for uncomplicated cases include aural toilet (thorough 14. McCormick DP, et al. Nonsevere acute otitis media: a clinical metronidazole with ciprofloxacin or ofloxacin) and in the
cleansing and mopping of the ear), systemic antibacterials, trial comparing outcomes of watchful waiting versus immediate quality and methodology of studies conducted, antibacte-
and topical treatments with either an antiseptic or antibac- antibiotic treatment. Pediatrics 2005; 115: 1455–65. rial prophylaxis appeared to reduce the risk of death in pa-
15. Chonmaitree T, et al. A randomized, placebo-controlled trial of
terial, sometimes also with a corticosteroid. Surgery may the effect of antihistamine or corticosteroid treatment in acute tients with pancreatic necrosis but not, overall, the rate of
be needed if complications develop.1,29 There is controver- otitis media. J Pediatr 2003; 143: 377–85. infected pancreatic necrosis. However, there was some evi-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
184 Antibacterials
dence that beta lactams were associated with both a reduc- oral clindamycin 450 mg four times daily or oral doxycy- vention of group B streptococcal infection in infants may
tion in risk of death, and risk of infected pancreatic necro- cline 100 mg twice daily plus oral metronidazole 400 mg be achieved by giving appropriate antibacterials to the
sis whereas quinolone plus imidazole regimens were not. twice daily mother during labour.1 Ideally maternal carriers of group
1. Golub R, et al. Role of antibiotics in acute pancreatitis: a meta- alternative regimens, given for a total of 14 days, are: B streptococci would be identified during pregnancy, but
analysis. J Gastrointest Surg 1998; 2: 496–503. • intravenous ofloxacin 400 mg twice daily plus this may not be practical. Factors that increase the risk of
2. Ho HS, Frey CF. The role of antibiotic prophylaxis in severe intravenous metronidazole 500 mg three times daily
acute pancreatitis. Arch Surg 1997; 132: 487–93. acquiring neonatal infection include premature labour,
3. Villatoro E, et al. Antibiotic therapy for prophylaxis against in- • intravenous ciprofloxacin 200 mg twice daily plus prolonged rupture of membranes, maternal fever, a previ-
fection of pancreatic necrosis in acute pancreatitis. Available in intravenous metronidazole 500 mg three times daily, plus ous child with neonatal group B streptococcal infection,
The Cochrane Database of Systematic Reviews; Issue 4. Chich- intravenous or oral doxycycline 100 mg twice daily
ester: John Wiley; 2006 (accessed 23/06/08).
and multiple pregnancy and they will influence the deci-
Metronidazole may be stopped in women with mild sion of whether or not to give intrapartum antibacterial
or moderate disease who tolerate it poorly, but the im- prophylaxis to the mother. A penicillin is the preferred
Pelvic inflammatory disease proved coverage of anaerobic infection that it pro- drug.
Pelvic inflammatory disease (PID) is a broad term for in- vides is more important in women with severe dis- Guidelines from the USA1 recommend prophylaxis based
fectious disorders of the upper genital tract in women and ease. on universal prenatal screening. Where required, they rec-
may include endometritis, salpingitis, tubo-ovarian ab- • outpatients: ommend benzylpenicillin or, alternatively, ampicillin, giv-
scess, and pelvic peritonitis. It is generally due to ascend- • a single intramuscular dose of ceftriaxone 250 mg or ce- en intravenously during labour. In women allergic to pen-
ing infection through the cervix and uterus to the fallopian foxitin 2 g with oral probenecid 1 g, then icillin but who are not considered to be at high risk of
tubes, resulting in salpingitis, and from there may extend oral doxycycline 100 mg twice daily plus oral metronida- anaphylaxis, intravenous cefazolin is recommended as an
to the ovaries and peritoneum. Long-term complications zole 400 mg twice daily for 14 days, or alternative; those considered to be at high risk of anaphy-
include infertility and ectopic pregnancy. The use of intra- • oral ofloxacin 400 mg plus oral metronidazole 400 mg laxis should be given clindamycin or erythromycin intra-
uterine contraceptive devices might increase the likelihood both twice daily for 14 days venously or, where there is resistance to clindamycin and
of PID although the risk may have been overstated;1 it ap- • USA: erythromycin or susceptibility is unknown, intravenous
pears to be greatest during the first 20 days after insertion • parenteral treatment: vancomycin.
of the device.2 • (regimen A): intravenous cefoxitin 2 g every 6 hours or In other parts of the world, including Europe, the incidence
The majority of these infections are probably sexually cefotetan 2 g every 12 hours plus of neonatal streptococcal infections is much lower and the
transmitted and at one time were mainly due to Neisseria oral or intravenous doxycycline 100 mg every 12 hours US model for prophylaxis may not be appropriate.2,3
gonorrhoeae, but Chlamydia trachomatis is increasingly • (regimen B): intravenous clindamycin 900 mg every 8
Another strategy suggested for areas with a high incidence
responsible and may be the commonest cause of PID in hours plus
of neonatal group B streptococcal disease (above 1.5 per
some areas. Other organisms that have been isolated in- parenteral gentamicin 2 mg/kg as a loading dose then
1.5 mg/kg every 8 hours 1000 live births) is to give a single dose of penicillin to all
clude Mycoplasma hominis; Ureaplasma urealyticum;
In each case parenteral treatment is continued for 24 neonates at birth.4
anaerobes such as Bacteroides, Peptococcus, and Pepto-
streptococcus spp.; Gram-negative enteric aerobes such as hours after substantial clinical improvement has oc- As mentioned under Premature Labour, p.188, the elimi-
Escherichia coli; and Gram-positive aerobes such as curred and then followed by oral therapy to complete nation of bacteria such as group B streptococci in pregnant
group B streptococci. Some of these organisms occur in a total of 14 days of treatment. women might also reduce the risk of premature labour.
the abnormal vaginal flora associated with bacterial vagi- • in regimen A, continuation is usually with oral doxycy- Streptococcus group B vaccines are under investigation
nosis (p.164). Thus, the aetiology of PID appears to be poly- cline 100 mg twice daily; in patients with tubo-ovarian ab- for use in pregnant women to prevent neonatal infection.
microbial; some think that primary infection with N. gon- scesses oral clindamycin or oral metronidazole may be 1. CDC. Prevention of perinatal group B streptococcal disease: re-
added to doxycycline vised guidelines from CDC. MMWR 2002; 51 (RR-11): 1–22.
orrhoeae or C. trachomatis, or both, allows opportunistic Also available at: http://www.cdc.gov/mmwr/PDF/rr/rr5111.pdf
infection with aerobic and anaerobic bacteria.1 • in regimen B, continuation may be with oral clindamycin
(accessed 20/05/04)
450 mg four times a day or doxycycline; oral clindamycin 2. Simpson AJA, Heard SR. Group B Streptococcus. Lancet 1995;
Treatment regimens are of necessity broad spectrum and is preferred in patients with tubo-ovarian abscesses 346: 700.
empirical and should include antibacterials active against Another parenteral regimen which has been tried is: 3. Jakobi P, et al. New CDC guidelines for prevention of perinatal
the major pathogens. Many consider that treatment should • ampicillin/sulbactam 3 g every 6 hours plus
group B streptococcal disease. Lancet 2003; 361: 351.
be started in hospital so that drugs can be given parenteral- 4. Siegel JD, Cushion NB. Prevention of early-onset group B strep-
oral or intravenous doxycycline 100 mg every 12 hours. tococcal disease: another look at single-dose penicillin at birth.
ly. Guidelines produced by WHO,3 by an expert group in Obstet Gynecol 1996; 87: 692–8.
the UK,4 and by the CDC in the USA5 are as follows, al- • oral treatment:
• a single intramuscular dose of cefoxitin 2 g plus oral
though recommendations may need to be localised be- probenecid 1 g, or a single intramuscular dose of ceftriax-
cause of differences in patterns of infection and drug resist- Peritonitis
one 250 mg (or equivalent third-generation cepha-
ance: losporin), plus
Intra-abdominal infections include peritonitis, which may
• WHO oral doxycycline 100 mg twice daily, with or without oral
be complicated by intraperitoneal abscesses, and abscesses
• inpatients: metronidazole 500 mg twice daily, for 14 days of the intra-abdominal viscera such as those of the liver
Pregnant women who have suspected PID disease should (see under Abscess, Liver, p.162), pancreas, and spleen.
• intramuscular ceftriaxone 250 mg daily, plus
be hospitalised and treated with a parenteral regimen.5 Infective peritonitis may be primary or secondary or may
oral or intravenous doxycycline 100 mg twice daily (or
oral tetracycline 500 mg four times a day), plus be a complication of continuous ambulatory peritoneal
Sexual partners of patients with PID should be tested and dialysis (CAPD).
oral or intravenous metronidazole 400 to 500 mg twice treated.5
daily or chloramphenicol 500 mg four times daily Primary peritonitis. In primary or spontaneous bacterial
Women co-infected with HIV appear to be more likely to peritonitis there is no specific focus of infection and it oc-
• intravenous clindamycin 900 mg every 8 hours, plus
develop tubo-ovarian abscesses but respond similarly to curs most often as a complication of ascites. Infecting bac-
intravenous gentamicin 1.5 mg/kg every 8 hours
treatment compared to women who are HIV-negative.5 teria include Escherichia coli, other Enterobacteriaceae,
• oral ciprofloxacin 500 mg twice daily or intramuscular
1. Pearce JM. Pelvic inflammatory disease. BMJ 1990; 300:
spectinomycin 1 g four times daily, plus 1090–1. and streptococci. Initial empirical treatment has been with
oral or intravenous doxycycline 100 mg twice daily (or 2. Farley TMM, et al. Intrauterine devices and pelvic inflammatory broad-spectrum chemotherapy such as ampicillin plus an
oral tetracycline 500 mg four times a day), plus disease: an international perspective. Lancet 1992; 339: 785–8. aminoglycoside, but third-generation cephalosporins such
oral or intravenous metronidazole 400 to 500 mg twice 3. WHO. Guidelines for the management of sexually transmitted as cefotaxime are considered by some to be the treatment
daily or chloramphenicol 500 mg four times daily in fe c tio ns . G e ne va : W HO , 20 03. A l so a v ai la ble at :
http://whqlibdoc.who.int/publications/2003/9241546263.pdf of choice.1-3 Other alternatives include other broad-spec-
Therapy should be continued for at least 48 hours af- (accessed 23/03/07) trum penicillins, carbapenems, and combinations of peni-
ter clinical improvement, and then followed by doxy- 4. Clinical Effectiveness Group (British Association for Sexual cillins with beta-lactamase inhibitors.2,3 Oral ofloxacin has
cycline or tetracycline orally for 14 days. Health and HIV). United Kingdom National Guideline for the
management of pelvic inflammatory disease (issued 14th Febru- been reported to be as effective as intravenous cefotaxime
• outpatients: ary 2005). Available at: http://www.bashh.org/documents/118/ in uncomplicated infections.4 If infection with anaerobic
• a single-dose treatment for uncomplicated gonorrhoea 118.pdf (accessed 18/08/08) organisms is suspected, metronidazole or clindamycin
such as a single intramuscular dose of ceftriaxone 125 mg 5. CDC. Sexually transmitted diseases treatment guidelines 2006. may be added to the chosen regimen.2 In cirrhotic patients
MMWR 2006; 55 (RR-11): 1–94. Also available at: http://
is recommended (see Gonorrhoea, p.191) plus www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07) with low levels of ascitic fluid protein5 the use of oral nor-
oral metronidazole 400 to 500 mg twice daily and oral Updated recommended treatment regimens for gonococcal in- floxacin for selective intestinal decontamination appeared
doxycycline 100 mg twice daily (or oral tetracycline fections and associated conditions—United States, April 2007. to prevent spontaneous bacterial peritonitis and prophylax-
500 mg four times a day) for 14 days. Available at: http://www.cdc.gov/std/treat ment/2006/
GonUpdateApril2007.pdf (accessed 12/04/07) is with norfloxacin has been recommended to decrease the
• UK: recurrence of spontaneous bacterial peritonitis.1 However,
• inpatients: prophylaxis with norfloxacin will not prevent infection by
with the regimens below intravenous therapy is con- Peptic ulcer disease Gram-positive bacteria including Staphylococcus aureus
tinued until 24 hours after clinical improvement, and The Gram-negative bacterium Helicobacter pylori is in- or quinolone-resistant Gram-negative bacteria.2 Co-tri-
the oral regimen is then substituted until therapy has volved in the aetiology of gastritis and peptic ulceration, moxazole has also been reported to be an effective prophy-
been given for at least 14 days. and treatment regimens to eradicate the organism are rec- lactic.6
• intravenous cefoxitin 2 g three times daily plus intrave- ommended in peptic ulcer disease (p.1702).
Secondary peritonitis. Secondary peritonitis is associated
nous (or oral if tolerated) doxycycline 100 mg twice daily, with perforation of the gastrointestinal tract, conditions
until clinical improvement, then
Perinatal streptococcal infections such as appendicitis and diverticulitis, and contamination
oral doxycycline 100 mg twice daily, plus oral metronida-
zole 400 mg twice daily Group B streptococci are a major cause of perinatal infec- at surgery. Infections are generally mixed and originate
• intravenous clindamycin 900 mg three times daily plus in-
tions, often leading to neonatal pneumonia or septicaemia, from the gastrointestinal tract. Bacteria responsible in-
travenous gentamicin (2 mg/kg as a loading dose, then sometimes with meningitis, although the incidence varies clude E. coli and other Enterobacteriaceae, anaerobes (es-
1.5 mg/kg three times daily or a single daily dose of in different parts of the world. Infections are acquired pecially Bacteroides fragilis), enterococci, and sometimes
7 mg/kg) until clinical improvement, then through maternal genital carriage during pregnancy. Pre- Pseudomonas aeruginosa. Broad-spectrum antibacterial
 Antibacterials 185
therapy is therefore usually used, at least until the infecting 6. Singh N, et al. Trimethoprim–sulfamethoxazole for the preven- genes from the throat.1-3 The incidence of rheumatic fever
tion of spontaneous bacterial peritonitis in cirrhosis: a rand-
organisms are known, and a combination of two or three omized trial. Ann Intern Med 1995; 122: 595–8.
has been low for many years in developed countries, but
drugs is often given. The intravenous route is generally 7. Piraino B, et al. Peritoneal dialysis-related infections recommenda- there was evidence of a resurgence in parts of the USA in
preferred. Nevertheless, it is difficult to assess the relative tions: 2005 update. Perit Dial Int 2005; 25: 107–31. Also available at: the mid-1980s. Thus, in addition to shortening the illness
merits of surgical therapy against medical management http://www.ispd.org/guidelines/03Piraino4237ISPD%20with% and interrupting transmission, the antibacterial treatment
20watermark.pdf (accessed 27/06/06)
that includes antibacterial therapy.2 An aminoglycoside 8. Ludlam H, et al. Prevention of peritonitis in continuous ambula- of streptococcal pharyngitis also serves as primary preven-
such as gentamicin or a cephalosporin, plus metronidazole tory peritoneal dialysis. Lancet 1990; 335: 1161. tion of rheumatic fever (see below). However, in countries
or clindamycin, have often been used, but many other reg- in which the incidence of rheumatic fever remains low the
imens have been tried. Patterns of resistance further com- routine use of antibacterials for the management of sore
Pertussis
plicate the choice of antibacterial: resistance to beta throats is discouraged.4,5
Pertussis or whooping cough1 is caused by infection with
lactams may emerge among some Gram-negative organ- Penicillin is the standard treatment for streptococcal phar-
the respiratory pathogen Bordetella pertussis, a Gram-
isms, which are most likely to infect patients with pro- yngitis or tonsillitis,6-8 generally as phenoxymethylpeni-
negative aerobic bacterium. The related species B. parap-
longed hospital stays, previous antibacterial treatment, cillin by mouth for 10 days; benzylpenicillin may be given
ertussis causes a similar but generally milder illness. Per-
postoperative peritonitis, or recurrent peritonitis. Such pa- by injection initially. A single intramuscular injection of
tussis is very infectious and occurs most frequently in chil-
tients are best treated with a regimen that includes a car- benzathine benzylpenicillin is perhaps the treatment of
dren, but may be more common in adults than once
bapenem, cefepime, a fluoroquinolone, or an aminoglyco- choice, especially if compliance with a 10-day course of
thought. The incidence of pertussis has been greatly re-
side.2 Resistant isolates of B. fragilis and Clostridium oral penicillin is unlikely, and is advocated by WHO and
duced by the active immunisation of infants (see under
difficile (with associated diarrhoea) are more common af- the American Heart Association for the primary preven-
Pertussis Vaccines, p.2231) and effective prevention by
ter clindamycin than after metronidazole.2 Microaer- tion of rheumatic fever (see under Rheumatic Fever,
the adequate uptake of vaccine remains the ultimate objec-
ophilic Gram-positive cocci are resistant to metronidazole p.189), but the injection may not be available in some
tive.
but not to clindamycin,2 so metronidazole should be used countries. Ampicillin should probably be avoided because
with a beta lactam other than aztreonam.2 Erythromycin has been the antibacterial of choice, but the
newer macrolides, clarithromycin and azithromycin, have of the risk of maculopapular rash if the patient proves to
For reference to the prevention of postoperative infection, similar effectiveness and are also recommended for the have infectious mononucleosis.9 Erythromycin or another
see under Surgical Infection, p.195. treatment of pertussis.1-3 Once infection has occurred an- macrolide may be given to penicillin-allergic patients, ex-
CAPD peritonitis. Peritonitis is the main complication of tibacterial therapy is thought to render the patient non-in- cept where there is evidence of significant resistance, as in
CAPD, a technique widely used in end-stage renal failure. fectious by eliminating nasopharyngeal carriage of B. per- some parts of Europe,6 the USA,10 Japan,11 and Finland;12
Unlike secondary peritonitis, above, a single infecting or- tussis. Such treatment is unlikely to affect the clinical it may also be a better choice than penicillin if there is a
ganism is often responsible. The most common infections course of pertussis because diagnosis is difficult until the likelihood of infection with Arcanobacterium haemolyti-
have usually been due to Gram-positive organisms, espe- paroxysmal stage, by which time the bacteria have already cum (Corynebacterium haemolyticum) (see below). Oral
cially staphylococci, but infections with Gram-negative damaged the respiratory tract and released their toxins. Ef- cephalosporins are another alternative, and a meta-
bacteria (typically Enterobacteriaceae) are becoming more fective regimens include:2,3 analysis13 has shown that the likelihood of treatment fail-
common, and fungi are an increasingly important cause of ure with oral cephalosporins may be approximately half
• oral azithromycin 500 mg daily on the first day of treat- that with penicillin.
peritonitis in CAPD.2 The International Society for Perito- ment then 250 mg for 4 days; infants and children may
neal Dialysis recommends7 that the choice of antibacterial be given oral azithromycin 10 mg/kg daily for 3 to 5 Despite the general effectiveness of penicillin a trend of
for empirical therapy be based on the history of sensitivi- days, or 10 mg/kg daily on the first day of treatment then increasing numbers of relapses and recurrent infections
ties of organisms causing peritonitis in the particular hos- 5 mg/kg daily for 4 days has been noted.14 Some treatment failures have been at-
pital or centre involved. In some cases a first-generation tributed to poor patient compliance with a 10-day course
cephalosporin (such as cefalotin or cefazolin) for Gram- • oral clarithromycin 500 mg twice daily for 7 days; in-
of penicillin and attempts to overcome this have included
positive organisms, with a third-generation cephalosporin fants and children may be given oral clarithromycin
giving fewer daily doses or shortening the length of treat-
or an aminoglycoside for Gram-negative coverage, may 7.5 mg/kg twice daily for 7 days
ment. Meta-analysis of studies supports the use of twice-
be suitable; however, many centres have a high rate of • oral erythromycin 500 mg four times daily for 14 days; daily dosing of phenoxymethylpenicillin which appears to
meticillin-resistant infections and vancomycin for Gram- infants and children may be given oral erythromycin 40 be as effective as doses three or four times daily,15 but a
positive coverage may be necessary. Quinolones for to 50 mg/kg daily in 3 to 4 divided doses for 7 to 14 single daily dose is less effective. Courses of phe-
Gram-negative organisms should only be used if local sen- days, or 60 mg/kg daily in 3 divided doses for 14 days noxymethylpenicillin shorter than 10 days have not
sitivity is demonstrated. Aztreonam can be used in patients Oral co-trimoxazole for 7 to 14 days may be given as an proved effective.16,17 There is some evidence that shorter
with cephalosporin hypersensitivity. The antibacterials are alternative treatment for patients unable to tolerate mac- courses may be possible with some alternative antibacteri-
given intraperitoneally by mixing with the dialysate. rolides. Oxytetracycline or chloramphenicol are not rec- als. Studies have shown that courses of 5 days or less of
Once-daily dosing regimens for aminoglycosides are con- ommended because of their potential side effects. erythromycin,18 cefotiam hexetil,19 azithromycin,20,21
sidered appropriate for CAPD patients. Once the infecting Macrolide antibacterials, given in the same doses as for clarithromycin,22 or cefuroxime axetil23,24 may be as effec-
organism is identified, an appropriate narrow-spectrum treatment and within 3 weeks of onset of cough in the in- tive as a 10-day course of phenoxymethylpenicillin. How-
antibacterial can be substituted. Treatment is generally dex patients, may also be given prophylactically to close ever, definitive studies have not been done, and the broad-
continued for 14 days in patients who have a clinical re- contacts.2 However, protection is limited and a systematic er spectrum and higher cost of these regimens are
sponse. Treatment should be extended to 21 days in pa- review3 concluded there was insufficient evidence to de- drawbacks.6,7
tients with severe infections (such as Staph. aureus, Gram- termine the benefit of prophylactic treatment of healthy Penicillin resistance in Str. pyogenes remains rare. In addi-
negative, or enterococcal peritonitis). pertussis contacts. tion to poor compliance, treatment failures with penicillin,
Exit-site infections can be treated with an oral penicilli- 1. Crowcroft NS, Pebody RG. Recent developments in pertussis. leading to recurrent infection, might be explained by the
Lancet 2006; 367: 1926–36.
nase-resistant penicillin, a first-generation cephalosporin 2. CDC. Recommended antimicrobial agents for the treatment and presence of beta-lactamase-producing oropharyngeal bac-
such as cefalexin, or co-trimoxazole for Gram-positive in- postexposure prophylaxis of pertussis: 2005 CDC Guidelines. teria that are able to protect Str. pyogenes against penicil-
fections. Vancomycin should be avoided for routine use MMWR Recomm Rep 2005; 54(RR-14): 1–16. Also available at: lin,25 although this theory was not supported by a study in
http://www.cdc.gov/mmwr/PDF/rr/rr5414.pdf (accessed
but may be needed if there is meticillin resistance. Ri- 18/08/08)
462 children.26 Antibacterials less susceptible to beta
fampicin may be added in severe Staph. aureus infections. 3. Altunaiji S, et al. Antibiotics for whooping cough (pertussis). lactamase have been effective, sometimes more so than
An oral fluoroquinolone such as ciprofloxacin may be Available in The Cochrane Database of Systematic Reviews; Is- phenoxymethylpenicillin. They include the oral cepha-
used for Gram-negative infections.7 Intraperitoneal sue 3. Chichester: John Wiley; 2007 (accessed 27/06/08). losporins cefaclor,27 cefuroxime axetil,28 cefixime,29 cef-
ceftazidime may be added in cases of pseudomonal infec- prozil,30 and cefadroxil31 and the combined preparation
tion where resolution of infection is slow or where there is Pharyngitis amoxicillin with clavulanic acid32,33 (like ampicillin,
recurrence. Pharyngitis and tonsillitis are upper respiratory-tract infec- amoxicillin should perhaps be avoided because of the risk
Long-term antibacterial prophylaxis is not generally effec- tions with similar causes and occur especially in children. of maculopapular rash if the patient proves to have infec-
tive, but Staph. aureus nasal carriage is associated with Acute pharyngitis is an inflammatory syndrome of the tious mononucleosis). Clindamycin has eradicated Str. py-
increased risk of exit-site infections and intranasal or exit- oropharynx that may include the tonsils whereas tonsillitis ogenes and beta-lactamase-producing bacteria in children
site mupirocin (cream, as ointment may damage the cath- is, strictly speaking, a more localised infection. The com- of 12 years and under with recurrent tonsillitis, but might
eter) or exit-site gentamicin cream have been used to re- monest causes are viral and a sore throat is often a symp- be less effective in older patients.34 It was also effective
duce them.7 Dramatic reductions in peritonitis rates have tom of the common cold as well as influenza and infec- where penicillin and erythromycin had failed in an out-
been achieved with programmes based on stringent aseptic tious mononucleosis. For further details of these viral break of streptococcal pharyngitis.35
wound care and on minimising contact of the CAPD sys- infections, see under Choice of Antiviral, p.850. Pharyngeal carriage of Str. pyogenes is common, especial-
tem with domestic water.8 The most important bacterial cause of acute pharyngitis ly in primary-school children and thus its presence does
1. Gilbert JA, Kamath PS. Spontaneous bacterial peritonitis: an up- and tonsillitis is the group A beta-haemolytic streptococ- not necessarily reflect acute infection. Eradication may be
date. Mayo Clin Proc 1995; 70: 365–70. cus, Streptococcus pyogenes. An erythrogenic toxin-pro- beneficial in selected cases and has been achieved by a sin-
2. Johnson CC, et al. Peritonitis: update on pathophysiology, clini-
cal manifestations, and management. Clin Infect Dis 1997; 24: ducing strain causes pharyngitis and tonsillitis in scarlet fe- gle intramuscular injection of benzathine benzylpenicillin
1035–47. ver. together with a 4-day course of oral rifampicin;36 a 10-day
3. Rimola A, et al. Diagnosis, treatment and prophylaxis of sponta- In view of the prevalence of a viral cause, opinions have course of oral clindamycin has also been effective.37 In or-
neous bacterial peritonitis: a consensus document. J Hepatol der to ensure that outbreaks of Str. pyogenes are prevented
2000; 32: 142–53. differed over whether and when to treat pharyngitis with
4. Navasa M et al. Randomized comparative study of oral ofloxacin antimicrobial drugs. Some have advocated waiting until a in closely confined populations, some have recommended
versus intravenous cefotaxime in spontaneous bacterial peritoni- definite diagnosis of Str. pyogenes infection is made, but prophylactic antibacterials for all members of these popu-
tis. Gastroenterology 1996; 111: 1011–17. others treat immediately if streptococcal pharyngitis is sus- lations, without exception.38
5. Soriano G, et al. Selective intestinal decontamination prevents
spontaneous bacterial peritonitis. Gastroenterology 1991; 100: pected because of the risk of longer term complications Other bacterial causes of pharyngitis include Arcanobacte-
477–81. such as rheumatic fever and the need to eradicate Str. pyo- rium haemolyticum (Corynebacterium haemolyticum),
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
186 Antibacterials
Chlamydophila pneumoniae (Chlamydia pneumoniae), 33. Dykhuizen RS, et al. Phenoxymethyl penicillin versus co- mostly due to bacterial or viral infection, but may be
amoxiclav in the treatment of acute streptococcal pharyngitis,
Corynebacterium diphtheriae (see under Diphtheria, and the role of β-lactamase activity in saliva. J Antimicrob caused by fungi in immunocompromised patients or by the
p.168), Neisseria gonorrhoeae (see under Gonorrhoea, Chemother 1996; 37: 133–8. aspiration of chemical irritants. Pneumonia is a common
p.191), group C beta-haemolytic streptococci, and anaero- 34. Foote PA, Brook I. Penicillin and clindamycin therapy in recur- illness occurring in all age groups and throughout the
rent tonsillitis: effect of microbial flora. Arch Otolaryngol Head
bic bacteria. Neck Surg 1989; 115: 856–9. world; it is a major cause of death among the elderly and
A. haemolyticum is thought to be an important cause of 35. Raz R, et al. Clindamycin in the treatment of an outbreak of those who are chronically and/or terminally ill. Symptoms
pharyngitis in adolescents and young adults; there is often streptococcal pharyngitis in a kibbutz due to beta-lactamase and signs of pneumonia include chills, cough, dyspnoea,
producing organisms. J Chemother 1990; 2: 182–4.
an accompanying scarlatiniform rash. It has been reported 36. Tanz RR, et al. Penicillin plus rifampin eradicates pharyngeal fever, headache, myalgia, pleuritic chest pain, and sputum
to respond to a single injection of benzathine benzylpeni- carriage of group A streptococci. J Pediatr 1985; 106: 876–80. production. Treatment of pneumonia relies on prompt use
37. Tanz RR, et al. Clindamycin treatment of chronic pharyngeal of antibacterials and identification of the infecting organ-
cillin or a 10-day course of oral erythromycin, but not to carriage of group A streptococci. J Pediatr 1991; 119: 123–8.
phenoxymethylpenicillin.7 38. Gray GC, et al. Hyperendemic Streptococcus pyogenes infec- isms and their sensitivity to antibacterials. Cases of pneu-
Pharyngitis is often associated with Chlamydophila pneu- tion despite prophylaxis with penicillin G benzathine. N Engl J monia are usually classified as community-acquired or
Med 1991; 325: 92–7. hospital-acquired (nosocomial) pneumonia. Cases of com-
moniae infection and tetracycline or erythromycin are ef- 39. Grayston JT, et al. A new respiratory tract pathogen: Chlamydia
fective antibacterials.39 pneumoniae strain TWAR. J Infect Dis 1990; 161: 618–25. munity-acquired pneumonia can also be further sub-divid-
1. Anonymous. Bacterial pharyngitis. Lancet 1987; i: 1241–2. ed into those who can be treated in an ambulatory (outpa-
2. Marcovitch H. Sore throats. Arch Dis Child 1990; 65: 249–50. tient) setting and those that need hospitalisation. Patients
3. Lang SDR, Singh K. The sore throat: when to investigate and Pinta who need hospitalisation are generally infected with unu-
when to prescribe. Drugs 1990; 40: 854–62. See under Syphilis, p.192. sual pathogens and/or have more severe disease. Pneumo-
4. Little P, et al. Reattendance and complications in a randomised
trial of prescribing strategies for sore throat: the medicalising nia occurring in long-term-care facilities can be treated as
effect of prescribing antibiotics. BMJ 1997; 315: 350–2. Plague either community-acquired or hospital-acquired pneumo-
5. Del Mar CB, et al. Antibiotics for sore throat. Available in The
Cochrane Database of Systematic Reviews; Issue 4. Chichester: Plague1 is caused by the Gram-negative bacillus Yersinia nia. Cases of hospital-acquired pneumonia are divided ac-
John Wiley; 2006 (accessed 18/08/08). pestis (Yersinia pseudotuberculosis subsp. pestis) and is cording to whether ventilator assistance is needed. These
6. WHO. WHO model prescribing information: drugs used in the usually transmitted to man via rodents and their infected categories also provide a rough guide as to the likely path-
treatment of streptococcal pharyngitis and prevention of rheu-
matic fever. Geneva: WHO, 1999. fleas. It has occurred as worldwide pandemics, for exam- ogen and severity of the disease.
7. Bisno AL. Acute pharyngitis. N Engl J Med 2001; 344: 205–11. ple, the Black Death in Europe in the Middle Ages. In the Other types of pneumonia include aspiration pneumonia
8. Bisno AL, et al. Practice guidelines for the diagnosis and man- 1980s the largest numbers of cases reported were in Tan-
agement of group A streptococcal pharyngitis. Clin Infect Dis and the various forms of interstitial pneumonia or pneu-
2002; 35: 113–25. zania, Vietnam, Brazil, Peru and more recently in Mada- monitis (see also Aspiration Syndromes, p.1693, and Dif-
9. Green AD. Treatment of choice for childhood tonsillitis. BMJ gascar. Plague may take several forms of which bubonic fuse Parenchymal Lung Disease, p.1502). Interstitial
1986; 293: 1030. plague is the most common; others include pneumonic,
10. Martin JM, et al. Erythromycin-resistant group A streptococci
pneumonitis is a common complication in cancer patients
in schoolchildren in Pittsburgh. N Engl J Med 2002; 346: septicaemic, and meningitic plague. Streptomycin, tetra- and has also been associated with certain drugs, for exam-
1200–6. cycline, and chloramphenicol have traditionally been used ple amiodarone, bleomycin, and nitrofurantoin.
11. Maruyama S, et al. Sensitivity of group A streptococci to anti- in the treatment of plague2 with streptomycin being the Community-acquired pneumonia. In community-ac-
biotics: prevalence of resistance to erythromycin in Japan. Am J
Dis Child 1979; 133: 1143–5. treatment of choice, although the possibility of a Jarisch- quired pneumonia2-7 the commonest pathogen in previ-
12. Seppälä H, et al. Resistance to erythromycin in group A strep- Herxheimer reaction resulting from the bactericidal effect ously healthy subjects is Streptococcus pneumoniae
tococci. N Engl J Med 1992; 326: 292–7. of streptomycin must be borne in mind; it is also contra-
13. Casey JR, Pichichero ME. Meta-analysis of cephalosporins ver- (pneumococcus). Other common pathogens include Hae-
sus penicillin for treatment of group A streptococcal tonsillo- indicated in pregnancy. Success has also been reported mophilus influenzae and atypical pathogens such as
pharyngitis in adults. Clin Infect Dis 2004; 38: 1526–34. with aminoglycosides such as gentamicin and kanamycin. Chlamydia pneumoniae, Mycoplasma pneumoniae, and
14. Dillon HC. Streptococcal pharyngitis in the 1980s. Pediatr In- Although there is no clinical experience with fluoroquin-
fect Dis J 1987; 6: 123–30. Legionella pneumophila (see Legionnaires’ Disease,
15. Lan AJ, et al. The impact of dosing frequency on the efficacy of olones, in-vitro susceptibilities and animal studies suggest p.176).2,4 Less common causes include Staphylococcus
10-day penicillin or amoxicillin therapy for streptococcal tonsil- that they would be effective.2 aureus, which usually occurs as a secondary bacterial in-
lopharyngitis: a meta-analysis. Abstract: Pediatrics 2000; 105:
414. Full version: http://pediatrics.aappublications.org/cgi/ In the UK, the recommended treatment for adults is gen- fection after influenza and is associated with high mortali-
content/full/105/2/e19 (accessed 20/05/04) tamicin (first choice in pregnancy); ciprofloxacin or doxy- ty; Moraxella catarrhalis (Branhamella catarrhalis) oc-
16. Gerber MA, et al. Five vs ten days of penicillin V therapy for cycline may be used if aminoglycosides are unsuitable and curs especially in patients with chronic lung disease;
streptococcal pharyngitis. Am J Dis Child 1987; 141: 224–7.
17. Strömberg A, et al. Five versus ten days treatment of group A
may also be used for first-line therapy in children, but dox- Gram-negative enteric bacilli; Pseudomonas aeruginosa;
streptococcal pharyngotonsillitis: a randomized controlled clin- ycycline is only suitable for children over 8 years of age. If Chlamydophila psittaci (Chlamydia psittaci) (see Psittaco-
ical trial with phenoxymethylpenicillin and cefadroxil. Scand J plague meningitis is suspected chloramphenicol should be
Infect Dis 1988; 20: 37–46. sis, p.188); and Coxiella burnetii (see Q Fever, p.188).
18. Adam D, et al. Five days of erythromycin estolate versus ten
used as it crosses the blood-brain barrier.2 Similar informa- Gram-negative bacilli rarely cause pneumonia in the com-
days of penicillin V in the treatment of group A streptococcal tion is provided by WHO,3 with sulfonamides being men- munity, especially in previously healthy patients, although
tonsillopharyngitis in children. Eur J Clin Microbiol Infect Dis tioned as alternatives. In UK guidelines2 ciprofloxacin is the frequency of such infections is increasing.8 Anaerobic
1996; 15: 712–17.
19. Carbon C, et al. A double-blind randomized trial comparing the considered to be the drug of choice for prophylaxis in bacteria are associated with aspiration pneumonia. Viruses
efficacy and safety of a 5-day course of cefotiam hexetil with adults and children considered to be at risk after close con- are the commonest pathogens in young children.
that of a 10-day course of penicillin V in adult patients with tact with cases of pneumonic disease or after a deliberate
pharyngitis caused by group A β-haemolytic streptococci. J An-
release of Y. pestis; doxycycline may be used as an alterna- Pneumococcal pneumonia usually develops over a
timicrob Chemother 1995; 35: 843–54. number of days and in elderly patients onset may be insid-
20. O’Doherty B, et al. Azithromycin versus penicillin V in the tive in those over 12 years of age. Other suggested antibac-
treatment of paediatric patients with acute streptococcal pharyn- terials include chloramphenicol and co-trimoxazole. ious. Str. pneumoniae has usually been considered to be
gitis/tonsillitis. Eur J Clin Microbiol Infect Dis 1996; 15: sensitive to penicillins (benzylpenicillin, amoxicillin, or
718–24. Commenting on the plague epidemic that occurred in In- ampicillin), cephalosporins, erythromycin, or co-trimoxa-
21. Hooton TM. A comparison of azithromycin and penicillin V for dia in 1994, workers from the US CDC4 also noted that zole, but there is increasing prevalence of global resistance
the treatment of streptococcal pharyngitis. Am J Med 1991; streptomycin continues to be the drug of choice for treat-
91(3A): 23S–26S. although there are marked geographical differences.9,10 A
22. Portier H, et al. Five day clarithromycin modified release versus ing plague, that tetracycline and gentamicin are alterna- survey10 which, during 1999 to 2000, collected data from
10 day penicillin V for group A streptococcal pharyngitis: a tives, and that chloramphenicol is preferred for plague 69 centres in 25 countries found 22.1% resistance overall
multi-centre, open-label, randomized study. J Antimicrob meningitis. They considered that prophylaxis should be
Chemother 2002; 49: 337–44. to benzylpenicillin (but 71.5% in South Korea, 46.2% in
23. Aujard Y, et al. Comparative efficacy and safety of four-day ce- given to those who have had face-to-face contact or who France, 42.1% in Spain, 32.6% in the USA, 15.3% in Latin
furoxime axetil and ten-day penicillin treatment of group A have occupied a closed space with someone who has pneu- America, 5.5% in the UK, 4.4% in Australia, and 0% in the
beta-hemolytic streptococcal pharyngitis in children. Pediatr
Infect Dis J 1995; 14: 295–300. monic plague. For prophylaxis, tetracycline can be given Netherlands); resistance overall to erythromycin was
24. Adam D, et al. Comparison of short-course (5 day) cefuroxime to adults and older children or sulfonamides to children of 31.0% (87.6% in South Korea, 57.6% in France, 28.6% in
axetil with a standard 10 day oral penicillin V regimen in the 8 years or less; chloramphenicol is also effective.4 Spain, 30.9% in the USA, 15.3% in Latin America, 13.2%
treatment of tonsillopharyngitis. J Antimicrob Chemother 2000;
45 (suppl): 23–30. Infection with a strain of Y. pestis resistant to all the drugs in the UK, 12.3% in Australia, and 7.8% in the Nether-
25. Brook I. The role of β-lactamase-producing bacteria in the per- usually effective against plague identified in a patient from lands). Macrolide resistance as high as 35% has been re-
sistence of streptococcal tonsillar infection. Rev Infect Dis Madagascar5 responded to treatment with co-trimoxazole
1984; 6: 601–7. ported in some areas of the USA and Europe; 96% resist-
26. Gerber MA, et al. Potential mechanisms for failure to eradicate and streptomycin. ance has been reported in Taiwan. Fluoroquinolone
group A streptococci from the pharynx. Pediatrics 1999; 104: A vaccine is available for active immunisation. resistance was low overall (1%) although 14.3% of iso-
911–17.
27. Stillerman M. Comparison of oral cephalosporins with penicil- 1. Prentice MB, Rahalison L. Plague. Lancet 2007; 369: lates were resistant in Hong Kong.9,10 However, in clinical
1196–1207.
lin therapy for group A streptococcal pharyngitis. Pediatr Infect
2. Health Protection Agency. Guidelines for action in the event of
practice pneumococcal pneumonia frequently responds to
Dis 1986; 5: 649–54. high doses of penicillins or cephalosporins and the routine
28. Gooch WM, et al. Efficacy of cefuroxime axetil suspension a deliberate release: plague (issued April 2007). Available at:
compared with that of penicillin V suspension in children with h t t p : / / w w w. h p a . o rg . u k / w e b / H PAw e b F i l e / H PAw eb _ C / use of penicillin for community-acquired pneumonia may
group A streptococcal pharyngitis. Antimicrob Agents Chem- 1194947396073 (accessed 18/08/08) still be reasonable in many countries.
other 1993; 37: 159–63. 3. WHO. Plague manual: epidemiology, distribution, surveillance
29. Kiani R, et al. Comparative, multicenter studies of cefixime and and control. Available at: http://www.who.int/csr/resources/ The treatment of community-acquired pneumonia is com-
amoxicillin in the treatment of respiratory tract infections. Am J publications/plague/WHO_CDS_CSR_EDC_99_2_EN/en/ (ac- plicated by the increasing spectrum of causative organisms
Med 1988; 85 (suppl 3A): 6–13. cessed 27/06/06)
30. Milatovic D, et al. Cefprozil versus penicillin V in treatment of 4. Campbell GL, Hughes JM. Plague in India: a new warning from and prevalence of antibacterial resistance. Furthermore,
streptococcal tonsillopharyngitis. Antimicrob Agents Chemoth- an old nemesis. Ann Intern Med 1995; 122: 151–3. since the causative pathogen is often unknown, initial an-
er 1993; 37: 1620–3. 5. Galimand M, et al. Multidrug resistance in Yersinia pestis medi- tibacterial therapy is usually empirical. Guidelines for the
31. Milatovic D, Knauer J. Cefadroxil versus penicillin in the treat- ated by a transferable plasmid. N Engl J Med 1997; 337: 677–80.
ment of streptococcal tonsillopharyngitis. Eur J Clin Microbiol treatment of pneumonia have been issued by bodies in
Infect Dis 1989; 8: 282–8. many countries.8,11-18 Although common principles can be
32. Brook I. Treatment of patients with acute recurrent tonsillitis Pneumonia identified, recommendations must be localised because of
due to group A β-haemolytic streptococci: a prospective rand-
omized study comparing penicillin and amoxycillin/clavulanate Pneumonia1 is a respiratory disease characterised by in- differences in patterns of infection and drug resistance,
potassium. J Antimicrob Chemother 1989; 24: 227–33. flammation of the lung parenchyma with congestion. It is variations in the availability of antibacterials and local
 Antibacterials 187
policies for their use, and differences in medical practice. taxime, or ceftriaxone, or oral or intravenous fluoroquin- infants up to 3 months of age for which erythromycin may
Countries also vary in the degree to which such guidelines olone be used or, alternatively, sulfafurazole.
are accepted in practice. These guidelines generally give • Gram-negative enteric bacilli: preferred treatment, in- Pneumonia in neonates is usually due to organisms ac-
advice for differences associated with age, the severity of travenous cefuroxime, cefotaxime, or ceftriaxone; alter- quired from the mother’s genital tract, especially group B
the infection and the presence or absence of underlying or natives, intravenous fluoroquinolone, imipenem, or streptococci, Escherichia coli, and Klebsiella pneumoni-
co-existent disorders. meropenem ae; initial treatment with gentamicin and benzylpenicillin
In the UK, guidelines for the management of community- • Ps. aeruginosa: preferred treatment, intravenous or ampicillin has been suggested. For prophylaxis against
acquired pneumonia have been produced by the British ceftazidime plus either gentamicin or tobramycin; alter- group B streptococci in neonates, see under Perinatal
Thoracic Society (BTS).8 For initial empirical treatment natives, intravenous ciprofloxacin or piperacillin plus Streptococcal Infections, p.184.
in the community amoxicillin is usually preferred. Eryth- either gentamicin or tobramycin Similar guidelines for the empirical management of com-
romycin is an alternative in penicillin-allergic patients and • Staph. aureus (non-meticillin-resistant): preferred treat- munity-acquired pneumonia in children have been devel-
should also be given during epidemics of mycoplasmal ment, intravenous flucloxacillin with or without oral or oped in South Africa.15 Additional recommendations have
pneumonia and when Legionella is suspected; clarithro- intravenous rifampicin; alternative, intravenous teico- been made to take into account the high prevalence of HIV
mycin may be given if there is gastrointestinal intolerance planin with or without oral or intravenous rifampicin infection. The drug of choice is amoxicillin; although
to erythromycin. • Staph. aureus (meticillin-resistant): preferred treatment, standard doses of amoxicillin will treat most cases of
In those patients hospitalised with non-severe communi- intravenous vancomycin; alternative, intravenous teico- pneumococcal pneumonia the use of high-dose amoxicil-
ty-acquired pneumonia there is an increased likelihood of planin with or without oral or intravenous rifampicin lin (30 mg/kg given 3 times daily) is recommended in or-
infection with atypical pathogens, or with Legionella spp.; der to overcome and limit the emergence of resistant pneu-
In the USA, guidelines for the management of communi-
consequently, combined empirical treatment orally with mococci, and to successfully treat those few children with
ty-acquired pneumonia in adults have been jointly pro-
amoxicillin plus either erythromycin or clarithromycin is high-level pneumococcal resistance the following addi-
duced by the Infectious Diseases Society of America (ID-
preferred.8 When oral therapy is inappropriate, intrave- tional factors should be considered:
SA) and by the American Thoracic Society (ATS).12 For
nous ampicillin or benzylpenicillin is given, together with previously healthy outpatients with no risk factors for • children younger than 2 months have more Gram-nega-
intravenous erythromycin or, preferably, clarithromycin. drug-resistant Str. pneumoniae (DRSP) infection they rec- tive infections and therefore need an intravenous
For those intolerant of beta-lactams and macrolides or ommend a macrolide (such as erythromycin, azithromy- aminoglycoside or an intravenous cephalosporin, while
when there are local concerns over Clostridium difficile- cin, or clarithromycin); doxycycline may be given as an children older than 5 years have more infections caused
associated diarrhoea, a fluoroquinolone with enhanced ac- alternative. In those with co-existing cardiopulmonary dis- by M. pneumoniae and C. pneumoniae and need a mac-
tivity against pneumococci may be given as an alternative ease and/or other complicating factors (such as renal dis- rolide (erythromycin, clarithromycin, or azithromycin)
(levofloxacin orally or intravenously or moxifloxacin oral- ease, diabetes mellitus, alcoholism, malignancies, or as- • HIV-infected children requiring hospitalisation and
ly).8 In practice, however, many patients with non-severe plenia), taking immunosuppressive drugs, those who have those with a high risk of being HIV-infected or who
community-acquired pneumonia are admitted to hospital received antibacterial therapy within the previous 3 have symptomatic HIV disease or who are severely
for non-clinical reasons such as old age, family preference, months, or those with other risks for DRSP infection a malnourished should be given an aminoglycoside plus
inadequate home care, or adverse social circumstances, ‘respiratory fluoroquinolone’ (gemifloxacin, levofloxacin, their empirical antibacterial regimen; alternatively they
and in these patients it is considered appropriate to treat or moxifloxacin) is recommended. Alternatively a beta- may be given a regimen that provides effective treat-
with monotherapy as for patients treated in the community lactam (high dose amoxicillin with or without clavulanic ment against Gram-negative bacteria
(see above).8 acid, or ceftriaxone, cefpodoxime, or cefuroxime) plus a • if pneumocystis pneumonia is suspected, co-trimoxa-
Patients hospitalised with severe community-acquired macrolide (or doxycycline) may be given. zole should be added. All hospitalised HIV-exposed
pneumonia should receive parenteral empirical treatment In hospitalised patients who are not in intensive care the children less than 6 months of age should be treated em-
regardless of their ability to take oral medication. Since preferred treatment is a beta-lactam (cefotaxime, ceftriax- pirically with co-trimoxazole, unless HIV infection sta-
community-acquired pneumonia caused by Legionella one, ampicillin, or ertapenem) plus a macrolide (or doxy- tus is negative and the child is not being breast-fed. Em-
spp. is more likely to result in severe disease, the initial cycline). In penicillin-allergic patients a respiratory fluor- pirical treatment with co-trimoxazole plus amoxicillin
empirical regimen should include appropriate therapy. oquinolone is recommended. In hospitalised patients who and an aminoglycoside should also be given to older
Current recommendations8 are for combined intravenous are in intensive care the preferred treatment is a beta- HIV-infected children with features of AIDS who are
treatment with a broad-spectrum beta-lactamase-stable an- lactam (cefotaxime, ceftriaxone, or ampicillin/sulbactam) not on co-trimoxazole prophylaxis
tibacterial such as amoxicillin with clavulanic acid or a plus either azithromycin or a respiratory fluoroquinolone. • when Staph. aureus, is suspected, cloxacillin is the drug
second- or third-generation cephalosporin such as cefurox- In penicillin-allergic patients a respiratory fluoroquinolone of choice. In HIV-infected children, about 60% of com-
ime, cefotaxime, or ceftriaxone, together with a macrolide and aztreonam are recommended. For Pseudomonas in- munity-acquired Staph. aureus may be resistant to
(clarithromycin or erythromycin). For life-threatening fection, an antipneumococcal, antipseudomonal beta- cloxacillin and vancomycin should be given
infection where Legionella is suspected, the further addi- lactam (such as piperacillin/tazobactam, cefepime, imi- Hospital-acquired pneumonia. Most reports on hospital-
tion of rifampicin is recommended;8 although rifampicin penem, or meropenem) plus either ciprofloxacin or levo- acquired or nosocomial pneumonia have been from the
may result in reduced serum concentrations of macrolides, floxacin are recommended. Alternative regimens include USA. The organisms most commonly responsible for hos-
this is not known to be of clinical significance when treat- an antipneumococcal, antipseudomonal beta-lactam plus pital-acquired pneumonia are Gram-negative enteric ba-
ing community-acquired pneumonia. As in non-severe in- an aminoglycoside and azithromycin, or an antipneumo- cilli, Staph. aureus, Str. pneumoniae, Enterobacteriaceae,
fection, in patients who are intolerant of beta-lactams and coccal, antipseudomonal beta-lactam plus an aminoglyco- and H. influenzae; others that may need to be considered,
macrolides or when there are local concerns over C. diffi- side and an antipneumococcal fluoroquinolone. In penicil- particularly in the presence of specific risk factors, are Le-
cile-associated diarrhoea, levofloxacin may be given as an lin-allergic patients aztreonam should be used in place of gionella spp., Ps. aeruginosa, anaerobes and, in severe in-
alternative, but with the addition of benzylpenicillin for se- the beta-lactam. For community-acquired meticillin-re- fection, Acinetobacter spp. Hospital-acquired pneumonia
vere infection.8 sistant Staph. aureus infection, vancomycin or linezolid occurring 48 hours after mechanical ventilation is termed
The following treatments are recommended in the UK,8 in should be added. ventilator-associated pneumonia; cases usually result from
conjunction with local microbiological advice, for the mi- In children pneumonia is caused by a wider spectrum of aspiration of pathogenic material that commonly colonises
nority of patients with community-acquired pneumonia in organisms than in adults. Viruses, especially respiratory the oropharynx. The organisms often responsible for early
whom the causative organism has been identified, usually syncytial virus, are very common pathogens in infants and onset ventilator-associated pneumonia are Staph. aureus,
in hospital: children up to 4 years of age and, as in adults, pneumococ- Str. pneumoniae, and H. influenzae while late-onset venti-
ci are very common bacterial pathogens. Guidelines for lator-associated pneumonia is often caused by resistant
• Str. pneumoniae: preferred treatment, oral amoxicillin or nosocomial pathogens such as Ps. aeruginosa, meticillin
intravenous benzylpenicillin; alternatives, oral erythro- the management of community-acquired pneumonia in
children have been produced by the BTS.11 Amoxicillin is resistant Staph. aureus, Klebsiella spp., and Acinetobacter
mycin or clarithromycin, or intravenous cefuroxime, ce- baumannii.19
fotaxime, or ceftriaxone considered the antibacterial of first choice for empirical
oral therapy in children under 5 years of age because it is Broad spectrum antibacterial therapy is essential for hospi-
• M. pneumoniae or C. pneumoniae: preferred treatment, effective against the majority of causative organisms. Al- tal-acquired pneumonia and most initial therapy is empiri-
oral or intravenous erythromycin or clarithromycin; al- ternatives are amoxicillin with clavulanic acid, cefaclor, cal. As in the treatment of community-acquired pneumo-
ternatives, oral tetracycline or oral or intravenous fluoro- erythromycin, clarithromycin, or azithromycin. Mac- nia selection of antibacterials must be localised. For initial
quinolone rolides should be given as first-line empirical therapy in empirical treatment of early-onset hospital-acquired pneu-
• C. psittaci or C. burnetii: preferred treatment, oral or in- children over 5 years since M. pneumoniae pneumonia is monia or ventilator-associated pneumonia in patients with
travenous tetracycline; alternatives, oral or intravenous more prevalent in older children. Macrolides should also no known risk factors for multidrug-resistant pathogens,
erythromycin or clarithromycin be used in children of any age if either M. pneumoniae or and any disease severity, ATS recommends20 the follow-
• Legionella spp.: preferred treatment, oral or intravenous C. pneumoniae are suspected. Amoxicillin should be used ing drugs: ceftriaxone; levofloxacin, moxifloxacin, or cip-
clarithromycin with or without oral or intravenous rif- as first-line treatment at any age if Str. pneumoniae is rofloxacin; ampicillin/sulbactam; or ertapenem. Where
ampicin; alternative, oral or intravenous fluoroquinolo- thought to be the likely pathogen. If Staph. aureus is sus- there is late-onset infection or risk factors for multidrug re-
ne pected then a macrolide or a combination of flucloxacillin sistance the following are recommended: an antipseu-
with amoxicillin is appropriate. Intravenous therapy domonal cephalosporin (cefepime or ceftazidime) or an
• H. influenzae (non-beta-lactamase-producing): pre- should be given in severe infection or when the child is antipseudomonal carbapenem (imipenem or meropenem)
ferred treatment, oral amoxicillin or intravenous ampi- unable to absorb oral antibacterials, for example due to or piperacillin-tazobactam together with an antipseu-
cillin; alternatives, intravenous cefuroxime, cefotaxime, vomiting; appropriate intravenous drugs for severe pneu- domonal fluoroquinolone (ciprofloxacin or levofloxacin)
or ceftriaxone, or oral or intravenous fluoroquinolone monia include amoxicillin with clavulanic acid, cefuroxi- or an aminoglycoside (amikacin, gentamicin, or tobramy-
• H. influenzae (beta-lactamase-producing): preferred me, or cefotaxime. If the causative organism is known to cin); if MRSA is likely then linezolid or vancomycin
treatment, oral or intravenous amoxicillin with clavu- be Str. pneumoniae a penicillin may be used alone. should also be used. Intravenous therapy should be given
lanic acid; alternatives, intravenous cefuroxime, cefo- Chlamydia trachomatis is another common cause in to all patients initially, and changed to the oral or enteral
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
188 Antibacterials
route as soon as possible. Efforts should be made to short- 16. Infectious Diseases Society of Taiwan, Taiwan Society of Pulmo- 6. Mercer BM, Arheart KL. Antimicrobial therapy in expectant
nary and Critical Medicine, and Medical Foundation in Memory management of preterm premature rupture of the membranes.
en the duration of therapy from the traditional 14 to 21 of Dr. Deh-Lin Cheng. Guidelines on antimicrobial therapy of Lancet 1995; 346: 1271–9. Correction. ibid. 1996; 347: 410.
days to as little as 7 days provided Ps. aeruginosa is absent pneumonia in adults in Taiwan, revised 2006. J Microbiol Immu- 7. Egarter C, et al. Antibiotic treatment in preterm premature rup-
and that the patient shows a good clinical response. nol Infect 2007; 40: 279–83. Also available at: http:// ture of membranes and neonatal morbidity: a metaanalysis. Am J
www.jmii.org/content/pdf/v40n3p279.pdf (accessed 05/03/08) Obstet Gynecol 1996; 174: 589–97.
Nosocomial pneumonia is especially likely in immuno- 17. Miyashita N, et al. Japanese Respiratory Society. The JRS
compromised or neutropenic patients. Prophylactic meas- guidelines for the management of community-acquired pneu-
ures in ventilated patients are those mentioned under In- monia in adults: an update and new recommendations. Intern Proctitis
Med 2006; 45: 419–28. Also available at: http://
tensive Care, p.175. www.jstage.jst.go.jp/article/internalmedicine/45/7/419/_pdf Proctitis is inflammation of the rectum that may be caused
Immunocompromised patients. Immunosuppressed pa- (accessed 05/03/08) by sexually transmitted pathogens, most commonly Neis-
tients are at increased risk of pneumonia. In addition to the 18. Maxwell DJ, et al. Empiric management of community-ac- seria gonorrhoeae, Chlamydia trachomatis, Treponema
quired pneumonia in Australian emergency departments. Med J
bacteria mentioned above they are susceptible to oppor- Aust 2005; 183: 520–4. pallidum, or herpes simplex virus.
tunistic infections with Mycobacterium tuberculosis (see 19. Hunter JD. Ventilator associated pneumonia. Postgrad Med J For empirical treatment of sexually transmitted proctitis
2006; 82: 172–8.
under Tuberculosis, p.196); viruses such as Cytomegalovi-
20. American Thoracic Society; Infectious Diseases Society of
the CDC1 in the USA recommends a single intramuscular
rus and fungi, in particular Pneumocystis jirovecii (see America. Guidelines for the management of adults with hospital- dose of ceftriaxone 125 mg, plus oral doxycycline 100 mg
p.521), are also causes of pneumonia in these patients. acquired, ventilator-associated, and healthcare-associated pneu- twice daily for 7 days.
Aspiration pneumonia. Aspiration of organisms present monia. Am J Respir Crit Care Med 2005; 171: 388–416. Also
available at: http://www.thoracic.org/sections/publications/ The specific treatment of rectal infections caused by C.
in the upper respiratory tract into the lungs, often as a result statements/pages/mtpi/guide1-29.html (accessed 25/05/06) trachomatis and N. gonorrhoeae is discussed under
of loss of consciousness or difficulty in swallowing, can 21. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Chlamydial Infections (p.166) and Gonorrhoea (p.191) re-
cause aspiration pneumonia.21 When community acquired Engl J Med 2001; 344: 665–71.
spectively. Patients with herpes proctitis should be treated
the organisms responsible are predominantly anaerobes, in the same way as those with genital herpes (p.854).
but in hospital-acquired aspiration pneumonia Gram-neg- Pregnancy and the neonate 1. CDC. Sexually transmitted diseases treatment guidelines 2006.
ative bacilli and Staph. aureus are also found. Confusion For infections associated specifically with pregnancy, see MMWR 2006; 55(RR-11): 1–94. Also available at: http://
has arisen over the term ‘aspiration pneumonia’ because it www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07)
under Endometritis (p.170), Perinatal Streptococcal Infec-
has also been applied more generally to aspiration, for ex- tions (p.184), and Premature Labour (below).
ample, of gastric acid (Mendelson’s syndrome), resulting Prostatitis
in chemical pneumonitis and not associated with bacterial See under Urinary-tract Infections, p.199.
infection. Lung abscess generally characterises late-stage Premature labour
aspiration pneumonia involving anaerobic bacteria. The Preterm birth, with or without rupture of membranes,
aetiology is rarely established, but specific anaerobic bac- causes significant perinatal morbidity and mortality. There Psittacosis
teria involved include Peptostreptococcus, Prevotella mel- is evidence that infection appears to have an important role The causative organism of psittacosis (ornithosis) is
aninogenica (Bacteroides melaninogenicus), and Fuso- in the cause or as a consequence of ruptured membranes1,2 Chlamydophila psittaci (Chlamydia psittaci). It is usually
bacterium nucleatum. Nearly all patients with anaerobic and as many as 50% of spontaneous preterm births are due transmitted to humans by direct or indirect contact with in-
pulmonary infections are treated empirically. Some21 have to infection, with Mycoplasma spp. being the most com- fected birds and the primary site of infection is the lung.1
expressed the view that penicillin and clindamycin are in- monly isolated organisms from the amniotic cavity.3 Other The clinical presentation of psittacosis can vary widely
adequate and that antibacterials with activity against bacteria that have been implicated include group B strep- from a mild ‘flu-like’ illness to a fulminating toxic state
Gram-negative organisms, such as third-generation cepha- tococci, Chlamydia trachomatis, and those associated with with multiple organ involvement.1 Most patients will have
losporins, fluoroquinolones, and piperacillin are usually bacterial vaginosis. The role of antibacterial treatment has a cough, although this is not always prominent. Tetracy-
required even in community-acquired aspiration pneumo- been evaluated. However, it is possible that maternal anti- clines are the treatment of choice1,2 and early therapy may
nia. Most patients with lung abscess receive parenteral bacterial treatment may suppress the stimulation of labour be life-saving; a 21-day course has been recommended
therapy until they become afebrile and show clinical im- without effectively treating fetal infection2 and concerns since relapses have occurred after shorter periods.1 An al-
provement; oral therapy may then continue for weeks or have been expressed that delaying delivery in the presence ternative is chloramphenicol.2 Erythromycin or a similar
months if necessary. of a subclinical infection may not produce the best out- macrolide have also been used successfully.3,4
1. Hoare Z, Lim WS. Pneumonia: update on diagnosis and man- come for the neonate.4 1. Macfarlane JT, Macrae AD. Psittacosis. Br Med Bull 1983; 39:
163–7.
agement. BMJ 2006; 332: 1077–9. A meta-analysis5 and a systematic review1 of studies of the 2. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
2. File TM. Community-acquired pneumonia. Lancet 2003; 362:
1991–2001. routine use of antibacterials as adjuncts in the management book of antimicrobial therapy. 18th ed. New Rochelle NY: The
3. Ostapchuk M, et al. Community-acquired pneumonia in infants of premature labour in women with intact membranes Medical Letter, 2008; 73.
and children. Am Fam Physician 2004; 70: 899–908. have failed to demonstrate an overall improvement in neo- 3. Morrison WM, et al. An outbreak of psittacosis. J Infect 1991;
4. Lutfiyya MN, et al. Diagnosis and treatment of community-ac- 22: 71–5.
quired pneumonia. Am Fam Physician 2006; 73: 442–50. natal morbidity; indeed, an increase in neonatal mortality 4. Chang KP, Veitch PC. Fever, haematuria, proteinuria, and a par-
5. Niederman MS. Recent advances in community-acquired pneu- was actually noted.5 rot. Lancet 1997; 350: 1674.
monia: inpatient and outpatient. Chest 2007; 131: 1205–15.
6. Epstein BJ, Gums JG. Optimal pharmacological therapy for In women with preterm premature rupture of membranes,
community-acquired pneumonia: the role of dual antibacterial meta-analyses6,7 and a systematic review2 have shown that Q fever
therapy. Drugs 2005; 65: 1949–71. antibacterials could delay delivery, and reduce both mater-
7. Garau J, Calbo E. Community-acquired pneumonia. Lancet Q fever1,2 (or query fever) is a rickettsial infection (p.190)
2008; 371: 455–8. nal morbidity (chorioamnionitis and postpartum infec- caused by Coxiella burnetii. It is a zoonosis occurring
8. British Thoracic Society. BTS Guidelines for the management of tions) and some aspects of neonatal morbidity (sepsis, worldwide and is transmitted to humans from domestic
community acquired pneumonia in adults. Thorax 2001; 56 (suppl pneumonia, and intraventricular haemorrhage). No effects
IV): iv1–iv64. Also available at: http://www.brit-thoracic.org.uk/ animals such as cattle and sheep, mainly by inhalation of
portals/0/Clinical%20Information/Pneumonia/Guidelines/ on neonatal mortality or gestational age-related morbidity infected dust. Q fever is asymptomatic in about 50 to 60%
MACAP2001gline.pdf (accessed 18/08/08) 2004 Update. Availa- were noted.2,7 An increased incidence of neonatal necrotis- of infected persons. Symptomatic acute infection general-
ble at: http://www.brit-thoracic.org.uk/portals/0/Clinical% ing enterocolitis has been found after maternal use of
20Information/Pneumonia/Guidelines/MACAPrevisedApr04.pdf ly presents as a febrile flu-like illness and many patients
(accessed 18/08/08) amoxicillin with clavulanic acid and it is considered best may also have hepatitis or pneumonia that can progress to
9. Garau J. Treatment of drug-resistant pneumococcal pneumonia. avoided in women at risk of premature delivery; erythro- acute respiratory distress syndrome. Endocarditis is the
Lancet Infect Dis 2002; 2: 404–15.
10. Felmingham D, et al. Increasing prevalence of antimicrobial re-
mycin may be the antibacterial of choice.2 A systematic most frequent form of chronic infection and the most seri-
sistance among isolates of Streptococcus pneumoniae from the review and meta-analysis3 evaluated the effect of antibac- ous form of Q fever; infection may be difficult to eradicate
PROTEKT surveillance study, and comparative in vitro activity terials on the rate of preterm births when given in the sec-
of the ketolide, telithromycin. J Antimicrob Chemother 2002; 50 and prolonged treatment is generally needed. There is also
(suppl S1): 25–37. ond trimester of pregnancy to women at risk of preterm evidence of long-term sequelae including lethargy and fa-
11. British Thoracic Society. BTS Guidelines for the management of births. Giving macrolides or clindamycin was associated tigue in patients who have not had cardiac involvement.
community acquired pneumonia in childhood. Thorax 2002; 57 with a lower rate of preterm delivery, whereas giving met-
(suppl 1): i1–i24. Also available at: http://www.brit-thoracic.org.uk/ Subclinical acute infections should be treated if recog-
portals/0/Clinical%20Information/Pneumonia/Guidelines/ ronidazole alone in the second trimester was associated nised and if possible treatment should be started within 3
paediatriccap.pdf (accessed 18/08/08) with a greater risk of preterm delivery in a high-risk popu- days of the onset of symptoms. A tetracycline such as doxy-
12. Mandell LA, et al. Infectious Diseases Society of Ameri- lation.
ca/American Thoracic Society consensus guidelines on the cycline for 14 days is the treatment of choice for acute Q
management of community-acquired pneumonia in adults. Clin Clinical infections of the genito-urinary tract during preg- fever. The role of macrolides in acute infection is unclear
Infect Dis 2007; 44 (suppl 2): S27–S72. Also available at: http:// nancy are a cause of significant morbidity in the neonate
www.journals.uchicago.edu/doi/pdf/10.1086/511159 (accessed and clinical data on the use of fluoroquinolones are limit-
22/01/08) and antimicrobial treatment is necessary (see Bacterial ed.1,2 Co-trimoxazole is recommended for children young-
13. Woodhead M, et al. European Respiratory Society, European Vaginosis, p.164, Chlamydial Infections, p.166, and Peri- er than 8 years of age.1Q fever endocarditis is more diffi-
Society of Clinical Microbiology and Infectious Diseases. natal Streptococcal Infections, p.184).
Guidelines for the management of adult lower respiratory tract cult to treat and surgery may be required in addition to
infections. Eur Respir J 2005; 26: 1138–80. Also available at: 1. King J, Flenady V. Prophylactic antibiotics for inhibiting pre- antibacterial treatment.2 Monotherapy with tetracycline
http://erj.ersjournals.com/cgi/reprint/26/6/1138.pdf (accessed term labour with intact membranes. Available in The Cochrane decreases symptoms but fails to eradicate C. burnetii and
18/08/08) Database of Systematic Reviews; Issue 4. Chichester: John Wi-
14. Brink A, et al. South African Thoracic Society (SATS). Guideline ley; 2002 (accessed 16/05/05). combination antibacterial therapy has been evaluated.
for the management of nosocomial infections in South Africa. S Afr 2. Kenyon S, et al. Antibiotics for preterm rupture of membranes. Long-term treatment with doxycycline plus rifampicin or
Me d J 2 0 0 6 ; 96: 6 4 2 – 5 2 . A l s o a v a i l a b l e a t : h tt p : / / Available in The Cochrane Database of Systematic Reviews; Is- with ciprofloxacin alone3 has been successful in individual
www.pulmonology.co.za/guidelines/nosocomial%20infections% sue 2. Chichester: John Wiley; 2003 (accessed 16/05/05).
20guideline.pdf (accessed 26/02/08). 3. Morency AM, Bujold E. The effect of second-trimester antibiot-
patients with endocarditis, whereas pefloxacin alone4 was
15. Zar HJ, et al. Working Groups of the Paediatric Assembly of the ic therapy on the rate of preterm birth. J Obstet Gynaecol Can not. A retrospective comparison of doxycycline alone or
South African Thoracic Society. Diagnosis and management of 2007; 29: 35–44. with rifampicin, fluoroquinolones (ofloxacin or pe-
community-acquired pneumonia in childhood—South African
Thoracic Society Guidelines. S Afr Med J 2005; 95: 977–81, 4. Brocklehurst P. Infection and preterm delivery. BMJ 1999; 318: floxacin), or co-trimoxazole, recommended treatment for
984–90. Also available at: http://blues.sabinet.co.za/WebZ/ 548–9. at least 3 years with doxycycline plus a fluoroquinolone;5
Authorize?sessionid=0:autho=pubmed:password=pubmed2004&/ 5. Egarter C, et al. Adjunctive antibiotic treatment in preterm labor
AdvancedQuery?&format=F&next=images/ejour/m_samj/ and neonatal morbidity: a meta-analysis. Obstet Gynecol 1996; doxycycline plus rifampicin also appeared effective, but in
m_samj_v95_n12_a21.pdf (accessed 05/05/08) 88: 303–9. most cases rifampicin had been stopped after a few months
 Antibacterials 189
because of interactions with anticoagulants often pre- ral in origin, but bacterial pathogens similar to those caus- benzylpenicillin or as a course of phenoxymethylpenicillin
scribed at the same time. Patients given doxycycline plus ing pneumonia are commonly isolated from patients with by mouth for 10 days. An injection containing benzathine
hydroxychloroquine needed a shorter treatment course these milder respiratory infections;2 even so, about one- benzylpenicillin and procaine benzylpenicillin has been
and had fewer relapses than those treated with doxycycline quarter of patients fail to respond satisfactorily to empiri- used in children.5 Erythromycin may be given to patients
plus ofloxacin; mortality rate for both groups was 5%.6 cal antibacterial treatment. For previously healthy adults allergic to penicillin. Other macrolides or oral cepha-
Successful treatment with doxycycline and chloroquine with non-specific upper respiratory-tract infection, US losporins may also be used. For further details on the treat-
for 2 years has been reported in a patient with a biological guidelines3 recommend that antibacterials are not given. ment of streptococcal sore throat, see under Pharyngitis,
prosthetic aortic valve and aortic homograft.7 The combi- Broad-spectrum antibacterials such as a penicillin or p.185. Treatment failure is more common after oral anti-
nation of doxycycline 100 mg twice daily and hydroxy- erythromycin may be necessary in some cases of uncom- bacterials and in the USA most of these patients are strep-
chloroquine 200 mg three times daily, both given orally for plicated upper or lower respiratory-tract infection. First tococcal carriers.5 Treatment of chronic carriers is not usu-
at least 18 months, is considered to be the treatment of line empirical treatment with a fluoroquinolone has been ally necessary, but eradication of pharyngeal carriage has
choice for Q fever endocarditis.1,2 An alternative regimen avoided in the past because of poor activity against strep- been achieved by an injection of benzathine benzylpenicil-
for patients unable to tolerate hydroxychloroquine is doxy- tococci,4,5 although some newer fluoroquinolones have lin plus rifampicin by mouth for 4 days;8 a 10-day course
cycline plus a fluoroquinolone for at least 3 to 4 years.2 much greater activity against streptococci.6 of oral clindamycin has also been effective.9 Broad-based
Q fever during pregnancy may result in obstetric compli- In respiratory-tract infections complicating chronic ob- primary prophylaxis in communities rather than individu-
cations, such as spontaneous abortion, intra-uterine growth structive pulmonary disease, amoxicillin has been recom- als is controversial and requires careful planning, but, for
retardation, intra-uterine fetal death, and premature deliv- mended for first-line treatment.7 If a further course is nec- example, penicillin prophylaxis did control an epidemic of
ery.8 Treatment with co-trimoxazole for at least 5 weeks essary, drugs with activity against penicillin-resistant H. acute tonsillitis associated with Str. pyogenes in a junior
during pregnancy was reported to protect against maternal influenzae and M. catarrhalis should probably be given, detention centre.10 However, a study in military recruits
chronic Q fever, placental infection, and obstetric compli- such as amoxicillin with clavulanic acid, a fluoroquinolo- demonstrated that Str. pyogenes infection could not be pre-
cations (in particular intra-uterine fetal death).8 ne (bearing in mind that some are not very active against vented in closely confined communities unless all individ-
A vaccine is available in some countries for prophylaxis Str. pneumoniae), or a second-generation cephalosporin. uals in the population received prophylaxis.11
in occupational groups who regularly handle potentially Ofloxacin has been reported to be beneficial in patients If acute rheumatic fever occurs, a full therapeutic course of
infected animal tissues. with chronic obstructive pulmonary disease who require penicillin should be given initially, as for primary preven-
1. Parker NR, et al. Q fever. Lancet 2006; 367: 679–88. mechanical ventilation.8 tion, to eradicate group A streptococci.5 Treatment then
2. Hartzell JD, et al. Q fever: epidemiology, diagnosis, and treat- For details on infections of the upper respiratory tract, see comprises bed rest and anti-inflammatory drugs, usually
ment. Mayo Clin Proc 2008; 83: 574–9. corticosteroids or salicylates, in an attempt to prevent val-
3. Yebra M, et al. Ciprofloxacin in a case of Q fever endocarditis. under Epiglottitis (p.170), Pharyngitis (p.185), and Sinusi-
N Engl J Med 1990; 323: 614. tis (p.193); see also Otitis Media (p.182). For infections of vular scarring. However, it is unclear whether anti-inflam-
4. Cacoub P, et al. Q-fever endocarditis and treatment with the fluo- the lower respiratory tract, see under Bronchitis (p.165), matory treatment has any influence on such long-term se-
roquinolones. Arch Intern Med 1991; 151: 816, 818. Cystic Fibrosis (p.166), and Pneumonia (p.186); those quelae.12 Carbamazepine or valproate may be given for
5. Levy PY, et al. Comparison of different antibiotic regimens for severe and distressing chorea.7 Secondary prevention is
therapy of 32 cases of Q fever endocarditis. Antimicrob Agents with a specific cause include Legionnaires’ Disease
Chemother 1991; 35: 533–7. (p.176), Nocardiosis (p.181), Pertussis (p.185), and Tuber- then continued with prolonged antibacterial prophylaxis
6. Raoult D, et al. Treatment of Q fever endocarditis: comparison culosis (p.196). because of the high risk of recurrent attacks of rheumatic
of 2 regimens containing doxycycline and ofloxacin or hydroxy- fever after subsequent streptococcal upper respiratory-
1. Murphy TF. Branhamella catarrhalis: epidemiological and clini-
chloroquine. Arch Intern Med 1999; 159: 167–73.
7. Calza L, et al. Doxycycline and chloroquine as treatment for
cal aspects of a human respiratory tract pathogen. Thorax 1998; tract infections. Again, penicillin is the preferred antibac-
53: 124–8. terial, the usual recommendation being an intramuscular
chronic Q fever endocarditis. J Infect 2002; 45: 127–9. 2. Macfarlane JT, et al. Prospective study of aetiology and outcome
8. Carcopino X, et al. Managing Q fever during pregnancy: the of adult lower-respiratory-tract infections in the community. injection of benzathine benzylpenicillin every 4 weeks, al-
benefits of long-term cotrimoxazole therapy. Clin Infect Dis Lancet 1993; 341: 511–14. though injections every 3 weeks may be warranted where
2007; 45: 548–55. 3. Snow V, et al. American College of Physicians, American Soci- the risk of recurrence is high.5-7 This advice has been influ-
ety of Internal Medicine, American Academy of Family Physi-
cians, Centers for Disease Control. Principles of appropriate an- enced by reports of high recurrence rates with the monthly
Relapsing fever tibiotic use for treatment of nonspecific upper respiratory tract regimen in such situations.13 A 12-year study in Taiwan14
Relapsing fever is caused by spirochaetes of the Borrelia infections in adults. Ann Intern Med 2001; 134: 487–9. Also confirmed that prophylaxis with benzathine benzylpenicil-
genus that are transmitted to humans by body lice or Orni- available at: http://www.annals.org/cgi/reprint/134/6/487 (ac-
cessed 05/08/08)
lin injections every 3 weeks is more effective than injec-
thodoros ticks. B. recurrentis causes louse-borne relapsing 4. Körner RJ, et al. Dangers of oral fluoroquinolone treatment in tions every 4 weeks and it was recommended that the 3-
fever and can occur widely, but is endemic especially in community acquired upper respiratory tract infections. BMJ week regimen should be used in adults and children with a
Ethiopia. Many species of Borrelia may cause tick-borne 1994; 308: 191–2. recent episode of rheumatic fever, especially in developing
5. Hosker HSR, et al. Management of community acquired lower
relapsing fever. respiratory tract infection. BMJ 1994; 308: 701–5. countries where exposure to streptococci is still intense. In
The treatment of choice for infection due to B. recurrentis 6. Guthrie R. Community-acquired lower respiratory tract infec- addition, pharmacokinetic studies have indicated relative-
is a tetracycline; benzylpenicillin or erythromycin are al- tions: etiology and treatment. Chest 2001; 120: 2021–34. ly low serum concentrations of penicillin in the fourth
7. Hosker H, et al. Antibiotics in chronic obstructive pulmonary
ternatives.1 Therapy with single oral doses of tetracy- disease. BMJ 1994; 308: 871–2. week after an intramuscular injection of benzathine ben-
cline,2,3 erythromycin,2,3 or chloramphenicol3 has been ef- 8. Nouira S, et al. Once daily oral ofloxacin in chronic obstructive zylpenicillin,15,16 despite the successful use of monthly in-
fective. Antibacterial treatment often causes a Jarisch- pulmonary disease exacerbation requiring mechanical ventila- jections in most patients. However, Australian and New
tion: a randomised placebo-controlled trial. Lancet 2001; 358:
Herxheimer reaction characterised by rigor, fever and hy- 2020–5.
Zealand guidelines consider the 4-week regimen suitable
potension, which may be fatal.2,4 Attempts to prevent this in most patients.7 Alternatively, oral prophylaxis with phe-
reaction include use of paracetamol and corticosteroids;2,4 noxymethylpenicillin or sulfadiazine may be given, al-
antibodies against tumour necrosis factor α have shown Rheumatic fever though, over the long time scale involved, compliance is
promise.5 Acute rheumatic fever occurs especially in children aged 6 likely to be a problem;4,6,7 erythromycin is suggested for
Tick-borne relapsing fever is milder than the louse-borne to 15 years as a consequence of upper respiratory-tract the rare patient who is allergic to penicillin and sulfona-
variety, but has been treated similarly. infections, such as pharyngitis or tonsillitis, with rheuma- mides. Sulfonamides should not be used for primary pre-
1. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
togenic strains of the group A beta-haemolytic streptococ- vention because they do not eradicate the streptococci. The
book of antimicrobial therapy. 18th ed. New Rochelle NY: The cus, Streptococcus pyogenes. The pathogenesis of rheu- duration of secondary prophylaxis depends on the individ-
Medical Letter, 2008: 75. matic fever is not known, but an immune mechanism may ual patient, but in those who have not had rheumatic cardi-
2. Butler T, et al. Borrelia recurrentis infection: single-dose antibi- be involved. There may be a latent period of 1 to 5 weeks
otic regimens and management of the Jarisch-Herxheimer reac- tis it should generally continue for a minimum of 5 years
tion. J Infect Dis 1978; 137: 573–7. after the initial infection, before clinical manifestations of after the last attack of rheumatic fever,5,6 and at least until
3. Perine PL, Teklu B. Antibiotic treatment of louse-borne relaps- rheumatic fever appear. The major ones are arthritis, cardi- the age of 18 or early 20s. A study from Chile supported
ing fever in Ethiopia: a report of 377 cases. Am J Trop Med Hyg tis, chorea, erythema marginatum, and subcutaneous nod- this view.17 Those who have had rheumatic carditis but
1983; 32: 1096–1100.
4. Butler T. Relapsing fever: new lessons about antibiotic action.
ules. Those affecting the heart are the most serious and are without residual valvular disease should perhaps receive
Ann Intern Med 1985; 102: 397–9. a major cause of cardiovascular death in children and prophylaxis for 10 years5 or at least until the age of 25
5. Fekade D, et al. Prevention of Jarisch-Herxheimer reactions by young adults in developing countries. Rheumatic fever has years.6 For those with carditis and persistent valvular dis-
treatment with antibodies against tumor necrosis factor α. N Engl been associated with poverty and overcrowding and has
J Med 1996; 335: 311–15. ease, prophylaxis should continue at least until the age of
declined dramatically in developed countries, but is still a 40 years, or sometimes for life.5,6 Fears of serious allergic
major problem in the developing world. However, in the reactions associated with long-term benzathine ben-
Respiratory-tract infections 1980s there was evidence of a resurgence in the USA with zylpenicillin prophylaxis appear to be unfounded.18
Principal community-acquired bacterial pathogens in the outbreaks of rheumatic fever reported in middle-class Household contacts of rheumatic fever patients who them-
respiratory tract are Streptococcus pneumoniae and Hae- children1 and military recruits.2 Increased pathogenicity of selves have positive streptococcal cultures should be treat-
mophilus influenzae, although Moraxella catarrhalis Str. pyogenes serotypes might have contributed to this re- ed.5
(Branhamella catarrhalis)1 is increasingly important in surgence.3 A high incidence is also seen among indige-
some areas. Other respiratory pathogens include Chlamy- nous populations in Australia and New Zealand.4 Patients with rheumatic valvular heart disease as a result of
dophila pneumoniae (Chlamydia pneumoniae), Legionel- rheumatic fever are at risk of developing infective endo-
Guidelines for the management and prevention of rheu- carditis and may need additional appropriate short-term
la pneumophila, and Mycoplasma pneumoniae. Strepto- matic fever have been published by sources including the
coccus pyogenes is the predominant cause of pharyngitis. antibacterial prophylaxis when undergoing dental and
American Heart Association (AHA),5 WHO,6 and an ex-
Staphylococcus aureus and aerobic Gram-negative bacilli some surgical procedures (see Endocarditis, p.168).
pert group from Australia and New Zealand.7 Rheumatic
such as Pseudomonas aeruginosa and Klebsiella spp. may 1. Veasy LG, et al. Resurgence of acute rheumatic fever in the in-
fever can usually be prevented by primary prophylaxis, termountain area of the United States. N Engl J Med 1987; 316:
be responsible for hospital-acquired (nosocomial) infec- that is, by the prompt treatment of streptococcal upper res- 421–7.
tions. piratory-tract infection with eradication of group A strep- 2. Wallace MR, et al. The return of acute rheumatic fever in young
adults. JAMA 1989; 262: 2557–61.
Community-acquired lower respiratory-tract infections tococci from the throat. Penicillin is the drug of choice, ei- 3. Schwartz B, et al. Changing epidemiology of group A strepto-
are very common and are traditionally considered to be vi- ther as a single intramuscular injection of benzathine coccal infection in the USA. Lancet 1990; 336: 1167–71.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
190 Antibacterials
4. Cilliers AM. Rheumatic fever and its management. BMJ 2006; • severe sepsis, sepsis associated with organ dysfunction, Enterococcal Infections, p.170, and Staphylococcal Infec-
333: 1153–6.
5. Dajani A, et al. Treatment of acute streptococcal pharyngitis
perfusion abnormalities (such as lactic acidosis, oligu- tions, p.195.
and prevention of rheumatic fever: a statement for health pro- ria, or an acute alteration in mental status), or hypoten- In addition to antimicrobial therapy, patients with sepsis or
fessionals. Pediatrics 1995; 96: 758–64. sion septic shock9,10 require rigorous supportive measures
6. WHO. Rheumatic fever and rheumatic heart disease. WHO Tech
Rep Ser 923 2004. Also available at: http://www.who.int/ • septic shock, sepsis with hypotension, despite adequate (p.1183).
cardiovascular_diseases/resources/en/cvd_trs923.pdf (accessed fluid resuscitation, together with perfusion abnormali- Septicaemia is generally most lethal in the very old and the
05/08/08)
7. Heart Foundation of Australia, Cardiac Society of Australia and ties very young.
New Zealand. Diagnosis and management of acute rheumatic fever • multiple organ dysfunction syndrome (MODS), the Neonatal septicaemia may be divided into early-onset,
and rheumatic heart disease in Australia - an evidence-based re-
view (issued June 2006). Available at: presence of altered organ function in an acutely ill pa- which is acquired from the mother’s genital tract and man-
h t t p : / / w w w. h e a r t f o u n d a t i o n . o rg . a u / d o c u m e n t / N H F / tient such that homoeostasis cannot be maintained with- ifests itself during the first few days after birth, and late-
PP-590_Diagnosis-Management_ARF-RHD_Evidence-Based% out intervention; it may be a cause as well as a conse- onset which may be nosocomially acquired. Bacteria
20Review_Sep06Update_FINAL.pdf (accessed 05/08/08)
8. Tanz RR, et al. Penicillin plus rifampin eradicates pharyngeal quence of SIRS. commonly causing early-onset sepsis include enterococci,
carriage of group A streptococci. J Pediatr 1985; 106: 876–80. Septicaemia can be caused by many bacteria.4 Communi- E. coli, H. influenzae, Listeria monocytogenes, and strep-
9. Tanz RR, et al. Clindamycin treatment of chronic pharyngeal tococci. Some of these organisms may also produce men-
carriage of group A streptococci. J Pediatr 1991; 119: 123–8. ty-acquired primary septicaemia is often associated with
10. Colling A, et al. Minimum amount of penicillin prophylaxis re- a specific infectious disease, such as meningococcal septi- ingitis in the neonate (p.178). Empirical treatment for both
quired to control Streptococcus pyogenes epidemic in closed caemia with meningococcal meningitis (p.178) or strepto- early- and late-onset sepsis is based on similar principles to
community. BMJ 1982; 285: 95–6. those in other patients, giving consideration to local pat-
11. Gray GC, et al. Hyperendemic Streptococcus pyogenes infec- coccal septicaemia with pneumonia (p.186). Streptococ-
tion despite prophylaxis with penicillin G benzathine. N Engl J cus pneumoniae and Haemophilus influenzae are common terns of infection and resistance and to the suitability of
Med 1991; 325: 92–7. causes of primary septicaemia in children (although this individual antibacterials for this age group. However,
12. Cilliers AM, et al. Anti-inflammatory treatment for carditis in early-onset sepsis is usually best controlled by prenatal
acute rheumatic fever. Available in The Cochrane Database of pattern is changing in countries where immunisation
Systematic Reviews; Issue 2. Chichester: John Wiley; 2003 (ac- against H. influenzae type b is routine); Gram-negative treatment of the mother or by perinatal prophylaxis.
cessed 06/08/08). rods and group B streptococci are commonest in neonates. Prophylaxis for group B streptococcal infections is dis-
13. Ayoub EM. Prophylaxis in patients with rheumatic fever: every cussed under Perinatal Streptococcal Infections, p.184.
three or every four weeks? J Pediatr 1989; 115: 89–91. Hospital-acquired septicaemia is often iatrogenic and
14. Lue H-C, et al. Long-term outcome of patients with rheumatic may occur as a complication of surgery or indwelling While vancomycin has been shown to prevent infections
fever receiving benzathine penicillin G prophylaxis every three catheters5 or may be associated with neutropenia in immu- with coagulase-negative staphylococci and to reduce the
weeks versus every four weeks. J Pediatr 1994; 125: 812–16. incidence of neonatal sepsis, widespread prophylactic use
15. Kaplan EL, et al. Pharmacokinetics of benzathine penicillin G: nocompromised patients (see under Infections in Immuno-
serum levels during the 28 days after intramuscular injection of compromised Patients, p.174). Gram-positive organisms of this drug is not recommended.11 Intravenous normal im-
1,200,000 units. J Pediatr 1989; 115: 146–50. have been reported to be responsible for most infections.6 munoglobulin (see Neonatal Infection, p.2229) and fil-
16. Meira ZMA, et al. Evaluation of secondary prophylactic grastim (see Neutropenia, p.1071) have been tried for the
schemes, based on benzathine penicillin G, for rheumatic fever Hospital-acquired septicaemia is often associated with
in children. J Pediatr 1993; 123: 156–8. acute respiratory distress syndrome (p.1498). prevention of septicaemia in preterm neonates with varia-
17. Berrios X, et al. Discontinuing rheumatic fever prophylaxis in ble results.
selected adolescents and young adults: a prospective study. Ann Whatever the cause, septicaemia requires prompt treat-
Intern Med 1993; 118: 401–6. Correction. ibid.; 119: 173. ment without waiting for the results of laboratory tests. Treatment failure in patients with sepsis or septic shock,
18. International Rheumatic Fever Study Group. Allergic reactions Choice of antibacterial depends on the probable source of occurring despite apparently adequate anti-infective thera-
to long-term benzathine penicillin prophylaxis for rheumatic fe- py, might be due in part to a continuing inflammatory
ver. Lancet 1991; 337: 1308–10. infection. For example, urinary-tract infection is likely to
be associated with Gram-negative septicaemia due to Es- process and attempts to modify this are under investiga-
cherichia coli; abdominal sepsis with Gram-negative sep- tion.10,12 Endotoxin, a lipopolysaccharide associated with
Rickettsial infections ticaemia due to mixed infection with E. coli, enterococci, the cell membrane of Gram-negative bacteria, is an impor-
Bacteria of the Rickettsiaceae family that infect man in- and anaerobic bacteria; and skin sepsis, bacterial arthritis, tant mediator in the septic syndrome. Endotoxin release
clude Rickettsia spp. (see under Spotted Fevers, p.194 and acute osteomyelitis, and cardiovascular shunts with Gram- may occur spontaneously or during antibacterial therapy.13
Typhus, p.198) and Coxiella burnetii (see under Q fever, positive septicaemia due to staphylococci. The antibacteri- When in the circulation it stimulates the release of endog-
p.188). Ehrlichia spp. (see under Ehrlichiosis, p.168) and als used should also reflect current patterns of bacterial re- enous mediators such as interleukin-1, interleukin-6, tu-
Bartonella quintana (Rochalimaea quintana) (see under sistance in the community or hospital. International mour necrosis factor alpha, and other cytokines.14 These in
Trench Fever, p.196) are no longer classified as a rickett- guidelines7 have recommended starting intravenous anti- turn induce a cascade of secondary inflammatory media-
sia. The treatment of choice for rickettsial infections is bacterial therapy as early as possible, and within the first tors resulting eventually in endothelial damage and severe
usually doxycycline; chloramphenicol or a fluoroquino- hour of recognition of septic shock; the initial choice of haemodynamic and metabolic derangements. It is now un-
lone are alternatives.1 therapy should be broad enough to cover all likely patho- derstood that a similar inflammatory response also occurs
1. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
gens, and it should be reassessed daily to optimise activity after non-infective insults. However, adjunctive therapy
book of antimicrobial therapy. 18th ed. New Rochelle NY: The with endotoxin antibodies, anticytokines such as anakinra
Medical Letter, 2008: 74. and prevent the development of resistance. De-escalation
of combination therapy to the most appropriate single ther- and tumour necrosis factor antibodies, soluble tumour
apy should be carried out as soon as susceptibility of the necrosis factor receptor, bactericidal permeability increas-
Salmonella enteritis infection is known. The typical duration of therapy will be ing protein, nitric oxide synthase inhibitors, guanylate cy-
See p.173. 7 to 10 days. Empirical treatment has often begun with a clase inhibitors such as methylthioninium chloride, and
penicillin and an aminoglycoside, metronidazole being platelet-activating factor antagonists has generally pro-
Salpingitis added if anaerobic infection is suspected. In the UK, the duced disappointing results.12,15,16 A systematic review17
See under Pelvic Inflammatory Disease, p.184. BNF recommends that initial empirical treatment for com- of the use of intravenous polyclonal immunoglobulin con-
munity-acquired septicaemia is with either a broad-spec- cluded that it had a promising role as adjuvant therapy in
trum antipseudomonal penicillin (such as ticarcillin-clavu- sepsis and septic shock. Specific monoclonal immu-
Septicaemia lanic acid or piperacillin-tazobactam) or a broad-spectrum noglobulins were not effective.17 Recent theories suggest
Traditionally, transient bacteraemia (the presence of bacte- cephalosporin (such as ceftazidime or cefotaxime); for that a more complex interplay of pro- and anti-inflamma-
ria in the blood) has been regarded as a fairly common hospital-acquired septicaemia a broad-spectrum antipseu- tory responses may be involved in the pathophysiology of
condition which does not usually cause complications, domonal beta-lactam antibacterial (such as ceftazidime, SIRS and MODS and this may explain the failure of many
whereas uncontrolled bacteraemia leads to septicaemia ticarcillin-clavulanic acid, piperacillin-tazobactam, imi- of these mainly anti-inflammatory treatment modalities.18
with serious symptoms such as fever and shock. This dis- penem-cilastatin, or meropenem) is recommended. In both Reduced mortality has been reported19 after the treatment
tinction has not always been adhered to in published sourc- cases, an aminoglycoside should be added if Pseu- of patients with severe sepsis with recombinant activated
es and the terms have sometimes been used interchange- domonas is suspected or if sepsis is severe, metronidazole protein C (drotrecogin alfa) which has antithrombotic,
ably. Added to this, the identification of the cascade of if anaerobic organisms are suspected, and vancomycin (or anti-inflammatory, and pro-fibrinolytic properties, but its
inflammatory mediators involved and the realisation that teicoplanin) if meticillin-resistant staphylococci are sus- benefits appear to be limited to those at high risk of death.
what had been called ‘sepsis’ could arise in the absence of pected. US guidelines8 recommend a third- or fourth-gen- Studies with other physiological anticoagulants such as
infection have prompted reassessment of the terminology eration cephalosporin (cefotaxime, ceftriaxone, ceftazi- antithrombin III20 and tissue factor pathway inhibitor (ti-
used both in the UK and in the USA.1 In the UK, some dime, or cefepime), or piperacillin-tazobactam, or facogin)21 have not been successful.
authorities2 considered that the term ‘septicaemia’ should imipenem-cilastatin, or meropenem, in each case with an 1. Bone RC. Why new definitions of sepsis and organ failure are
no longer be used since it does not distinguish between aminoglycoside (gentamicin, tobramycin, or amikacin) for
needed. Am J Med 1993; 95: 348–50.
mild and severe disease. The term ‘sepsis syndrome’ was 2. Lynn WA, Cohen J. Management of septic shock. J Infect 1995;
the initial treatment of life-threatening sepsis in adults. 30: 207–12.
preferred for patients with a generalised systemic response When there is some information on which to base choice 3. American College of Chest Physicians/Society of Critical Care
together with evidence of organ dysfunction and ‘septic of treatment, but before the infecting organisms are defi- Medicine Consensus Conference Committee. Definitions for
shock’ to describe patients who also have hypotension not sepsis and organ failure and guidelines for the use of innovative
nitely known, the following treatment is suggested: therapies in sepsis. Crit Care Med 1992; 20: 864–74.
due to hypovolaemia or cardiac causes. The American 4. Eykyn SJ, et al. The causative organisms of septicaemia and
College of Chest Physicians and Society of Critical Care • suspected bacterial endocarditis—ceftriaxone with van- their epidemiology. J Antimicrob Chemother 1990; 25 (suppl
Medicine proposed the following series of definitions to comycin, possibly with gentamicin as well C): 41–58.
cover the spectrum of syndromes resulting from this in- • suspected meticillin-resistant staphylococci—vanco- 5. Mermel LA, et al. Infectious Diseases Society of America.
American College of Critical Care Medicine. Society for
flammatory response:1,3 mycin, alone or with gentamicin and/or rifampicin Healthcare Epidemiology of America. Guidelines for the man-
• systemic inflammatory response syndrome (SIRS), agement of intravascular catheter-related infections. Clin Infect
Once the infecting organisms have been identified, choice Dis 2001; 32: 1249–72. Also available at: http://
the systemic inflammatory response to infection or var- of treatment will again depend on their sensitivity and cur- www.journals.uchicago.edu/doi/pdf/10.1086/320001 (accessed
ious other severe clinical insults including pancreatitis, rent patterns of resistance in the community or hospital. 18/08/08)
ischaemia, trauma, and haemorrhagic shock 6. Edmond MB, et al. Nosocomial bloodstream infections in Unit-
For comments on the consequences of emerging multid- ed States hospitals: a three-year analysis. Clin Infect Dis 1999;
• sepsis, the SIRS caused specifically by infection rug-resistant strains of enterococci and staphylococci, see 29: 239–44.
 Antibacterials 191
7. Dellinger RP, et al. Surviving Sepsis Campaign: international painful genital ulcers and a risk factor in the transmission Guidelines produced by WHO,4
by an expert group in the
guidelines for management of severe sepsis and septic shock:
2008. Crit Care Med 2008; 36: 296–327. of HIV. UK,5 and by the CDC in the USA1 for the treatment of
8. Anonymous. The choice of antibacterial drugs. In: Handbook of Specific treatment guidelines have been provided by gonorrhoea are as follows, although recommendations
antimicrobial therapy. 17th ed. New York: The Medical Letter, WHO,1 by expert groups in the UK,2 and by the CDC in may need to be localised because of differences in patterns
2005: 43–63.
9. Astiz ME, Rackow EC. Septic shock. Lancet 1998; 351: the USA.3 Treatment failure may be more common in pa- of infection and drug resistance:
1501–5. tients also infected with HIV1 (see below), but in other pa- • UNCOMPLICATED ANOGENITAL GONOCOCCAL INFECTIONS
10. Wheeler AP, Bernard GR. Treating patients with severe sepsis. tients single-dose treatment regimens might be preferable IN ADULTS.
N Engl J Med 1999; 340: 207–14.
11. Craft AP, et al. Vancomycin for prophylaxis against sepsis in if compliance is a problem. Guideline regimens are as fol- • WHO:
preterm neonates. Available in The Cochrane Database of Sys- lows: • a single oral dose of ciprofloxacin 500 mg, or
tematic Reviews; Issue 1. Chichester: John Wiley; 2000 (ac-
cessed 16/05/05). • WHO: • a single oral dose of cefixime 400 mg, or
12. Baumgartner J-D, Calandra T. Treatment of sepsis: past and fu- • oral ciprofloxacin 500 mg twice daily for 3 days, or • a single intramuscular dose of ceftriaxone 125 mg, or
ture avenues. Drugs 1999; 57: 127–32. • oral erythromycin 500 mg four times daily for 7 days, or • a single intramuscular dose of spectinomycin 2 g
13. Prins JM. Clinical relevance of antibiotic-induced endotoxin re-
lease. Antimicrob Agents Chemother 1994; 38: 1211–18. • a single oral dose of azithromycin 1 g • UK:
14. Blackwell TS, Christman JW. Sepsis and cytokines: current sta- an alternative regimen is: • a single intramuscular dose of ceftriaxone 250 mg, or
tus. Br J Anaesth 1996; 77: 110–17. • a single intramuscular dose of spectinomycin 2 g, or
15. Verhoef J, et al. Issues in the adjunct therapy of severe sepsis. J • a single intramuscular injection of ceftriaxone 250 mg
Antimicrob Chemother 1996; 38: 167–82. • UK: • a single oral dose of cefixime 400 mg
16. Opal SM, Yu RL. Antiendotoxin strategies for the prevention
• a single oral dose of azithromycin 1 g, or alternative regimens are:
and treatment of septic shock: new approaches and future direc-
tions. Drugs 1998; 55: 497–508. • a single intramuscular dose of ceftriaxone 250 mg, or • a single oral dose of ciprofloxacin 500 mg
17. Alejandria MM, et al. Intravenous immunoglobulin for treating • oral ciprofloxacin 500 mg twice daily for 3 days or as a single • a single oral dose of ofloxacin 400 mg
sepsis and septic shock. Available in The Cochrane Database of oral dose • a single oral dose of ampicillin 2 or 3 g plus probenecid 1 g
Systematic Reviews; Issue 1. Chichester: John Wiley; 2002 (ac-
cessed 16/05/05). further alternatives are: • a single intramuscular dose of cefotaxime 500 mg
18. Bone RC. Immunologic dissonance: a continuing evolution in • oral erythromycin 500 mg four times daily for 7 days • a single intramuscular dose of cefoxitin 2 g plus oral
our understanding of the systemic inflammatory response syn- probenecid 1 g
drome (SIRS) and the multiple organ dysfunction syndrome • single oral doses of other fluoroquinolones such as fleroxacin
(MODS). Ann Intern Med 1996; 125: 680–7. 400 mg or norfloxacin 800 mg • USA:
19. Bernard GR, et al. Efficacy and safety of recombinant human • a single intramuscular injection of spectinomycin 2 g • a single oral dose of cefixime 400 mg, or
activated protein C for severe sepsis. N Engl J Med 2001; 344: • a single intramuscular dose of ceftriaxone 125 mg
699–709. • USA:
20. Warren BL, et al. High-dose antithrombin III in severe sepsis: a • a single oral dose of azithromycin 1 g, or Other single dose cephalosporins may be substituted.
randomized controlled trial. JAMA 2001; 286: 1869–78. Cor- • a single intramuscular dose of ceftriaxone 250 mg, or A single intramuscular dose of spectinomycin 2 g is
rection. ibid. 2002; 287: 192. an alternative in patients who cannot tolerate cepha-
21. Abraham E, et al. Efficacy and safety of tifacogin (recombinant • oral ciprofloxacin 500 mg twice daily for 3 days
tissue factor pathway inhibitor) in severe sepsis: a randomized a further alternative is: losporins.
controlled trial. JAMA 2003; 290: 238–47. • PHARYNGEAL INFECTIONS.
• oral erythromycin 500 mg three times daily for 7 days
Sexual partners of patients with chancroid should also be • UK:
Sexually transmitted diseases tested and treated.2,3 • a single oral dose of ciprofloxacin 500 mg, or
The sexually transmitted diseases, formerly termed vene- Patients co-infected with HIV have ulcers that heal more • a single oral dose of ofloxacin 400 mg, or
real diseases, are defined as a group of communicable dis- slowly and may need to be treated for longer to prevent • a single intramuscular dose of ceftriaxone 250 mg
eases that are transferred mainly by sexual contact. Many treatment failure;3 treatment failure is common with sin- • USA:
pathogens are known to be transmitted sexually including: gle-dose regimens.1 • a single intramuscular dose of ceftriaxone 125 mg
• bacteria: 1. WHO. Guidelines for the management of sexually transmitted • GONOCOCCAL INFECTIONS IN PREGNANT WOMEN.
• Chlamydia trachomatis (see Lymphogranuloma Venereum, infections. Geneva: WHO, 2003. Also available at: http:// • WHO:
p.192 and Chlamydial Infections, p.166) whqlibdoc.who.int/publications/2003/9241546263.pdf (ac- • a single oral dose of cefixime 400 mg, or
cessed 23/03/07)
• Haemophilus ducreyi (see Chancroid, p.191) 2. Clinical Effectiveness Group (Association for Genitourinary • a single intramuscular dose of ceftriaxone 125 mg, or
• Klebsiella granulomatis (see Granuloma Inguinale, p.192) Medicine and the Medical Society for the Study of Venereal Dis- • a single intramuscular dose of spectinomycin 2 g
• Neisseria gonorrhoeae (see Gonorrhoea, p.191) eases – now British Association for Sexual Health and HIV). • UK:
• Treponema pallidum (see Syphilis, p.192) 2001 National guideline for the management of chancroid.
Available at: http://www.bashh.org/documents/85/85.pdf (ac- • a single intramuscular dose of ceftriaxone 250 mg, or
• Ureaplasma urealyticum cessed 18/08/08) • a single intramuscular dose of spectinomycin 2 g, or
• protozoa: 3. CDC. Sexually transmitted diseases treatment guidelines 2006. • a single oral dose of cefixime 400 mg, or
MMWR 2006; 55(RR-11): 1–94. Also available at: http://
• Trichomonas vaginalis (see Trichomoniasis, p.827). • a single oral dose of amoxicillin 3 g (or ampicillin 2 or 3 g)
www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07)
• viruses: plus probenecid 1 g
• human immunodeficiency virus (see HIV Infection and Gonorrhoea. Gonorrhoea is a sexually transmitted dis- • USA:
AIDS, p.856) ease caused by infection of mucosa with Neisseria gonor- • a cephalosporin or spectinomycin
• hepatitis viruses (see Hepatitis, p.851) rhoeae (gonococcus), a Gram-negative bacterium. It oc- • GONOCOCCAL EYE INFECTIONS IN ADULTS.
• herpesviruses (see Herpesvirus Infections, p.853) curs mainly in the lower genital tract as urethritis (p.199) • WHO: frequent irrigation of the infected eye with
Clinical syndromes associated with sexually transmitted in men and cervicitis (p.166) in women, but also as saline together with:
diseases, and which are discussed in this section, include pharyngitis, proctitis (p.188), or conjunctivitis. Infection • a single intramuscular dose of ceftriaxone 125 mg, or
urethritis (p.199) and epididymitis (p.170) in men; cervici- may sometimes ascend to the upper genital tract to cause • a single intramuscular dose of spectinomycin 2 g, or
tis (p.166), pelvic inflammatory disease (p.184), and bac- complications such as pelvic inflammatory disease (p.184) • a single oral dose of ciprofloxacin 500 mg
terial vaginosis (p.164) in women; and proctitis (p.188). in women and epididymitis (p.170) in men. In the USA1 a further alternative is:
Perinatal transmission of sexually transmitted pathogens routine screening is recommended for all sexually active
• a single intramuscular dose of kanamycin 2 g
from the mother can result in neonatal conjunctivitis women with an increased risk of infection. Disseminated
gonococcal infection resulting from gonococcal bacterae- • USA: irrigation of the infected eye with saline togeth-
(p.180) or pneumonia (p.186). er with:
General guidelines for the management of sexually trans- mia is rare and may lead to septic arthritis, an arthritis-der-
• a single intramuscular dose of ceftriaxone 1 g
mitted diseases have been published1-3 although recom- matitis syndrome (not to be confused with Reiter’s disease
which has been associated with non-gonococcal or non- • DISSEMINATED GONOCOCCAL INFECTIONS IN ADULTS.
mendations may need to be localised because of differenc- • WHO:
es in patterns of infection and drug resistance. Early specific urethritis), and more rarely to conditions such as
endocarditis or meningitis. Gonorrhoea in pregnant wom- • parenteral ceftriaxone 1 g once daily for 7 days, or
detection and treatment are required to prevent long-term • intramuscular spectinomycin 2 g twice daily for 7 days
complications, including infertility, still-births and neona- en may cause neonatal gonococcal conjunctivitis (ophthal-
mia neonatorum). Another third-generation cephalosporin may be sub-
tal infections, genital cancers, and an increased risk of ac- stituted if neither of these drugs is available. Treat-
quiring and transmitting HIV. Antibacterial drug resistance is a problem in the manage-
ment of gonococcal infection. Penicillins were once the ment for endocarditis should continue for 28 days.
The suggestion that spermicidal contraceptives may pro- • USA:
vide some protection against sexually transmitted diseases treatment of choice for N. gonorrhoeae but are no longer
recommended. High-level plasmid-mediated and chromo- • parenteral ceftriaxone 1 g every 24 hours
is discussed under Nonoxinols, p.1917.
1. CDC. Sexually transmitted diseases treatment guidelines 2006.
somally mediated resistances have also been reported with alternatives are:
MMWR 2006; 55 (RR-11): 1–94. Also available at: http:// tetracycline, and chromosomally mediated resistance to • intravenous ceftizoxime 1 g every 8 hours
www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07) other antibiotics may occur. Gonococcal resistance is now • cefotaxime 1 g every 8 hours
2. WHO. Guidelines for the management of sexually transmitted monitored in England and Wales via the Gonococcal Re- • intramuscular spectinomycin 2 g every 12 hours
infections. Geneva: WHO, 2003. Also available at: http://
whqlibdoc.who.int/publications/2003/9241546263.pdf (ac- sistance to Antimicrobials Surveillance Programme Once improvement has been established for 24 to 48
cessed 23/03/07) (GRASP)2 and in the USA by the Gonococcal Isolate Sur- hours, oral therapy with cefixime 400 mg twice daily,
3. Clinical Effectiveness Group (Association for Genitourinary veillance Project (GISP).3 Of concern are the increasing or cefpodoxime 400 mg twice daily may be substitut-
Medicine and the Medical Society for the Study of Venereal Dis-
eases - now British Association for Sexual Health and HIV). Na- number of reports worldwide of resistance to fluoroqui- ed until at least a 1-week treatment period is com-
tional guideline on the management of suspected sexually trans- nolones which has resulted in revision of treatment guide- plete. Provided antimicrobial susceptibility is docu-
mitted infections in children and young people. Available at: lines. In the UK fluoroquinolones are no longer recom- mented fluoroquinolones may be given as an
http://www.bashh.org/documents/41/41.pdf (accessed 18/08/08) mended as first-line drugs, while in the USA they are no alternative treatment.
Chancroid. Chancroid is a sexually transmitted disease longer recommended for gonococcal infections. For gonococcal meningitis and endocarditis, intrave-
caused by the Gram-negative bacterium Haemophilus Infection with Chlamydia trachomatis (see under Chlamy- nous ceftriaxone 1 to 2 g every 12 hours is recom-
ducreyi. It occurs worldwide, but is endemic in parts of Af- dial Infections, p.166) often occurs along with gonorrhoea mended; treatment for meningitis should continue for
rica and South East Asia, where it is a frequent cause of and should be tested for or treated presumptively. 10 to 14 days and for endocarditis for at least 4 weeks.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
192 Antibacterials
• GONOCOCCAL INFECTIONS IN NEONATES AND CHILDREN. • oral doxycycline 100 mg twice daily, or infection; early latent infection is defined in the UK1 and
Neonates born to mothers with gonorrhoea are at high • oral erythromycin 500 mg four times daily, or by WHO2 as of not more than 2 years’ duration or of less
risk of infection and require prophylaxis: • oral norfloxacin 400 mg twice daily than 1 year’s duration by the CDC in the USA.3
• WHO: The addition of parenteral gentamicin 1 mg/kg every 8 • Late stage disease includes late latent infection and all
• a single intramuscular injection of ceftriaxone 50 mg/kg
hours should be considered if lesions do not respond late clinical stages. The late clinical stages fall broadly
(maximum 125 mg) during the first few days of treatment. into three types: neurosyphilis manifesting as neurolog-
alternatives are: • USA: ical symptoms, commonly including dorsal column loss
• a single intramuscular dose of spectinomycin 25 mg/kg • oral doxycycline 100 mg twice daily for a minimum of 3 (tabes dorsalis), dementia, or meningovascular involve-
(maximum 75 mg) weeks ment; cardiovascular syphilis, characterised by aortitis
• a single intramuscular dose of kanamycin 25 mg/kg (max- alternatives are: which may manifest as aortic regurgitation, aortic aneu-
imum 75 mg) • oral ciprofloxacin 750 mg twice daily, or rysm, or angina; and gummata, inflammatory fibrous
• USA: • oral erythromycin 500 mg four times daily, or nodules or plaques which may be locally destructive
• a single parenteral dose of ceftriaxone 25 to 50 mg/kg • oral azithromycin 1 g once weekly, or and which commonly affect the bone and skin but may
(maximum 125 mg) • oral co-trimoxazole 960 mg twice daily occur in any organ. Some term all these late clinical
For those neonates with disseminated gonococcal infec- In each case treatment is for 3 weeks. The addition of an stages tertiary syphilis whereas others use tertiary for
tion (sepsis, arthritis, meningitis), US recommendations aminoglycoside may be considered if lesions do not re- benign gummatous syphilis and quaternary for the more
are: spond during the first few days of treatment, in pregnant serious complications of cardiovascular syphilis and
• parenteral ceftriaxone 25 to 50 mg/kg once daily for 7 women, and in those co-infected with HIV. neurosyphilis. The term neurosyphilis has generally
days, or Sexual partners of patients with granuloma inguinale been applied to late-stage symptomatic neurological
• parenteral cefotaxime 25 mg/kg every 12 hours for 7 days should be tested and treated.2,3 disease, although it is recognised that CNS invasion by
T. pallidum is common in early syphilis and that CNS
Treatment should be extended to 10 to 14 days if Patients co-infected with HIV should receive the same involvement may occur at any stage.
meningitis is present. treatment as those who are HIV-negative.3
Treatment for children with uncomplicated gonococcal 1. WHO. Guidelines for the management of sexually transmitted
• Congenital syphilis may result from transplacental in-
infections, most commonly due to sexual abuse in pre- in fe c tio ns . G e ne va : W HO , 20 03. A l so a v ai la ble at : fection at any stage of pregnancy and any stage of ma-
adolescents, is as for adults in those weighing 45 kg or
http://whqlibdoc.who.int/publications/2003/9241546263.pdf ternal syphilis.
(accessed 23/03/07)
more. For those weighing less than 45 kg a single intra- 2. Clinical Effectiveness Group (Association for Genitourinary The incidence of syphilis fell dramatically after the intro-
muscular dose of ceftriaxone 125 mg or spectinomycin Medicine and the Medical Society for the Study of Venereal Dis- duction of penicillin and T. pallidum remains sensitive to
eases – now British Association for Sexual Health and HIV). it. There has, however, been a resurgence of syphilis,
40 mg/kg (maximum 2 g) is recommended. For dissem- 2001 National guideline for the management of donovanosis
inated infection in all children an intramuscular or intra- (granuloma inguinale). Available at: http://www.bashh.org/
linked in part with HIV infection. In HIV-infected patients
venous dose of ceftriaxone 50 mg/kg once daily for 7 documents/39/39.pdf (accessed 18/08/08) syphilis appears more virulent and neurosyphilis occurs
days, up to a maximum dose of 1 g in those weighing 3. CDC. Sexually transmitted diseases treatment guidelines 2006. more quickly. Like other diseases causing genital ulcers,
MMWR 2006; 55(RR-11): 1–94. Also available at: http:// syphilis is a risk factor for HIV infection.
less than 45 kg is recommended. www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07)
The prevention and treatment of neonatal gonococcal con- The treatment of choice for both early and late syphilis is
junctivitis is discussed under Neonatal Conjunctivitis, Lymphogranuloma venereum. Lymphogranuloma still penicillin and long-acting injections are generally
p.180. venereum or chlamydial lymphogranuloma is an invasive, used. Treatment for late syphilis is less well-established
systemic infection caused by certain serotypes of Chlamy- than that for early disease and is usually given for longer.
Sexual partners of patients with gonococcal infection dia trachomatis and is endemic in tropical and subtropical
should be tested and treated.1 A Jarisch-Herxheimer reaction may occur after the first
areas, but may also occur in the developed world. It is a dose of antibacterial, especially in patients with early
Patients co-infected with HIV should receive the same sexually transmitted disease and in the early phase may syphilis, and corticosteroid cover may be beneficial, espe-
treatment as those who are HIV-negative.1 cause genital ulceration although the commonest clinical cially in patients with cardiovascular or neurological in-
1. CDC. Sexually transmitted diseases treatment guidelines 2006. manifestation is unilateral inguinal and/or femoral lym-
MMWR 2006; 55(RR-11): 1–94. Also available at: http:// volvement.
www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07) phadenopathy. There is multisystem involvement and late Guidelines produced by WHO,2 by an expert group in the
Updated recommended treatment regimens for gonococcal in- complications, including those related to fibrosis and ab- UK,1 and by the CDC in the USA3 for the treatment of
fections and associated conditions—United States, April 2007. normal lymphatic drainage, may require surgery. acquired and congenital syphilis are as follows:
Available at: http://www.cdc.gov/s td/treat ment/2006/
GonUpdateApril2007.pdf (accessed 12/04/07) Guidelines produced by WHO,1 by an expert group in the • EARLY SYPHILIS
2. Health Protection Agency. GRASP The Gonococcal Resistance UK,2 and by the CDC in the USA3 for the treatment of
to Antimicrobials Surveillance Programme: annual report, year lymphogranuloma venereum are as follows: • WHO:
2006. Available at: http://www.hpa.org.uk/webc/HPAwebFile/ • intramuscular benzathine benzylpenicillin 1.8 g
HPAweb_C/1194947393147 (accessed 18/08/08) • WHO: treatment for 2 weeks with:
(2.4 million units) usually given as 2 injections at separate
3. CDC. Sexually transmitted disease surveillance 2005 supple- • oral doxycycline 100 mg twice daily, or sites in a single session, or
ment: Gonococcal Isolate Surveillance Project (GISP) annual re- • oral erythromycin 500 mg four times daily
port—2005. Available at: http://www.cdc.gov/std/GISP2005/ • intramuscular procaine benzylpenicillin 1.2 g
GISPSurvSupp2005short.pdf (accessed 20/04/07) an alternative is: (1.2 million units) daily for 10 days
4. WHO. Guidelines for the management of sexually transmitted • oral tetracycline 500 mg four times daily alternatives for non-pregnant penicillin-allergic pa-
i n f e c t i o n s . G e n e v a : W HO , 2 0 0 3 . A l s o a va i l a b l e a t :
http://whqlibdoc.who.int/publications/2003/9241546263.pdf • UK and USA: treatment for 3 weeks with: tients are:
(accessed 20/06/07) • oral doxycycline 100 mg twice daily, or • oral doxycycline 100 mg twice daily for 14 days, or
5. Clinical Effectiveness Group (British Association for Sexual • oral tetracycline 2 g daily, or • oral tetracycline 500 mg four times daily for 14 days
Health and HIV). National guideline on the diagnosis and treat-
• oral minocycline 300 mg as a loading dose then 200 mg twice
ment of gonorrhoea in adults 2005. Available at: http:// Pregnant women allergic to penicillin may be given:
www.bashh.org/documents/116/116.pdf (accessed 18/08/08) daily, or
• oral erythromycin 500 mg four times daily for 14 days (but
• oral erythromycin 500 mg four times daily
Granuloma inguinale. Granuloma inguinale or dono- see Syphilis in Pregnancy, below)
Sexual partners of patients with lymphogranuloma ve-
vanosis is caused by the Gram-negative bacterium Kleb- • UK:
nereum should be treated with:
siella granulomatis (formerly known as Calymmatobacte- • a single oral dose of azithromycin 1 g or
• intramuscular benzathine benzylpenicillin 1.8 g
rium granulomatis) and occurs most commonly in the (2.4 million units) as a single dose, or
• oral doxycycline 100 mg twice daily for 7 days
tropics and subtropics, especially Papua New Guinea and • intramuscular procaine benzylpenicillin 600 mg
India. It is characterised by genital ulcers and is generally Patients co-infected with HIV should receive the same (600 000 units) daily for 10 days
considered to be a sexually transmitted disease. treatment as those who are HIV-negative, although longer An additional alternative if parenteral therapy is re-
therapy may be required.3 fused is:
Guidelines produced by WHO,1 by an expert group in the 1. WHO. Guidelines for the management of sexually transmitted
UK,2 and by the CDC in the USA3 for the treatment of in fe c tio ns . G e ne va : W HO , 20 03. A l so a v ai la ble at : • oral amoxicillin 500 mg plus oral probenecid 500 mg,
granuloma inguinale are as follows: http://whqlibdoc.who.int/publications/2003/9241546263.pdf both four times daily for 14 days
(accessed 23/03/07) alternatives for penicillin-allergic patients are:
• WHO: 2. Clinical Effectiveness Group (British Association for Sexual
• oral azithromycin 1 g on the first day then 500 mg once daily, Health and HIV). 2006 National guideline for the management • oral doxycycline 100 mg twice daily for 14 days
or of lymphogranuloma venereum (LGV). Availabl e at : • oral erythromycin 500 mg four times daily for 14 days
http://www.bashh.org/documents/92/92.pdf (accessed 18/08/08)
• oral doxycycline 100 mg twice daily • oral azithromycin 2 g as a single dose
3. CDC. Sexually transmitted diseases treatment guidelines 2006.
alternatives include: MMWR 2006; 55(RR-11): 1–94. Also available at: http:// • oral azithromycin 500 mg daily for 10 days
• oral erythromycin 500 mg four times daily www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07) • intramuscular ceftriaxone 500 mg daily for 10 days (in the
• oral tetracycline 500 mg four times daily Syphilis. Syphilis is a sexually transmitted disease caused absence of anaphylaxis to penicillin)
• oral co-trimoxazole 960 mg twice daily by the spirochaete Treponema pallidum and occurs world- • USA:
Treatment is continued until all lesions have completely wide. Non-venereal treponematoses include endemic • a single intramuscular dose of benzathine benzylpenicillin
resolved. The addition of parenteral gentamicin should syphilis or bejel, also caused by T. pallidum; pinta, caused 1.8 g (2.4 million units)
be considered for HIV-infected patients. Streptomycin by T. carateum; and yaws, caused by T. pertenue. alternatives for penicillin-allergic patients are:
is no longer recommended because of its toxicity and Syphilis may be classified as acquired or congenital and in • oral doxycycline 100 mg twice daily for 14 days
the need to reserve it for tuberculosis. each case has early and late stages. Syphilis may be de- • oral tetracycline 500 mg four times daily for 14 days
• UK: scribed as latent, when serological and CSF tests are posi- Preliminary data suggest that azithromycin 2 g orally
• oral azithromycin 1 g once weekly or 500 mg daily, or tive but the patient is asymptomatic. as a single dose may also be effective, or parenteral
• parenteral ceftriaxone 1 g once daily, or • In acquired sexually transmitted disease the early stage ceftriaxone 1 g daily for 8 to 10 days may also be con-
• oral co-trimoxazole 960 mg twice daily, or includes primary and secondary syphilis and early latent sidered.
 Antibacterials 193
• LATE SYPHILIS is serological evidence of re-infection or relapse, and the encapsulated Haemophilus influenzae, with Moraxella ca-
• WHO: infant treated.2 UK guidelines1 list alternative antibacte- tarrhalis (Branhamella catarrhalis) increasingly impor-
• intramuscular benzathine benzylpenicillin 1.8 g rials that may be given as: amoxicillin, ceftriaxone, tant in children. Other bacterial causes, especially in
(2.4 million units) once weekly for 3 consecutive weeks, erythromycin or azithromycin. they also state that de- adults, include mixed anaerobic bacteria (usually associat-
or sensitisation should be considered in those allergic to ed with dental disease and more frequent in chronic sinusi-
• intramuscular procaine benzylpenicillin 1.2 g penicillin. tis), Staphylococcus aureus, Streptococcus pyogenes, and
(1.2 million units) daily for 20 consecutive days • CONGENITAL SYPHILIS Gram-negative bacteria including Enterobacteriaceae and
alternatives for non-pregnant penicillin-allergic pa- • WHO: Pseudomonas aeruginosa (in nosocomial sinusitis). About
tients are: for early congenital syphilis, infants up to 2 years of 5% of primary sinusitis in young adults has been associat-
• oral doxycycline 100 mg twice daily for 30 days, or
age and having abnormal CSF may be given: ed with Chlamydophila pneumoniae (Chlamydia pneumo-
• oral tetracycline 500 mg four times daily for 30 days niae).
• intravenous benzylpenicillin 30 mg/kg (50 000 units/kg)
Pregnant women allergic to penicillin may be given: twice daily for the first 7 days of life and then three times Acute sinusitis may resolve spontaneously. In an evi-
• oral erythromycin 500 mg four times daily for 30 days daily for a total of 10 days, or dence-based report on the diagnosis and treatment of rhi-
For those with neurosyphilis: • intramuscular procaine benzylpenicillin 50 mg/kg nosinusitis,1 the Agency for Health Care Policy and Re-
• intravenous benzylpenicillin 1.2 to 2.4 g (2 to (50 000 units/kg) once daily for 10 days search in the USA has stated that most patients with the
4 million units) every 4 hours for 14 days, or For infants with normal CSF (although some treat all acute condition will recover without antibacterial therapy,
• if outpatient compliance can be ensured, intramuscular infants as if the CSF were abnormal): although they will recover faster if antibacterials are given.
procaine benzylpenicillin 1.2 g (1.2 million units) daily • a single intramuscular dose of benzathine benzylpenicillin However, a systematic review concluded that any treat-
plus oral probenecid 500 mg four times daily each for 10 37.5 mg/kg (50 000 units/kg) ment effect of antibacterials was small.2 The Agency also
to 14 days Children older than 2 years may be given: considered1 that the use of new antibacterials for treating
alternatives for non-pregnant penicillin-allergic pa- • parenteral benzylpenicillin 30 mg/kg (50 000 units/kg) uncomplicated community-acquired acute bacterial rhi-
tients are: every 4 to 6 hours for 10 to 14 days nosinusitis was not justified and that amoxicillin or folate
• oral doxycycline 200 mg twice daily for 30 days For penicillin-allergic infants aged over 1 month: inhibitors were sufficiently effective. This view was sup-
• oral tetracycline 500 mg four times daily for 30 days • oral erythromycin 7.5 to 12.5 mg/kg four times daily for ported by a meta-analysis.3 US guidelines for the manage-
• UK: 30 days ment of sinusitis in adults4 state that most cases will re-
• intramuscular benzathine benzylpenicillin 1.8 g • UK: recommended doses are as for infants up to 2 solve without antibacterial treatment and recommend that
(2.4 million units) weekly for 3 doses, or years with abnormal CSF in WHO guidelines, above. antibacterials should be reserved for those patients with
• intramuscular procaine benzylpenicillin 600 mg • USA: persistent moderate or severe symptoms. However, a later
(600 000 units) daily for 17 days
Neonates (up to 4 weeks of age) and having proven or meta-analysis5 considered that antibacterials could not be
alternatives for patients allergic to penicillin and probable disease: justified, even in patients who reported symptoms for
those declining parenteral therapy are: • intravenous benzylpenicillin 30 mg/kg (50 000 units/kg)
longer than 7 to 10 days; the only reason for antibacterial
• oral doxycycline 100 mg twice daily for 28 days, or twice daily for the first 7 days of life and then three times treatment was the presence of signs suggestive of a serious
• if penicillin can be tolerated, oral amoxicillin 2 g three daily for a total of 10 days, or complication (such as high fever, periorbital swelling, ery-
times daily plus oral probenecid 500 mg four times daily, • intramuscular procaine benzylpenicillin 50 mg/kg thema, or intense facial pain). Guidelines from the Ameri-
both for 28 days (50 000 units/kg) once daily for 10 days can Academy of Pediatrics for the management of sinusitis
For those with neurosyphilis recommendations are: Neonates who have a normal physical and a non- in children6 recommend that antibacterials be given to
• intramuscular procaine benzylpenicillin 1.8 to 2.4 g (1.8 to treponemal serum titre the same as or less than 4 children clinically diagnosed with persistent or severe
2.4 million units) once daily plus oral probenecid 500 mg times the maternal titre may be given, depending on acute bacterial sinusitis in order to achieve a more rapid
four times daily for 17 days, or clinical cure.
how successfully the mother was treated during preg-
• intravenous benzylpenicillin 1.8 to 2.4 g (3 to
4 million units) every 4 hours for 17 days
nancy: If antibacterials are considered necessary, treatment should
• one of the above treatment regimens or be given for an adequate length of time, usually 2 weeks.6-8
alternatives are: Topical decongestants may also be used to promote drain-
• a single intramuscular dose of benzathine benzylpenicillin
• oral doxycycline 200 mg twice daily for 28 days 37.5 mg/kg (50 000 units/kg) age and ventilation.7,8 The choice of antibacterial is similar
• oral amoxicillin 2 g three times daily plus oral probenecid to that for acute otitis media (p.182). Effective antibacteri-
500 mg four times daily, both for 28 days
Infants and children may be given:
• intravenous benzylpenicillin 30 mg/kg (50 000 units/kg) als include amoxicillin with or without clavulanic acid, ce-
• intramuscular or intravenous ceftriaxone 2 g daily for 10 to
14 days (in the absence of anaphylaxis to penicillin)
every 4 to 6 hours for 10 days. furoxime, clarithromycin, clindamycin and azithromycin;6
Those who are allergic to penicillin should be desen- the emergence of penicillin-resistant strains of H. influen-
• USA: zae, M. catarrhalis, and Str. pneumoniae is of concern.9
sitised if necessary.
• intramuscular benzathine benzylpenicillin 1.8 g
Sexual partners of patients with syphilis in any stage Co-trimoxazole or erythromycin with sulfafurazole have
(2.4 million units) weekly for 3 consecutive weeks
should be examined, tested, and treated.2,3 also been used although pneumococcal resistance has been
alternatives in penicillin-allergic patients are: reported to be substantial.6 Patients with evidence of se-
• oral doxycycline 100 mg twice daily for 28 days, or In the UK,1 it is advised that all cases of syphilis in HIV-
infected patients be treated as for the appropriate stage of vere infections may need initial intravenous therapy with
• oral tetracycline 500 mg four times daily for 28 days vancomycin and ceftriaxone or cefotaxime.9 Tetracycline
For those with neurosyphilis: infection as in HIV-negative patients; some experts recom-
mend treatment as for neurosyphilis but the UK guidelines or erythromycin are the most effective antibacterials
• intravenous benzylpenicillin 1.8 to 2.4 g (3 to
note that evidence for this policy is lacking. The CDC3 and against Chlamydophila pneumoniae.10
4 million units) every 4 hours for 10 to 14 days (or the total
daily dose may be given by continuous infusion), or WHO2 consider that standard treatment with a single intra- Failure to treat acute sinusitis that does not resolve sponta-
• if outpatient compliance can be ensured, then intramuscu- muscular dose of benzathine benzylpenicillin 1.8 g neously can result in chronic sinusitis or occasionally in
lar procaine benzylpenicillin 2.4 g (2.4 million units) daily (2.4 million units) is sufficient, but acknowledge that complications such as brain abscess or meningitis. Exacer-
plus oral probenecid 500 mg four times daily, both for 10 some authorities recommend more intensive treatment bations of chronic sinusitis are treated as for acute infec-
to 14 days regimens. tion. Management of chronic sinusitis is based on reducing
Since the duration of treatment for neurosyphilis is 1. Clinical Effectiveness Group British Association for Sexual obstruction of the sinus cavity using antihistamines, de-
shorter than that for late syphilis in the absence of Health and HIV. 2008 UK national guidelines on the manage- congestants, anti-inflammatory drugs (including cortico-
ment of syphilis. http://www.bashh.org/documents/1771 (ac- steroids), and saline washes as appropriate.7,11,12 The use-
neurosyphilis, some clinicians give intramuscular cessed 18/08/08)
benzathine benzylpenicillin 1.8 g (2.4 million units) 2. WHO. Guidelines for the management of sexually transmitted fulness of antibacterials is more contentious,11 although
once weekly for up to 3 weeks after completion of i n f e c t i o n s . G e n e v a: W HO , 2 0 0 3 . A l s o a v a i l a b l e a t : some clinicians advocate prolonged courses as part of ini-
neurosyphilis treatment to provide a comparable total http://whqlibdoc.who.int/publications/2003/9241546263.pdf tial treatment.7,12 As well as their established antibacterial
(accessed 23/03/07)
duration of treatment. 3. CDC. Sexually transmitted diseases treatment guidelines 2006. effect, it has been suggested that macrolides also have im-
• SYPHILIS IN PREGNANCY MMWR 2006; 55(RR-11): 1–94. Also available at: http:// munomodulatory effects that could be useful in the man-
All guidelines recommend penicillin as under early and
www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07) agement of respiratory diseases including chronic sinusitis
late syphilis, together with close surveillance. In the but large placebo-controlled studies are needed. Surgical
USA, CDC3 note that some recommend a second dose Shigellosis intervention may be necessary if medical treatment fails.
See p.173. 1. Agency for Health Care Policy and Research. Diagnosis and
of benzathine benzylpenicillin a week after the initial treatment of acute bacterial rhinosinusitis. Evidence Re-
dose for patients with early syphilis. In the UK1 it is rec- port/Technology Assessment: Number 9, March 1999. Availa-
ommended that when the first dose is given in the third ble at: http://www.ahrq.gov/clinic/tp/sinustp.htm (accessed
Sickle-cell disease 21/05/04)
trimester a second dose should be given one week later. For prophylaxis against pneumococcal infection in sickle- 2. Ahovuo-Saloranta A, et al. Antibiotics for acute maxillary si-
According to CDC,3 pregnant patients who are allergic cell disease, see under Spleen Disorders, p.194. nusitis. Available in The Cochrane Database of Systematic Re-
to penicillin should be given penicillin, after desensitisa- views; Issue 2. Chichester: John Wiley; 2008 (accessed
19/08/08).
tion if necessary, since the alternatives, tetracyclines, are 3. de Ferranti SD, et al. Are amoxycillin and folate inhibitors as
contra-indicated during pregnancy and erythromycin Sinusitis effective as other antibiotics for acute sinusitis? A meta-analy-
cannot be relied upon to cure an infected fetus. WHO,2 Sinusitis or inflammation of the paranasal sinuses can be sis. BMJ 1998; 317: 632–7.
on the other hand, advise against desensitisation in a pri- caused by viral, bacterial, or fungal infection or may be 4. Snow V, et al. Principles of appropriate antibiotic use for acute
sinusitis in adults. Ann Intern Med 2001; 134: 495–7.
mary care setting and suggest that erythromycin, al- secondary to other disorders such as allergy. Serious com- 5. Young J, et al. Antibiotics for adults with clinically diagnosed
though inferior, should be given in these circumstances; plications include bacterial meningitis and brain abscess. acute rhinosinusitis: a meta-analysis of individual patient data.
consideration should probably be given to use of a third- Acute sinusitis often results from viral upper respiratory- Lancet 2008; 371: 908–14.
6. American Academy of Pediatrics: Subcommittee on Management
generation cephalosporin in the absence of anaphylaxis. tract infections. As in acute otitis media the most frequent of Sinusitis and Committee on Quality Improvement. Clinical prac-
After treatment, the mother should be re-treated if there bacterial pathogens are Streptococcus pneumoniae and un- tice guideline: management of sinusitis. Pediatrics 2001; 108:

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
194 Antibacterials
798–808. Corrections. ibid. 108 (5): A24 and ibid. 2002; 109 (5): infections not responding to penicillin.3 Topical retapamu- Phenoxymethylpenicillin 125 mg twice daily is effec-
A40. Also available at: http://pediatrics.aappublications.org/
cgi/reprint/108/3/798 (accessed 19/08/08) lin is licensed for the treatment of impetigo due to either tive in young children but amoxicillin may be preferred
7. Evans KL. Diagnosis and management of sinusitis. BMJ 1994; Staph. aureus or Str. pyogenes. For community-acquired in adults since it is better absorbed and has a broader
309: 1415–22. mixed infections associated with necrotising fasciitis a spectrum. There is evidence to suggest that, in children
8. Evans KL. Recognition and management of sinusitis. Drugs combination of ampicillin-sulbactam, clindamycin, and who have received pneumococcal immunisation, there
1998. 56: 59–71.
9. Gwaltney JM. Acute community-acquired sinusitis. Clin Infect ciprofloxacin has been advocated.2 is no benefit in continuing penicillin prophylaxis be-
Dis 1996; 23: 1209–25. Resistance is also emerging in Propionibacterium acnes; yond the age of 5 years,2 although indefinite prophylax-
10. Grayston JT, et al. A new respiratory tract pathogen: Chlamydia is has been recommended for those who have had a pre-
pneumoniae strain TWAR. J Infect Dis 1990; 161: 618–25. strains resistant to erythromycin, clindamycin, and tetracy-
11. Rowe-Jones J, Mackay I. Management of sinusitis: sinusitis and cline are reported to be common in patients after treatment vious pneumococcal septic event.3 Fears that prolonged
rhinitis, or rhinosinusitis? BMJ 1995; 310: 670. for acne.1 prophylaxis could encourage the emergence of resistant
12. Wald ER. Chronic sinusitis in children. J Pediatr 1995; 127:
Gram-negative bacteria are less frequently implicated in pneumococci have not been substantiated,4 although the
339–47.
skin infections, but Pseudomonas aeruginosa and Proteus prevalence of beta-lactam-resistant pneumococci con-
spp. can cause infections, especially if the skin is subjected tinues to increase. Neonatal screening for sickle-cell dis-
Skin infections to damp conditions. These organisms produce proteolytic ease is advocated, but compliance with regular penicil-
Bacterial infections of the skin may result from invasion of enzymes that cause the resulting skin damage. Ps. aerugi- lin prophylaxis may be poor and effective follow-up is
skin structures by endogenous skin flora or by exogenous nosa may colonise burns and skin ulcers. Pseudomonal in- necessary if the full benefit of such screening is to be
pathogenic organisms. They include the primary pyoder- fections are treated with aminoglycosides and the anti- achieved.5,6 Nevertheless, availability of penicillin in
mas (for example, impetigo, folliculitis, furunculosis, ery- pseudomonal penicillins. the home, even if not taken regularly, means that it can
sipelas, cellulitis, and ecthyma) and secondary infections be readily used if febrile illness occurs.5 If children with
complicating pre-existing skin lesions, for example diabet- Anaerobic organisms may colonise wounds, particularly sickle-cell disease develop a febrile illness they are gen-
ic or other chronic superficial skin ulcers, burns, bites and chronic ulcers and fungating tumours. Topical metronida- erally treated in hospital with intravenous antibacterials,
stings (p.164), eczema, or may occur as opportunistic in- zole has been used to control the offensive odour caused although outpatient management may often be possi-
fections after skin trauma in immunocompromised pa- by these infections. ble.7
1. Espersen F. Resistance to antibiotics used in dermatological
tients. practice. Br J Dermatol 1998; 139 (suppl 53): 4–8. 1. British Committee for Standards in Haematology Working Party
The pyodermas are commonly caused by Staphylococcus 2. Stevens DL, et al. Infectious Diseases Society of America. Prac- of the Haemato-Oncology Task Force. Update of guidelines for
tice guidelines for the diagnosis and management of skin and the prevention and treatment of infection in patients with an ab-
aureus or, less commonly, by beta-haemolytic streptococ- sent or dysfunctional spleen. Clin Med 2002; 2: 440–3. Also
soft-tissue infections. Clin Infect Dis 2005; 41: 1373–1406. Cor-
ci. Skin ulcers and burns may typically be colonised by rections. ibid.; 1830 and ibid. 2006; 42: 1219. [dose error] Also a v a i l a b l e a t : h t t p : / / w w w. b c s h g u i d e l i n e s . c o m / p d f /
Staph. aureus or Pseudomonas aeruginosa; chronic ulcers available at: http://www.journals.uchicago.edu/doi/pdf/ SPLEEN21.pdf (accessed 21/05/04)
and fungating tumours may also be colonised by anaer- 10.1086/497143 (accessed 06/08/08) 2. Falletta JM, et al. Discontinuing penicillin prophylaxis in chil-
3. Bisno AL, Stevens DL. Streptococcal infections of skin and soft dren with sickle cell anemia. J Pediatr 1995; 127: 685–90.
obes which can cause an offensive odour. 3. Hongeng S, et al. Recurrent Streptococcus pneumoniae sepsis in
tissues. N Engl J Med 1996; 334: 240–5.
Skin disorders of uncertain or mixed aetiology that are children with sickle cell disease. J Pediatr 1997; 130: 814–16.
treated with antibacterials include acne (p.1577) and rosa- Correction. ibid.; 131: 232.
cea (p.1583). Systemic infections with cutaneous involve- Spleen disorders 4. Norris CF, et al. Pneumococcal colonization in children with
sickle cell disease. J Pediatr 1996; 129: 821–7.
ment include anthrax (p.163), diphtheria (p.168), and myc- Splenectomised patients and those with hyposplenism as-
5. Milne RIG. Assessment of care of children with sickle cell dis-
etoma (p.180). sociated with, for example, sickle-cell disease have im- ease: implications for neonatal screening programmes. BMJ
Topical antibacterials and antiseptics may be useful for su- paired immunity and, like other immunocompromised pa- 1990; 300: 371–4.
perficial skin infections, but antibacterials should only be tients (p.174), are at increased risk of infection. Children 6. Cummins D, et al. Penicillin prophylaxis in children with sickle
are at special risk. Streptococcus pneumoniae is the com- cell disease in Brent. BMJ 1991; 302: 989–90.
used short term because of the risks of inducing bacterial 7. Wilimas JA, et al. A randomized study of outpatient treatment
resistance and contact allergy. Topical use of antibacterials monest infecting bacterium and may cause severe over- with ceftriaxone for selected febrile children with sickle cell dis-
that are of value systemically, such as gentamicin, is best whelming infection that is rapid in onset and sometimes ease. N Engl J Med 1993; 329: 472–6.
avoided, although fusidic acid is used topically in the UK. fatal. Hence, prophylaxis with an oral penicillin such as
Application of topical antibacterials to extensive areas of phenoxymethylpenicillin is advocated. Pneumococcal
vaccine is also used; the newer ones may be more effective Spotted fevers
damaged skin can result in systemic toxicity. Rickettsial infections of the spotted fever group are trans-
than earlier vaccines. Other organisms implicated include
Serious infections are treated systemically. Treatment of Neisseria meningitidis, Haemophilus influenzae, and Es- mitted to man by ticks and have also been called tick ty-
skin infections is increasingly based on knowledge of the cherichia coli in splenectomised patients and Salmonella phus. They include Rocky Mountain spotted fever, due to
likely infecting organisms and patterns of resistance; em- in children with sickle-cell disease. More unusual organ- Rickettsia rickettsii and occurring especially in the USA;
pirical treatment with broad-spectrum antibacterials is isms include Capnocytophaga canimorsus (formerly boutonneuse or Mediterranean spotted fever, due to R.
now discouraged in an attempt to minimise the emergence called DF-2) which may cause opportunistic infections in conorii and occurring in Mediterranean countries includ-
of resistant organisms.1 For burns, however, control of in- splenectomised patients after animal bites. There may also ing the Middle East, Africa, and India; Queensland tick ty-
fection is important to reduce the risk of sepsis. Topical be an increased risk of falciparum malaria and babesiosis. phus, due to R. australis and occurring in Australia; north
application of sulfadiazine silver or mafenide acetate has Asian tick typhus, due to R. sibirica and occurring in Sibe-
been used in addition to aggressive systemic antibacterial • SPLENECTOMISED PATIENTS
ria and Mongolia; and oriental spotted fever, due to R.
therapy. Guidelines for prophylaxis based on published evidence japonica and occurring in Japan. Rickettsialpox, due to R.
Gram-positive pathogens, especially staphylococci and and expert opinion have been published in a number of akari is transmitted from mice by mites and occurs in the
beta-haemolytic streptococci, are commonly associated countries including the UK.1 Immunisation with poly- USA, Russia, and Africa.
with primary pyodermas. Staphylococcus aureus is impli- valent pneumococcal vaccine is recommended for all
asplenic patients and those with functional hyposplen- Spotted fevers are recognised increasingly as a cause of
cated in impetigo, cellulitis, folliculitis, furunculosis, and febrile illness associated usually, but not always, with a
occasionally erysipelas and necrotising fasciitis (p.180), ism. Haemophilus influenzae (Hib) vaccine is recom-
mended for all patients who have not previously re- purpuric rash and are becoming an important cause of im-
and may colonise burns. Staphylococcal scalded skin syn- ported fevers in non-endemic areas.1,2 Rocky Mountain
drome is a severe manifestation of bullous impetigo ceived this vaccine. Influenza vaccination should be
given. Meningococcal group C conjugate vaccine is rec- spotted fever has been one of the most severe of these fe-
caused by infection with strains of Staph. aureus produc- vers, but others are potentially serious. A tetracycline, of-
ing exfoliative exotoxins. The term toxic epidermal ommended; however, the vaccine currently available
does not protect against the group B strain of N. menin- ten doxycycline, or chloramphenicol is the treatment of
necrolysis is used to cover both this syndrome and a mor- choice for all the spotted fevers. In Rocky Mountain spot-
phologically identical syndrome due to various aetiolo- gitidis causing the majority of infections in the UK. In
addition, patients travelling abroad should receive a ted fever, doxycycline 100 mg every 12 hours or chloram-
gies. A syndrome resembling scarlet fever may also occur. phenicol 500 mg every 6 hours for 5 to 10 days may be
Staphylococcal infections are usually treated systemically meningococcal vaccine which protects against group A
infections. Lifelong prophylaxis with a suitable antibac- used. Because tetracyclines are generally contra-indicated
with a penicillinase-resistant penicillin or a first-genera- in young children, chloramphenicol has been recommend-
tion cephalosporin.2 Erythromycin is an alternative for pa- terial should be offered. Phenoxymethylpenicillin is
usually given, but amoxicillin may be preferred, partic- ed for children with Rocky Mountain spotted fever under
tients unable to tolerate penicillin. Multidrug-resistant sta- the age of 9, but doxycycline is considered the treatment of
phylococci are becoming increasingly common, ularly in adults, as it is better absorbed after oral doses
and has a broader spectrum of activity. Erythromycin is choice for this and other potentially life-threatening tick-
particularly in hospitals, and treatment alternatives for in- borne rickettsioses, even in young children.2 The risk of
fections with these organisms are discussed under Staphy- a suitable alternative in those unable to tolerate penicil-
lins. On a practical level, compliance with lifelong tooth staining with a single short course of doxycycline is
lococcal Infections, p.195. Less severe infections in fol- considered negligible,2 and there is evidence that short
liculitis or furunculosis may respond to the application of prophylaxis is difficult, but is particularly important in
patients with underlying immunodeficiency, in children courses of tetracycline are effective in some of these dis-
moist heat without the need for antibacterials. In patients at eases.3 Relapses have occurred in patients with Mediterra-
risk of recurrent staphylococcal infections, nasal applica- up to the age of 16 years, and for the first 2 years after
splenectomy. Patients should keep a supply of a suitable nean spotted fever treated with chloramphenicol.4 Other
tion of chlorhexidine plus neomycin or mupirocin alone is alternatives to tetracycline used in Mediterranean spotted
used to eliminate nasal carriage of staphylococci. antibacterial for immediate use should symptoms of in-
fection occur, and be instructed to seek medical advice fever have included the macrolides azithromycin,2,5 clari-
Beta-haemolytic streptococci are also implicated in pyo- urgently. thromycin,2,5 and erythromycin,6 or ciprofloxacin7 or ri-
dermas including impetigo, erysipelas, and cellulitis. fampicin. Erythromycin was effective, but less so than tet-
Necrotising fasciitis (p.180) may be caused by group A • SICKLE-CELL DISEASE racycline, in children with Mediterranean spotted fever.6
streptococci. Streptococcal infections continue to respond Children with sickle-cell disease are particularly sus- Short 2-day courses of ciprofloxacin or doxycycline were
to phenoxymethylpenicillin or benzylpenicillin. Erythro- ceptible to severe pneumococcal infection which may curative in adults whose disease was not severe, although
mycin is an alternative in patients unable to tolerate peni- present as septicaemia, meningitis, or pneumonia. there was a more rapid response to doxycycline.7 A 5-day
cillins, but increasing resistance may be a problem;1 clin- Penicillin prophylaxis is usually combined with early course of ciprofloxacin has also been used successfully to
damycin may be effective in patients with aggressive immunisation with a polyvalent pneumococcal vaccine. treat infection with R. australis.8
 Antibacterials 195
Rickettsialpox can be mistaken for chickenpox. However, gent for washing and bathing. For eradication of nasal car- than prophylactic1,2 and should continue for several days
it will respond to tetracycline although patients have gen- riage they recommend mupirocin nasal ointment. Eradica- postoperatively.3
erally recovered without treatment.9 tion at other colonised sites is more difficult: antiseptic Guidelines for the treatment of intra-abdominal infections
1. Anonymous. Bitten, hot, and mostly spotty. Lancet 1991; 337: detergents may be used for skin and hair washing. A sys- have been produced in the USA by the Surgical Infection
143–4. tematic review8 has concluded that there is insufficient ev- Society4 and by the Infectious Disease Society of Ameri-
2. Parola P, et al. Tick-borne rickettsioses around the world: emerg-
ing diseases challenging old concepts. Clin Microbiol Rev 2005; idence to support the use of topical or systemic antimicro- ca.5
18: 719–56. bial therapy for eradicating nasal or extra-nasal MRSA. ANTIMICROBIAL PROPHYLAXIS. Strictly speaking the term
3. Yagupsky P. Tetracycline for Rocky Mountain spotted fever. Although ciprofloxacin may be used the emergence of
Pediatrics 1991; 87: 124. ‘prophylaxis’ should be confined to elective procedures
4. Shaked Y, et al. Relapse of rickettsial Mediterranean spotted fe- widespread resistance in meticillin-sensitive and meticil- with no evidence of sepsis at the time of operation. If pos-
ver and murine typhus after treatment with chloramphenicol. J lin-resistant Staph. aureus limits its usefulness (see p.246). sible any pre-existing infections should be treated before
Infect 1989; 18: 35–7. Combination therapy may be helpful. Rifampicin is highly
5. Cascio A, et al. Clarithromycin versus azithromycin in the treat- admission for surgery. For prophylaxis it is customary to
ment of Mediterranean spotted fever in children: a randomized active against MRSA, but it must always be used with an- give antibacterials systemically as a single pre-operative
controlled trial. Clin Infect Dis 2002; 34: 154–8. other drug to prevent the emergence of resistance. Combi- dose whereas more prolonged use is necessary when they
6. Muñoz-Espin T, et al. Erythromycin versus tetracycline for treat- nations of rifampicin with gentamicin, vancomycin, co-tri- are given therapeutically. Antimicrobial prophylaxis is
ment of Mediterranean spotted fever. Arch Dis Child 1986; 61: moxazole, fusidic acid, quinolones, or novobiocin have
1027–9. used in clean-contaminated operations and in clean opera-
7. Gudiol F, et al. Randomized double-blind evaluation of cipro- been tried. Newer antibacterials such as daptomycin, line- tions that involve the insertion of prosthetic materials or
floxacin and doxycycline for Mediterranean spotted fever. Anti- zolid, or quinupristin/dalfopristin may be effective and when an infection, however unlikely, would be catastroph-
microb Agents Chemother 1989; 33: 987–8. may assume increasing importance.
8. Hudson BJ, et al. Ciprofloxacin treatment for Australian spotted ic.1
fever. Med J Aust 1996; 165: 588. Isolated reports from around the world of MRSA with in- Contaminating organisms. The choice of prophylactic
9. Kass EM, et al. Rickettsialpox in a New York City hospital, 1980 termediate resistance or reduced susceptibility to vanco- antibacterial will be influenced by the likely contaminants
to 1989. N Engl J Med 1994; 331: 1612–17. mycin initially emerged in the late 1990s,9-11 and in re- for a particular surgical procedure. The most frequently
sponse the CDC produced interim12 and later13 guidelines isolated pathogens include Staphylococcus aureus, coagu-
Staphylococcal infections for preventing the spread of vancomycin-intermediate lase-negative staphylococci, Enterococcus spp., and Es-
Staphylococci are Gram-positive bacteria pathogenic to Staph. aureus (VISA) and vancomycin-resistant Staph. cherichia coli. Infections with antimicrobial-resistant
man. Species may be differentiated by various methods, aureus (VRSA). pathogens including Candida albicans and meticillin-re-
including the coagulase test. Those species of clinical im- Staphylococcal vaccines have been used for the prophy- sistant Staph. aureus (MRSA) are increasing in some hos-
portance are Staphylococcus aureus, which is usually co- laxis and treatment of staphylococcal infections. pitals.1 The most common source of infection is the endog-
agulase-positive, and Staph. epidermidis and Staph. sapro- For the management of staphylococcal infections in gener- enous flora of the patient’s skin, mucous membranes, or
phyticus, which are coagulase-negative. al, see under the specific disease headings. viscera. Thus, aerobic Gram-positive organisms (for ex-
Staph. aureus colonises the skin and mucous membranes 1. Rosenberg J. Methicillin-resistant Staphylococcus aureus (MR- ample staphylococci) are common infecting organisms
naturally and many people, including neonates, may be SA) in the community: who’s watching? Lancet 1995; 346: when the source is the skin and mucous membranes, while
132–3.
staphylococcal carriers from time to time. Localised Staph. 2. Herold BC, et al. Community-acquired methicillin-resistant infections with enterococci, Gram-negative aerobes (for
aureus infections may follow surgery or trauma and com- Staphylococcus aureus in children with no identified predispos- example E. coli), and anaerobic bacteria (for example
monly result in abscess formation. Staphylococcal skin in- ing risk. JAMA 1998; 279: 593–8. Bacteroides fragilis) can arise from the gastrointestinal
3. Collignon P, et al. Community-acquired meticillin-resistant Sta-
fections include impetigo and furunculosis. Conditions as- phylococcus aureus in Australia. Lancet 1998; 352: 145–6. tract.
sociated with staphylococcal extracellular toxin 4. Lowy FD. Staphylococcus aureus infections. N Engl J Med Route of administration. Systemic dosage, usually by the
production include staphylococcal scalded skin syndrome, 1998; 339: 520–32.
5. Salgado CD, et al. Community-acquired methicillin-resistant intravenous route, is generally preferred. The chosen anti-
toxic shock syndrome, and staphylococcal food poisoning. Staphylococcus aureus: a meta-analysis of prevalence and risk bacterial is usually given as a single dose intravenously
Staphylococcal septicaemia is usually a consequence of factors. Clin Infect Dis 2003; 36: 131–9. just before operation at the induction of anaesthesia. The
local infection and may sometimes be associated with in- 6. Humphreys H. National guidelines for the control and preven-
tion of methicillin-resistant Staphylococcus aureus—what do pharmacokinetic properties should be such that adequate
travascular or intraperitoneal catheters or with intravenous they tell us? Clin Microbiol Infect 2007; 13: 846–53. serum concentrations are maintained throughout the surgi-
drug abuse. Septicaemia often results in staphylococcal 7. Joint Working Party of the British Society for Antimicrobial cal procedure.1 Additional doses may be necessary when
endocarditis. Other possible complications of septicaemia Chemotherapy, the Hospital Infection Society and the Infection
Control Nurses Association. Guidelines for the control and pre- surgery is prolonged, when there is massive blood loss, or
are pneumonia and bone and joint infections, although in vention of meticillin-resistant Staphylococcus aureus infection when an antibacterial with a short half-life is used. More
these cases aspiration or local trauma, respectively, may be in healthcare facilities. J Hosp Infect 2006; 63S: S1–S44. controversial routes have included topical or intra-inci-
the cause. 8. Loeb M, et al. Antimicrobial drugs for treating methicillin-re-
sistant Staphylococcus aureus colonization. Available in The sional use and peritoneal lavage. Giving non-absorbable
Staph. epidermidis is also a natural inhabitant of skin and Cochrane Database of Systematic Reviews; Issue 4. Chichester: antibacterials orally to suppress the intestinal flora was tra-
mucous membranes and an increasingly important noso- John Wiley; 2003 (accessed 16/05/05). ditional before large bowel surgery, and neomycin with
9. CDC. Update: Staphylococcus aureus with reduced susceptibil-
comial pathogen. Many infections are hospital-acquired ity to vancomycin—United States, 1997. MMWR 1997; 46: erythromycin is still given for this purpose in the USA. For
and are often associated with indwelling catheters. There 813–15. reference to selective digestive tract decontamination
has been an increased incidence of bacteraemia due to 10. Smith TL, et al. Emergence of vancomycin resistance in Staphy- (SDD), see under Intensive Care, p.175. Other dosage
lococcus aureus. N Engl J Med 1999; 340: 493–501.
Staph. epidermidis in neonatal units. 11. Rybak MJ, Akins RL. Emergence of methicillin-resistant Sta- forms include bone cement and chains of beads for im-
Staph. saprophyticus is a common cause of urinary-tract phylococcus aureus with intermediate glycopeptide resistance: plantation, both containing gentamicin and used prophy-
infections in young women. clinical significance and treatment options. Drugs 2001; 61: lactically in orthopaedic surgery,6,7 and topical and some-
1–7.
Staphylococci were sensitive to benzylpenicillin when it 12. CDC. Interim guidelines for prevention and control of staphylo- times subconjunctival antibacterials for ophthalmic
was first introduced, but the majority of strains are now coccal infection associated with reduced susceptibility to van- surgery.3
comycin. MMWR 1997; 46: 626–8, 635. Also available at:
resistant as a result of penicillinase production. Meticillin http://www.cdc.gov/mmwr//preview/mmwrhtml/00048384.htm Choice of antibacterial. The most commonly used anti-
and other penicillinase-resistant penicillins such as flu- (accessed 21/05/04) bacterials are cephalosporins, aminoglycosides, and met-
cloxacillin were developed because of their activity 13. CDC. Investigation and control of vancomycin-intermediate ronidazole. In the UK, the BNF recommends that gen-
and resistant Staphylococcus aureus (VISA/VRSA): a guide for
against these resistant staphylococci. However, meticillin- health departments and infection control personnel (updated tamicin or cefuroxime is given before abdominal surgery;
resistant staphylococci soon emerged. Both coagulase- April 2004). Available at: http://www.cdc.gov/ncidod/ before colorectal surgery or hysterectomy metronidazole
negative staphylococci and Staph. aureus resistant to met- dhqp/pdf/ar/visa_vrsa_guide.pdf (accessed 06/07/06)
is given in addition, or amoxicillin with clavulanic acid
icillin are generally resistant to all beta lactams and often may be given alone; before endoscopic retrograde cholan-
exhibit multiple resistance to other antibacterials (see Met- Surgical infection giopancreatography gentamicin or ciprofloxacin may be
icillin, Antimicrobial Action, p.299). More studies have Infection is an important cause of postoperative surgical given; before transrectal prostate biopsy ciprofloxacin or
been published on meticillin-resistant Staph. aureus (MR- morbidity and mortality and antimicrobial prophylaxis is gentamicin is given with metronidazole, although for
SA) than meticillin-resistant coagulase-negative staphylo- one of several strategies used to reduce the risk of infec- transurethral resection ciprofloxacin, gentamicin, or ce-
cocci, but both types are a serious problem in hospitals tion. The value of infection prophylaxis is well established furoxime may be given alone; and before joint replace-
around the world. Resistant strains may be endemic to a in certain types of surgery, especially abdominal surgery ments, including the hip and knee, cefuroxime or flucloxa-
single hospital or may be epidemic causing outbreaks of and where prostheses are implanted, although recommen- cillin is recommended. In the USA, cefazolin is commonly
infection at more than one hospital. Colonisation of hospi- dations as to the choice of antibacterial and the route, tim- given before surgery, except that involving the lower gas-
tal staff and patients with meticillin-resistant staphylococci ing, and duration of treatment may vary. Surgical wounds trointestinal tract, for which cefoxitin or cefotetan are used
is an important factor in the spread of these infections. are classified as following clean, clean-contaminated (po- to provide activity against anaerobes.1,2,8 Alternatively, ce-
Current trends are towards health care at home rather than tentially contaminated), contaminated, and dirty opera- fazolin may be given with metronidazole in colorectal sur-
in hospital and there are reports suggesting that MRSA is tions. Clean operations exclude those involving the gas- gery.3 The choice of prophylaxis for patients unable to tol-
becoming more prevalent in the community.1-5 trointestinal, genital, urinary, or respiratory tracts. Clean- erate cephalosporins is less well established. Aztreonam
Guidelines for the control of MRSA are available in many contaminated operations include those where the gastroin- has been suggested as an alternative to cefazolin with the
countries.6 In the UK, revised guidelines7 for the control of testinal, genital, urinary, or respiratory tracts are opened, addition of clindamycin or metronidazole if activity
MRSA in healthcare facilities were produced by a joint but without unusual contamination. Contaminated opera- against anaerobes is necessary.1 However, the use of aztre-
working party of the British Society for Antimicrobial tions include those where there is acute inflammation or onam plus metronidazole may provide inadequate activity
Chemotherapy, the Hospital Infection Society, and the In- spillage from a hollow viscus. Dirty operations include against Gram-positive cocci.8 Another suggested alterna-
fection Control Nurses Association in 2006. They advise those where there is pus, gangrene, or perforated viscera. tive to cefazolin is vancomycin,3 but the routine use of
prompt isolation of infected or colonised patients, screen- In addition, surgery to repair compound fractures and lac- vancomycin should be avoided because of the risk of in-
ing of patients and staff in contact with such patients, the erations due to animal or human bites is considered dirty. ducing resistance.9 Vancomycin may be indicated for
use of protective clothing, handwashing with an antiseptic The use of antibacterials for the management of contami- high-risk procedures if MRSA infections are prevalent,9
detergent, and the use by all patients of an antiseptic deter- nated or dirty surgery is considered to be therapeutic rather and combination with aztreonam or an aminoglycoside
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
196 Antibacterials
has been suggested to provide activity against Gram-neg- Tonsillitis cal tetracycline.4,5 Azithromycin has therefore been
ative organisms.8 If vancomycin is used for prophylaxis, See under Pharyngitis, p.185. recommended6 as the treatment of choice for trachoma,
no more than two doses should be given.9 Other alterna- with combined oral and topical treatment with either a tet-
tives for colorectal procedures include an aminoglycoside Toxic shock syndrome racycline or a sulfonamide as an alternative.
with either clindamycin or metronidazole.8 Toxic shock syndrome is an acute febrile illness associated The SAFE strategy (surgery, antibacterials, facial cleanli-
The necessity for antibacterial prophylaxis in minimally with multisystem failure and caused by a toxin, usually ness, and environmental improvements) is the cornerstone
invasive procedures such as laparoscopy and endoscopy is toxic shock syndrome toxin-1 (TSST-1), produced by Sta- of efforts by WHO7 and the International Trachoma Initi-
often not clear.10 US guidelines1,8 suggest that standard phylococcus aureus.1,2 Bacteraemia has been reported to ative.8 The aim is to eliminate trachoma by 2020. Tetracy-
prophylaxis should be used pending further evidence. be absent in most cases.3 In the early 1980s, toxic shock cline is still, however, the antibacterial treatment of choice
Certain categories of patient continue to be at long-term syndrome was reported predominantly in menstruating in those countries that are not yet part of the initiative pro-
risk of infection after surgery and include splenectomised women using high-absorbency tampons, but it is now ap- gram and for patients in whom azithromycin is contra-in-
patients who have impaired immunity and are at risk of preciated that foci of staphylococcal infection such as sur- dicated.
pneumococcal and other infections (see under Spleen Dis- gical wounds, burns, abscesses, and sinuses are often re- 1. Mabey DCW, et al. Trachoma. Lancet 2003; 362: 223–9.
2. Dawson CR, et al. Guide to trachoma control. Geneva: WHO,
orders, p.194). Opinion is changing as to whether patients sponsible;1,2 mortality may be higher in non-menstrual 1981.
at special risk of endocarditis require prophylaxis before than menstrual cases.4 Treatment of the acute phase re- 3. Bailey RL, et al. Randomised controlled trial of single-dose azi-
dental and surgical procedures (see Endocarditis, p.168). quires prevention of further production or absorption of thromycin in treatment of trachoma. Lancet 1993; 342: 453–6.
4. Schachter J, et al. Azithromycin in control of trachoma. Lancet
Some have advocated prophylaxis in patients with joint toxin by local measures such as removal of tampons or 1999; 354: 630–5.
prostheses undergoing dental treatment,11 but a working packing, wound debridement, or drainage of abscesses; 5. Fraser-Hurt N, et al. Efficacy of oral azithromycin versus topical
party for the British Society for Antimicrobial Chemother- elimination of the toxin-producing bacteria by antistaphy- tetracycline in mass treatment of endemic trachoma. Bull WHO
apy considers such prophylaxis to be unjustified.12 lococcal antibacterials given intravenously initially; fluid 2001; 79: 632–40.
6. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand-
1. Mangram AJ, et al. Guideline for prevention of surgical site in- replacement; and sometimes corticosteroids.1,2 Drotrec- book of antimicrobial therapy. 18th ed. New Rochelle NY: The
fection, 1999. Infect Control Hosp Epidemiol 1999; 20: 250–78. ogin alfa has also been tried.5 Continuing antibacterial Medical Letter, 2008: 73.
2. American Society of Health-System Pharmacists. ASHP thera- treatment for 10 days during the convalescent phase to re- 7. Bailey R, Lietman T. The SAFE strategy for the elimination of
peutic guidelines on antimicrobial prophylaxis in surgery. Am J trachoma by 2020: will it work? Bull WHO 2001; 79: 233–6.
Health-Syst Pharm 1999; 56: 1839–88. duce the risk of recurrence has been recommended.1 The 8. ITI. International Trachoma Initiative. Available at: http://
3. Abramowicz M, ed. Antimicrobial prophylaxis for surgery. In: use of prophylactic antibacterial therapy has been suggest- www.trachoma.org/index.php (accessed 05/08/08)
Handbook of antimicrobial therapy. 18th ed. New Rochelle NY: ed in burns patients,6 but this is controversial.
The Medical Letter, 2008: 125–139.
4. Mazuski JE, et al. The Surgical Infection Society guidelines on Group A beta-haemolytic streptococci (Streptococcus py- Trench fever
antimicrobial therapy for intra-abdominal infections: an execu- ogenes) have been associated with a similar toxin-related Trench fever is a louse-borne bacterial infection so named
tive summary. Surg Infect (Larchmt) 2002; 3: 161–73. syndrome.7,8 Benzylpenicillin is the treatment of choice9 because of its prevalence among soldiers in the First World
5. Joseph S. Solomkin, et al. Guidelines for the selection of anti- but, since it may be difficult to exclude staphylococcal tox-
infective agents for complicated intra-abdominal infections. War. It is caused by Bartonella quintana (formerly Roch-
Clin Infect Dis 2003; 37: 997–1005. ic shock syndrome, an antistaphylococcal drug such as flu- alimaea quintana) which was until recently classified as a
6. Henry SL, Galloway KP. Local antibacterial therapy for the cloxacillin should also be given.9 Clinical improvement rickettsia. B. quintana and B. henselae have also been im-
management of orthopaedic infections: pharmacokinetic con- has been reported with intravenous normal immunoglobu-
siderations. Clin Pharmacokinet 1995; 29: 36–45. plicated in bacillary angiomatosis, especially in immuno-
7. Wininger DA, Fass RJ. Antibiotic-impregnated cement and
lins.10,11 compromised patients, and B. henselae is considered to be
beads for orthopedic infections. Antimicrob Agents Chemother Toxic shock syndromes may be associated with necrotis- a cause of cat scratch disease (p.166).
1996; 40: 2675–9. ing fasciitis (see p.180).
8. Dellinger EP, et al. Quality standard for antimicrobial prophy- Reports from France1,2 and the USA3 of B. quintana
1. Todd JK. Therapy of toxic shock syndrome. Drugs 1990; 39:
laxis in surgical procedures. Clin Infect Dis 1994; 18: 422–7. 856–61. bacteraemia, sometimes with endocarditis, in the urban
9. CDC. Recommendations for preventing the spread of vancomy- 2. Williams GR. The toxic shock syndrome. BMJ 1990; 300: 960. poor prompted the suggestion that trench fever has re-
cin resistance: recommendations of the Hospital Infection Con-
trol Practices Advisory Committee (HICPAC). MMWR 1995; 44
3. Eykyn SJ. Staphylococcal sepsis: the changing pattern of dis- turned.4,5 Cases of trench fever in Marseilles have been
ease and therapy. Lancet 1988; i: 100–4.
(RR-12): 1–13. Also available at: http://www.cdc.gov/mmwr// 4. Descloux E, et al. One in five mortality in non-menstrual toxic reported2 and might herald an increasing incidence as a re-
PDF/rr/rr4412.pdf (accessed 21/05/04) shock syndrome versus no mortality in menstrual cases in a bal- sult of migration from endemic areas, poverty, and louse
10. Wilson APR. Antibiotic prophylaxis and infection control anced French series of 55 cases. Eur J Clin Microbiol Infect Dis infestation.
measures in minimally invasive surgery. J Antimicrob Chemoth- 2008; 27: 37–43.
er 1995; 36: 1–5. 5. Haddadin DW, et al. Drotrecogin alfa (activated) for nonmen- Treatment of trench fever has usually been with a tetracy-
11. Grant A, Hoddinott C. Joint replacement, dental surgery, and strual toxic shock syndrome associated with methicillin resist- cline such as doxycycline or with a macrolide such as
antibiotic prophylaxis. BMJ 1992; 304: 959. ant Staphylococcus aureus infection. South Med J 2006; 99:
12. Simmons NA, et al. Case against antibiotic prophylaxis for den- 1295–6. erythromycin. Other antibacterials, for example ceftriax-
tal treatment of patients with joint prostheses. Lancet 1992; 339: 6. Rashid A, et al. On the use of prophylactic antibiotics in preven- one, were also used in cases of bacteraemia,3 but there was
301. tion of toxic shock syndrome. Burns 2005; 31: 981–5. limited follow-up and clear recommendations could not be
7. Cone LA, et al. Clinical and bacteriologic observations of a tox-
ic shock-like syndrome due to Streptococcus pyogenes. N Engl given. A review6 has suggested that gentamicin plus doxy-
Syphilis J Med 1987; 317: 146–9. cycline should be used in patients with trench fever or
8. Stevens DL, et al. Severe group A streptococcal infections asso- chronic B. quintana bacteraemia. Similarly, optimal thera-
See under Sexually Transmitted Diseases, p.192. ciated with a toxic shock-like syndrome and scarlet fever toxin
A. N Engl J Med 1989; 321: 1–7. py for Bartonella endocarditis has not been identified;
9. Sanderson P. Do streptococci cause toxic shock? BMJ 1990; however, it has been suggested that the usual treatment for
301: 1006–7. blood culture-negative endocarditis (a penicillin plus an
Tetanus 10. Barry W, et al. Intravenous immunoglobulin therapy for toxic
Clostridium tetani is a Gram-positive anaerobic spore- shock syndrome. JAMA 1992; 267: 3315–16. aminoglycoside) should be effective.7 Again, treatment
forming bacillus present in soil and faeces. The toxin it 11. Kaul R, et al. Intravenous immunoglobulin therapy for strepto- with gentamicin plus doxycycline has also been suggest-
coccal toxic shock syndrome—a comparative observational
produces, tetanospasmin, causes tetanus or lockjaw, with study. Clin Infect Dis 1999; 28: 800–7. ed.6
uncontrolled muscle spasm.1 Tetanus can be prevented by 1. Drancourt M, et al. Bartonella (Rochalimaea) quintana endocar-
active immunisation with tetanus vaccine or passive im- ditis in three homeless men. N Engl J Med 1995; 332: 419–23.
munisation with tetanus immunoglobulin. Nowadays it Trachoma 2. Brouqui P, et al. Chronic Bartonella quintana bacteremia in
homeless patients. N Engl J Med 1999; 340: 184–9.
occurs mostly in developing countries and especially in Trachoma1 results from chronic eye infection with certain 3. Spach DH, et al. Bartonella (Rochalimaea) quintana bacteremia
neonates. In developed countries immunity may be rela- Chlamydia trachomatis serotypes and is endemic in parts in inner-city patients with chronic alcoholism. N Engl J Med
tively low in the elderly. of Africa, the Middle East, and India where it is an impor- 1995; 332: 424–8.
tant cause of blindness. It is not a sexually transmitted dis- 4. Relman DA. Has trench fever returned? N Engl J Med 1995;
In addition to the control of muscle spasm with drugs such ease, but is associated with poverty, poor sanitation, and
332: 463–4.
as diazepam (see p.1901 for the symptomatic treatment of 5. Ohl ME, Spach DH. Bartonella quintana and urban trench fever.
poor personal hygiene. The reservoir is chronic eye infec- Clin Infect Dis 2000; 31: 131–5.
tetanus), treatment includes the use of tetanus immu- tion and transmission may be via fingers, fomites, and 6. Rolain JM, et al. Recommendations for treatment of human in-
noglobulin to neutralise any circulating toxin and the use flies. Inclusion conjunctivitis in infants (see under Neona- fections caused by Bartonella species. Antimicrob Agents Chem-
of antibacterials. Benzylpenicillin has traditionally been other 2004; 48: 1921–33.
tal Conjunctivitis, p.180) and in adults is associated with 7. Raoult D, et al. Diagnosis of 22 new cases of Bartonella endo-
used, with a tetracycline or metronidazole as possible al- sexually transmitted genital C. trachomatis infection and carditis. Ann Intern Med 1996; 125: 646–52. Correction. ibid.
ternatives, but some now consider metronidazole to be can progress to trachoma when there is persistent or recur- 1997; 127: 249.
preferable to benzylpenicillin.2-4 rent eye infection.
In rural developing countries where tetanus is common Guidelines for trachoma control published by WHO in Tuberculosis
and active immunisation little practised, pre-operative 1981 outlined topical or oral treatment with a tetracycline Tuberculosis1 refers to disease caused primarily by Myco-
metronidazole or penicillin might be used for patients un- or alternatively with erythromycin or a sulfonamide.2 bacterium tuberculosis and occasionally by M. bovis or M.
dergoing emergency operations who have not been immu- However, topical chemotherapy for trachoma must be in- africanum. Infection results from inhalation of infected
nised against tetanus; the duration of antibacterial cover tensive and prolonged, 6 weeks being the minimum rec- droplet nuclei. Primary infection is usually asymptomatic
depends on the contamination risk.5 ommended duration for continuous intensive treatment and in more than 95% of immune competent individuals is
1. Brook I. Current concepts in the management of Clostridium with tetracycline 1% ophthalmic ointment. With less fre- controlled by acquired (cell mediated) immunity. The im-
tetani infection. Expert Rev Anti Infect Ther 2008; 6: 327–36.
quent applications, the duration of treatment must be pro- mune response, however, is unable to eradicate the tuber-
2. Ahmadsyah I, Salim A. Treatment of tetanus: an open study to
compare the efficacy of procaine penicillin and metronidazole. longed and may need to be extended to months or even cle bacilli, and these bacilli may give rise to progressive
BMJ 1985; 291: 648–50. years. A single oral dose of azithromycin produces a sim- primary infection (if disease occurs within 2 years of initial
3. Sanford JP. Tetanus—forgotten but not gone. N Engl J Med ilar rate of resolution to conventional treatment with topi- infection) or post-primary (reactivated) tuberculosis (if
1995; 332: 812–13. cal tetracycline for 6 weeks.3 Mass treatment of African disease occurs years to decades after initial infection).
4. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand- village communities with oral azithromycin once weekly Young children and immunocompromised patients are at
book of antimicrobial therapy. 18th ed. New Rochelle NY: The
Medical Letter, 2008: 61. for 3 weeks has resulted in a lower incidence of trachoma increased risk of developing active disease. The most com-
5. Anonymous. Postoperative tetanus. Lancet 1984; ii: 964–5. at follow-up after one year than a standard course of topi- mon manifestation of tuberculosis is pulmonary disease,
 Antibacterials 197
although almost any organ may be affected. Patients usu- tuberculosis control programmes.8,9 Isoniazid and strepto- regimen (RHZE2/RH4).4,17-20 In children and patients
ally present with cough, fever, night sweats, and weight mycin resistance are the most prevalent. Multidrug-resist- whose clinical or bacteriological response is slow, treat-
loss. ant tuberculosis (caused by strains resistant to both isoni- ment should be extended to a total of 9 months.18-20 Chil-
During recent years the incidence of tuberculosis in many azid and rifampicin) requires a combination of first- and dren with extrapulmonary tuberculosis involving the
countries has increased in association with the increasing second-line drugs for at least 18 to 24 months (see be- bones or CNS, or in those with miliary disease, should be
prevalence of HIV infection. Supervised rifampicin-based low).4,5,8 Drug-resistant tuberculosis is a reflection of poor given treatment for a minimum of 12 months.18 Treatment
(short-course) therapy, using fixed-dose combination tab- tuberculosis management, control, and unreliable drug failures in HIV-infected patients have been associated with
lets, is recommended by WHO to improve cure rates and supply; it is difficult to treat, and not infrequently fatal, reduced drug concentrations due to malabsorption of an-
reduce the emergence of drug-resistant tuberculosis.2 particularly in HIV-infected patients. Whereas the WHO timycobacterials.21
WHO applies the term DOTS (Directly Observed Thera- DOTS programme may limit the development of multi- Most clinicians would defer starting antiretroviral therapy
py – Short Course) to its tuberculosis control strategy, drug-resistant tuberculosis, different strategies are re- in HIV co-infected patients with CD4+ counts greater than
which includes standards for diagnosis, supervised thera- quired in areas where multidrug resistance is already es- 200/microlitre until the tuberculosis treatment has been
py, ensuring secure drug supplies, and regular evaluation tablished. These have been formulated by the WHO in the completed. Patients with more severe immunodeficiency
of the tuberculosis control programme. The feasibility of DOTS-plus strategy for countries with well functioning benefit from co-administration of HIV and tuberculosis
implantable dosage forms has also been investigated. tuberculosis control programmes.10 therapy. In these patients, tuberculosis therapy is started
• First-line treatment. Multidrug treatment for 6 to 8 Patients with multidrug-resistant tuberculosis and those first, and HIV treatment added once the patient tolerates
months is required to cure tuberculosis, reduce the risk of who relapse after completing the WHO standard treatment tuberculosis therapy, or after 2 months when tuberculosis
relapse, and prevent the emergence of drug-resistant dis- regimens should receive a DOTS-plus regimen, which in- therapy is simplified. The use of rifamycin-based regi-
ease. Treatment regimens recommend an initial intensive cludes second-line antituberculous drugs. Drugs used in mens to treat tuberculosis is recommended as response
phase of 2 to 3 months that is aimed at achieving rapid spu- the treatment of drug-resistant tuberculosis are generally rates are better compared to non-rifamycin-based regi-
tum conversion followed by a continuation phase of 4 to 6 less effective and more toxic than standard therapy and mens. However, drug interactions between rifamycins and
months to eliminate residual bacilli and prevent relapse. need to be taken daily. They include the aminoglycosides antiretrovirals complicate the co-administration of HIV
The choice of regimen depends on local patterns of drug (amikacin, capreomycin, and kanamycin), aminosali- and tuberculosis treatment,19,20,22 and certain combina-
resistance and the availability of drugs, and are embodied cylates, cycloserine, ethionamide, fluoroquinolones (cip- tions may require dose adjustment or be contra-indicated
in national and regional treatment protocols in many coun- rofloxacin, levofloxacin, and ofloxacin), protionamide, (for details of the interactions of rifampicin and antiretro-
tries including those in Europe,3 the UK,4 and USA.5 and terizidone. The DOTS-plus regimen should consist of virals see p.327 and for those with rifabutin see p.324). It
WHO recommended treatment regimens6,7 are based on at least 3 or 4 oral drugs plus an injectable aminoglycoside, is important to note that guideline recommendations are
disease severity and history of previous tuberculosis treat- to which the patient has not been exposed and which do based on pharmacokinetic studies, often performed in
ment. not share cross-resistance with drugs given previously. healthy subjects, rather than on studies of treatment out-
• New cases of pulmonary or extrapulmonary tuberculo- These drugs should be given under direct observation for come in patients.
sis are treated with an initial phase consisting of ri- at least 6 months, and followed by a continuation phase of Directly observed therapy improves outcome and is rec-
fampicin (R), isoniazid (H), pyrazinamide (Z), and 12 to 18 months with at least 3 drugs.5,8 Cross-resistance ommended wherever possible. Due to the risk for acquired
ethambutol (E) for 2 months, followed by a continuation between rifampicin and rifabutin is common and rifabutin rifamycin resistance highly intermittent (once or twice
phase with rifampicin and isoniazid for 4 months, such is therefore not recommended as a second-line drug. weekly) tuberculosis regimens should not be used for co-
a regimen being described as: RHZE2/RH4. Rifampicin Cross-resistance among aminoglycosides is uncommon, infected patients with CD4+ cell counts less than
may be substituted with ethambutol in the continuation while cross-resistance is variable within the fluoroquinolo- 100 cells/microlitre.18-20,22 All HIV and tuberculosis co-
phase to reduce costs, although this regimen needs to be nes. Cross-resistance is complete between ethionamide infected patients should receive co-trimoxazole if CD4+
given for a total of 8 months and is associated with an and protionamide, and between cycloserine and teriz- counts are below 200 cells/microlitre.23 Thioacetazone
increased risk of relapse (RHZE2/HE6). In tuberculous idone. Where available, M. tuberculosis resistance testing should not be used in HIV-positive patients because of the
meningitis ethambutol should be replaced with strepto- should be performed to guide the choice of therapy. Single potential for severe skin toxicity. Paradoxical worsening of
mycin (S) (RHZS2) and a 6- to 10-month continuation drugs should never be added to a failing regimen. tuberculosis symptoms is common in HIV-infected pa-
phase with rifampicin and isoniazid is often recom- Extensively drug-resistant tuberculosis (XDR-TB) is de- tients who start antiretroviral therapy24 and incidences of
mended. Ethambutol may be omitted from the intensive fined as tuberculosis that is resistant to isoniazid and rif- up to 35% have been noted.22
phase in patients with less severe forms of extrapulmo- ampicin and also resistant to fluoroquinolones and at least • Adjunctive therapy. The inflammatory response to tu-
nary tuberculosis or with limited non-cavitary smear- one of three injectable second-line drugs (amikacin, capre- berculosis can cause considerable tissue damage and ad-
negative pulmonary tuberculosis if drug resistance has omycin, or kanamycin).11 XDR-TB can develop when the junctive steroid therapy may be used to counter this. Cor-
been excluded or the risk of drug resistance is deemed to second-line drugs are misused or mismanaged and by ticosteroids are of little benefit in uncomplicated
be low (RHZ2/RH4). Cure rates of greater than 90% are early 2006 cases were being reported from every region in pulmonary tuberculosis. However, a study25 found adjunc-
typically achieved in patients infected with drug-sus- the world.12 A report from the KwaZulu-Natal province of tive dexamethasone improved survival, but probably not
ceptible organisms who adhere to therapy. South Africa highlighted the risk for rapid death in HIV- severe disability, in adolescents and adults with tubercu-
• In patients previously treated for tuberculosis, the ini- infected persons with extensively-drug resistant tuberculo- lous meningitis. Systematic reviews of tuberculous
tial treatment phase is rifampicin, isoniazid, pyrazina- sis.13 In this local case series, all but one of 53 patients pleurisy26 and pericarditis,27 have concluded that there is
mide, and ethambutol given for 3 months with strepto- died, and where the date of death could be confirmed the insufficient evidence to support the use of corticosteroids
mycin being added for the first 2 months. The median survival was 16 days from the time of diagnosis. in these conditions. WHO17 suggests that corticosteroids
continuation phase includes 3 drugs (rifampicin, isoni- • Children and infants can be treated with regimens sim- may be useful adjuvants to antituberculous therapy for the
azid, and ethambutol) and is extended to 5 months ilar to adults but with appropriate dose adjustments for age management of tuberculous meningitis, pericarditis, pleu-
(RHZES2/RHZE1/RHE5). Because it is relatively or body-weight.4-7 While ethambutol is not usually given ral effusion, laryngitis, tuberculosis of the renal tract,
cheap thioacetazone has been used in some countries to young children because of the perceived difficulty in de- adrenocortical insufficiency due to adrenal gland tubercu-
with limited resources but its use is strongly discour- tecting ocular toxicity (see p.274), a literature review14 on losis, and massive lymph node enlargement in both HIV-
aged because of its weak antimycobacterial activity and its use in children found almost no ocular toxicity at daily positive and -negative patients. Corticosteroids may also
associated risk of fatal skin toxicity, particularly in HIV doses of 15 to 30 mg/kg and it was considered safe in chil- be useful for hypersensitivity reactions to antituberculosis
patients. All first-line drugs can be given intermittently dren of all ages. drugs. For further details on the possible role of cortico-
(at double doses 3 times each week) as an alternative to • Pregnancy, breast feeding, and the neonate. Tubercu- steroids as an adjunct to antituberculous therapy, see
daily use. Patients who remain smear-positive at the end losis, and especially drug-resistant tuberculosis, during p.1514.
of supervised short-course chemotherapy may have pregnancy poses a serious risk to the mother, fetus, and ne- Studies have suggested that injection of suspensions of
drug-resistant tuberculosis and treatment usually re- onate if not detected early and treated properly.15 The killed Mycobacterium vaccae improved immune respon-
quires the introduction of second-line drugs (see below). WHO recommends that pregnant women with tuberculo- siveness in patients with pulmonary tuberculosis, although
First-line drugs such as isoniazid, rifampicin, and particu- sis are treated similarly to non-pregnant patients a systematic review28 concluded that M. vaccae immuno-
larly pyrazinamide may cause severe and possibly fatal (RHZE2/RH4 or RHZ2/RH4). Fluoroquinolones, therapy was of no benefit.
drug-induced hepatitis. Further details covering hepato- aminoglycosides, ethionamide, and protionamide are best • Prevention. Studies have found that BCG vaccine offers
toxicity and special precautions for use in patients with liv- avoided. Liver enzymes and symptoms of drug-induced protection against serious forms of tuberculosis in chil-
er disorders are given in the respective drug mono- hepatitis should be monitored.4,5,15 Most antituberculous dren, such as miliary and meningeal tuberculosis, but has
graphs—see, Isoniazid p.289; Rifampicin p.326; and drugs may be used during breast feeding. Drug concentra- variable efficacy against pulmonary tuberculosis in adults.
Pyrazinamide p.320. UK4 and US5 guidelines recommend tions in the breast milk are too low to prevent or treat tu- In high prevalence areas, vaccination is recommended for
stopping all potentially hepatotoxic drugs if serum berculosis in infants. In the UK it is recommended that ne- children at birth, except for children with HIV infection.
transaminases rise to more than 5 times the upper limit of onates of mothers with tuberculosis should receive For further information on BCG vaccine see, p.2205.
normal or 3 times in the presence of symptoms of hepatitis isoniazid for 3 months16 after which time the infant should Tuberculosis skin testing may identify persons with latent
or elevated bilirubin. Cautious sequential re-introduction be re-evaluated. BCG vaccination is recommended by M. tuberculosis infection. Treatment of tuberculosis skin
of the same drugs (with or without pyrazinamide) after res- WHO and in the UK when isoniazid is stopped.16 test-positive persons (also referred to as preventative ther-
olution of the biochemical abnormalities is often possi- • Co-infection with HIV increases the risk of patients de- apy or chemoprophylaxis) reduces the risk of developing
ble.4-6 Patients in whom therapy is interrupted may be giv- veloping both pulmonary and extrapulmonary tuberculo- (reactivation) tuberculosis. Treatment is beneficial in HIV-
en streptomycin, ethambutol, and/or a fluoroquinolone sis, and mortality is higher than in HIV-negative patients in infected patients, contacts of active cases, persons who
until hepatotoxicity has resolved. the absence of antiretroviral therapy. HIV patients (includ- have recently become tuberculosis skin test positive, and
Management of drug-resistant disease. The incidence of ing children) with tuberculosis have a similar response to persons at high risk of disease. Chemoprophylaxis is not
drug resistance amongst M. tuberculosis strains has in- short-course chemotherapy as HIV-negative tuberculosis recommended routinely in developing countries where the
creased over recent years typically in countries with poor patients and most can be treated with the standard 6-month priority is to detect and treat patients with active tubercu-
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
198 Antibacterials
losis.17,29 Latent tuberculosis has been treated with isoni- 21. Gurumurthy P, et al. Decreased bioavailability of rifampin and therefore emphasise the use of a fluoroquinolone such as
other antituberculosis drugs in patients with advanced human
azid or rifampicin given alone, or with rifampicin given immunodeficiency virus disease. Antimicrob Agents Chemother ciprofloxacin or ofloxacin for initial treatment of typhoid
with either isoniazid or pyrazinamide. Daily isoniazid for 2004; 48: 4473–5. fever.3,4 In strains that remain sensitive, chloramphenicol,
6 to 12 months reduces the risk of active tuberculosis by 60 22. Pozniak AL, et al. British HIV Association. BHIVA treatment amoxicillin, or co-trimoxazole are alternatives, while in
guidelines for TB/HIV infection, February 2005. Available at:
to 90%1,30 and in HIV-infected, tuberculosis skin test-pos- http://www.bhiva.org/files/file1001577.pdf (accessed multidrug-resistant strains a third-generation cepha-
itive persons isoniazid for 6 months has also been shown 05/10/07) losporin such as cefixime, cefotaxime, or ceftriaxone may
to provide short-term protection against tuberculosis.31 23. Anonymous. International standards for tuberculosis care. The be given. The latter are also an alternative where fluoro-
Hague: Tuberculosis Coalition for Technical Assistance, 2006.
However, the combination of rifampicin and pyrazina- Av a i l a b l e a t : h t t p : / / w w w. w h o . i n t / t b / p u b l i c a t i o n s / quinolone resistance exists;3,4 this is an increasing prob-
mide has resulted in severe and fatal liver damage in HIV- 2006/istc_report.pdf (accessed 24/03/06) lem, particularly in Asia, but most fluoroquinolone-resist-
negative persons and is no longer recommended for tuber- 24. Breen RAM, et al. Paradoxical reactions during tuberculosis ant strains seen in the UK retain their sensitivity to
treatment in patients with and without HIV co-infection. Thorax
culosis prophylaxis.30,32,33 The American Thoracic Socie- 2004; 59: 704–7. cephalosporins, and to azithromycin, which is another al-
ty and the CDC,30,32 and NICE16 have issued detailed rec- 25. Thwaites GE, et al. Dexamethasone for the treatment of tuber- ternative.5 Combination regimens have been investigat-
ommendations for treatment of latent tuberculosis culous meningitis in adolescents and adults. N Engl J Med 2004; ed,4 but a study in patients infected with strains showing
351: 1741–51.
infection. Briefly, UK recommendations for HIV-negative 26. Engel ME, et al. Corticosteroids for tuberculous pleurisy. Avail- both multidrug resistance and reduced susceptibility to
adults and children over 2 years old are for either isoniazid able in The Cochrane Database of Systematic Reviews; Issue 4. fluoroquinolones found that azithromycin alone was pref-
alone for 6 months or isoniazid with rifampicin for 3 Chichester: John Wiley; 2007 (accessed 19/08/08). erable to azithromycin plus ofloxacin.6 Interestingly, there
27. Mayosi BM, et al. Interventions for treating tuberculous peri-
months; isoniazid alone for 6 months should be given to all carditis. Available in The Cochrane Database of Systematic Re- is some evidence that as fluoroquinolone resistance
HIV-positive patients. In the USA either isoniazid alone views; Issue 4. Chichester: John Wiley; 2002 (accessed spreads, sensitivity to some of the older drugs used to treat
for 9 months (or 6 months in HIV-negative patients) or ri- 02/03/06). the disease, such as chloramphenicol, may be returning.7,8
28. de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy
fampicin alone for 4 months is recommended. for treating tuberculosis. Available in The Cochrane Database of Although fluoroquinolones are not generally indicated in
1. Frieden TR, et al. Tuberculosis. Lancet 2003; 362: 887–99. Systematic Reviews; Issue 1. Chichester: John Wiley; 2003 (ac- children because of potential toxicity, WHO considers that
cessed 02/03/06).
2. Blomberg B, Fourie B. Fixed-dose combination drugs for tuber-
29. Woldehanna S, Volmink J. Treatment of latent tuberculosis in- their benefits in typhoid fever outweigh any putative risk.3
culosis: application in standardised treatment regimens. Drugs
2003; 63: 535–553. fection in HIV infected persons. Available in The Cochrane Da- Azithromycin may also be given.3 In pregnancy a beta-
3. Broekmans JF, et al. European framework for tuberculosis con- tabase of Systematic Reviews; Issue 1. Chichester: John Wiley; lactam such as ampicillin or one of the cephalosporins may
2004 (accessed 02/03/06).
trol and elimination in countries with a low incidence. Recom-
30. American Thoracic Society and the Centers for Disease Control. be preferable,3 although there are reports of the successful
mendations of the World Health Organization (WHO), Interna-
tional Union Against Tuberculosis and Lung Disease (IUATLD) Targeted tuberculin testing and treatment of latent tuberculosis use of fluoroquinolones. WHO also suggests that although
and Royal Netherlands Tuberculosis Association (KNCV) infection. Am J Respir Crit Care Med 2000; 161 (suppl): there is no evidence to suggest harm, azithromycin should
Working Group. Eur Respir J 2002; 19: 765–75. Also available S221–S247. Also available at: http://www.thoracic.org/
sections/publications/statements/pages/mtpi/latenttb1-27.html not be used in pregnant or nursing women if alternatives
at: http://erj.ersjournals.com/cgi/reprint/19/4/765.pdf (accessed
02/03/06) (accessed 08/06/07) are available.3
31. Johnson JL, et al. Duration of efficacy of treatment of latent
4. Joint Tuberculosis Committee of the British Thoracic Society. tuberculosis infection in HIV-infected adults. AIDS 2001; 15: Patients who develop mental changes should be evaluated
Chemotherapy and management of tuberculosis in the United 2137–47. for meningitis; if typhoid meningitis is suspected, high-
Kingdom: recommendations 1998. Thorax 1998; 53: 536–48. [Al- 32. CDC. Update: adverse event data and revised American Thorac-
though these guidelines were replaced by ones issued by NICE in dose intravenous dexamethasone should be given in addi-
ic Society/CDC recommendations against the use of rifampin
2006 the latter do not "explain tuberculosis or its treatment in de- and pyrazinamide for treatment of latent tuberculosis infec- tion to antibacterial treatment.3
tail" and therefore reference to the earlier guidelines has been re- tion—United States, 2003. MMWR 2003; 52: 735–9. Also avail-
tained] Also available at: http://www.brit-thoracic.org.uk/ On recovery, typhoid patients may continue to excrete S.
able at: http://www.cdc.gov/mmwr/PDF/wk/mm5231.pdf (ac-
Portals/0/Clinical%20Information/Tuberculosis/Guidelines/ cessed 05/10/07) typhi in the faeces or urine for several weeks. Unlike these
Chemotherapy.pdf (accessed 29/07/08) convalescent carriers, some 1 to 5% of patients become
33. Jasmer RM, et al. Short-course rifampin and pyrazinamide
5. American Thoracic Society, CDC, and the Infectious Diseases
Society of America. Treatment of tuberculosis. MMWR 2003;
compared with isoniazid for latent tuberculosis infection: a mul- chronic carriers3 who may excrete S. typhi for years with-
ticenter clinical trial. Ann Intern Med 2002; 137: 640–7.
52 (RR-11): 1–77. Also available at: http://www.cdc.gov/ out any symptoms; eradication is difficult and prolonged
mmwr/PDF/rr/rr5211.pdf (accessed 24/05/04) Correction. ibid. treatment is necessary. An increased risk of biliary-tract
2005: 53: 1203. [dose]
6. WHO. Treatment of tuberculosis: guidelines for national pro-
Tularaemia and bile-related cancers has been associated with chronic
grammes. 3rd ed. Geneva: WHO, 2003 (and 2004 revision). Tularaemia is caused by the Gram-negative bacillus Fran- carriage of S. typhi, and the importance of eradication has
Av a i l a b l e a t : h t t p : / / w h q l i b d o c . w h o . i n t / h q / 2 0 0 3 / cisella tularensis, an organism that primarily affects ro- been emphasised.9
WHO_CDS_TB_2003.313_eng.pdf (accessed 02/03/06) dents and rabbits but may be transmitted to man, usually
7. WHO. Guidance for national tuberculosis programmes on the Typhoid vaccines are used for the prevention of typhoid
management of tuberculosis in children. Geneva: WHO, 2006. by handling infected animals or carcasses, or by the bites fever.
Av a i l a b l e a t : h t t p : / / w h q l i b d o c . w h o . i n t / h q / 2 0 0 6 / of insect vectors. It may take several forms, the most com-
WHO_HTM_TB_2006.371_eng.pdf (accessed 19/08/08) Paratyphoid fever is less common and generally milder
mon of which is the ulceroglandular form, characterised
8. WHO. Guidelines for the programmatic management of drug- than typhoid fever. Treatment is similar.
resistant tuberculosis. Geneva: WHO, 2006. Available at: http:// by rash and ulceration at the site of inoculation accompa-
1. Parry CM, et al. Typhoid fever. N Engl J Med 2002; 347:
whqlibdoc.who.int/publications/2006/9241546956_eng.pdf nied by fever and lymphadenopathy; other forms include 1770–82.
(accessed 22/05/07) the typhoidal and pneumonic forms, which have a higher 2. Rowe B, et al. Multidrug-resistant Salmonella typhi: a world-
9. WHO. Anti-tuberculosis drug resistance in the world: 3rd glo- mortality rate. There has been some concern about its po- wide epidemic. Clin Infect Dis 1997; 24 (suppl 1): S106–S109.
b a l re p o r t . G e n e v a : W H O , 2 0 0 4 . Av a i l a b l e a t :
http://whqlibdoc.who.int/publications/2004/9241562854.pdf tential use as a biological weapon.1,2 3. WHO. Background document: the diagnosis, treatment and pre-
(accessed 02/03/06) vention of typhoid fever (issued May 2003). Available at:
Streptomycin is still considered the antibacterial of choice h t t p : / / w w w. w h o . i n t / v a c c i n e _ r e s e a r c h / d o c u m e n t s / e n /
10. Sterling TR, et al. Impact of DOTS compared with DOTS-plus in severe disease, although gentamicin is an alternative.1,2 typhoid_diagnosis.pdf (accessed 06/08/08)
on multidrug resistant tuberculosis and tuberculosis deaths: de-
cision analysis. BMJ 2003; 326: 574–9. A tetracycline or chloramphenicol may be given orally; 4. Bhutta ZA. Current concepts in the diagnosis and treatment of
typhoid fever. BMJ 2006; 333: 78–82.
11. CDC. Notice to readers: revised definition of extensively drug- clinical relapses are more frequent than with the aminogly- 5. Threlfall EJ, et al. Alternatives to ciprofloxacin use for enteric
resistant tuberculosis. MMWR 2006; 55: 1176. Also available
at: http://www.cdc.gov/mmwr/PDF/wk/mm5543.pdf (accessed
cosides,1,2 although relapsed disease will respond to a fur- fever, United Kingdom. Emerg Infect Dis 2008; 14: 860–1.
07/12/06) ther course. Ciprofloxacin has also been used successful- 6. Parry CM, et al. Randomized controlled comparison of
12. CDC. Emergence of Mycobacterium tuberculosis with extensive ly.1 Some patients have also responded to high-dose ofloxacin, azithromycin, and an ofloxacin-azithromycin combi-
nation for treatment of multidrug-resistant and nalidixic acid-re-
resistance to second-line drugs—worldwide, 2000–2004. MMWR intravenous erythromycin.3 sistant typhoid fever. Antimicrob Agents Chemother 2007; 51:
2006; 55: 301–5. Also available at: http://www.cdc.gov/
mmwr/PDF/wk/mm5511.pdf (accessed 07/12/06) A tularaemia vaccine is available in some countries for ac- 819–25.
13. Gandhi NR, et al. Extensively drug-resistant tuberculosis as a tive immunisation against the disease. 7. Gogia A, et al. Quinolone-resistant typhoid fever. Indian J Med
cause of death in patients co-infected with tuberculosis and HIV Sci 2006; 60: 389–90.
1. Dennis DT, et al. Tularemia as a biological weapon: medical and
in a rural area of South Africa. Lancet 2006; 368: 1575–80. public health management. JAMA 2001; 285: 2763–73. 8. Chitnis S, et al. Ciprofloxacin therapy for typhoid fever needs
14. WHO. Ethambutol efficacy and toxicity: literature review and rec- reconsideration. J Infect Chemother 2006; 12: 402–4.
2. Ellis J, et al. Tularemia. Clin Microbiol Rev 2002; 15: 631–46.
ommendations for daily and intermittent dosage in children. Gene- 3. Westerman EL, McDonald J. Tularemia pneumonia mimicking 9. Caygill CPJ, et al. Cancer mortality in chronic typhoid and para-
va: WHO, 2006. Available at: http://whqlibdoc.who.int/hq/2006/ Legionnaires’ disease: isolation of organism on CYE agar and typhoid carriers. Lancet 1994; 343: 83–4.
WHO_HTM_TB_2006.365_eng.pdf (accessed 08/12/06) successful treatment with erythromycin. South Med J 1983; 76:
15. Bothamley G. Drug treatment for tuberculosis during pregnan- 1169–70.
cy: safety considerations. Drug Safety 2001; 24: 553–65. Typhus
16. National Collaborating Centre for Chronic Conditions/National Rickettsial infections or fevers of the typhus group are
Institute for Health and Clinical Excellence. Tuberculosis: clin- Typhoid and paratyphoid fever
ical diagnosis and management of tuberculosis, and measures transmitted to man by various insect vectors. Louse-borne
for its prevention and control (issued March 2006). Available at: Typhoid and paratyphoid fever are systemic infections or epidemic typhus, due to Rickettsia prowazekii, and flea-
http://www.nice.org.uk/nicemedia/pdf/cg033guideline.pdf (ac- caused respectively by Salmonella typhi and S. paratyphi borne or murine typhus, due to the closely related R. typhi
cessed 19/08/08) A, B, or C, Gram-negative bacteria belonging to the En-
17. WHO. TB/HIV. A clinical manual. 2nd ed. Geneva: WHO, 2004. (R. mooseri), have occurred worldwide. Scrub typhus is
Ava ila bl e a t: http://whqlibdoc .w h o. int/pu b lic a t io n s/ terobacteriaceae family. They are sometimes termed col- due to Orientia tsutsugamushi (R. tsutsugamushi), trans-
2004/9241546344.pdf (accessed 02/03/06) lectively ‘enteric fever’ but, although initial infection is in- mitted by mites, and occurs mainly in Asia, Australia, and
18. CDC. Treating opportunistic infections among HIV-exposed testinal, dissemination in the blood leads to more the Pacific Islands.
and infected children: recommendations from CDC, the Nation-
al Institutes of Health, and the Infectious Diseases Society of widespread systemic effects. Typhoid and paratyphoid are A tetracycline, often doxycycline, or chloramphenicol is
America. MMWR 2004; 53 (RR-14): 1–92. Also available at: endemic in many countries and, in most, typhoid is more the treatment of choice for these infections although
http://www.cdc.gov/mmwr/PDF/RR/RR5314.pdf (accessed common. Most cases occurring in the UK are contracted
02/03/06) strains of O. tsutsugamushi resistant to doxycycline and
19. CDC. Treating opportunistic infections among HIV-infected
abroad. chloramphenicol have been reported in Thailand.1,2 Cipro-
adults and adolescents: recommendations from CDC, the Na- Treatment of typhoid fever has traditionally been with floxacin may be an effective alternative,3 and rifampicin
tional Institutes of Health, and the HIV Medicine Associa- chloramphenicol or alternatively amoxicillin, ampicillin,
tion/Infectious Diseases Society of America. MMWR 2004; 53 has been shown to be more effective against scrub typhus
(RR-15): 1–112. Also available at: http://www.cdc.gov/ or co-trimoxazole.1 However, there has been a spread of than doxycycline.4 Azithromycin is also effective.5 Prophy-
mmwr/PDF/RR/RR5315.pdf (accessed 02/03/06) strains of S. typhi resistant to chloramphenicol, ampicillin, laxis for scrub typhus with doxycycline has shown prom-
20. CDC. Managing Drug Interactions in the Treatment of HIV-Re- amoxicillin, trimethoprim, and co-trimoxazole,2,3 espe- ise when started before exposure to infection.6
lated Tuberculosis (issued December 2007). Available at: http://
www.cdc.gov/tb/TB_HIV_Drugs/PDF/tbhiv.pdf (accessed cially in the Indian subcontinent, in the Middle East, and in 1. Watt G, et al. Scrub typhus infections poorly responsive to anti-
29/07/08) South and South-East Asia. Current recommendations biotics in northern Thailand. Lancet 1996; 348: 86–9.
 Antibacterials 199
2. Panpanich R, Garner P. Antibiotics for treating scrub typhus. been significant bacteriuria with 105 or more colony form- 8. Nicolle LE. Urinary tract infection: traditional pharmacologic
Available in The Cochrane Database of Systematic Reviews; Is- therapies. Am J Med 2002; 113 (suppl 1A): 35S–44S.
sue 3. Chichester: John Wiley; 2002 (accessed 16/05/05).
ing units/mL of a midstream urine specimen; some also 9. Nicolle L. Best pharmacological practice: urinary tract infec-
3. Eaton M, et al. Ciprofloxacin treatment of typhus. JAMA 1989; consider lower counts to be indicative of infection. Most tions. Expert Opin Pharmacother 2003; 4: 693–704.
262: 772–3. urinary-tract infections are isolated uncomplicated infec- 10. Geerlings SE, et al. Optimaliseren van het antibioticabeleid in
4. Watt G, et al. Doxycycline and rifampicin for mild scrub-typhus Nederland X: SWAB-richtlijn voor antimicrobiële therapie bij
infections in northern Thailand: a randomised trial. Lancet 2000;
tions of the lower urinary tract. Recurrent infections may gecompliceerde urineweginfecties. Ned Tijdschr Geneeskd
356: 1057–61. be due to relapse, or more often, re-infection, and are more 2006; 150: 2370–6.
5. Kim Y-S, et al. A comparative trial of a single dose of azithro- serious. Patients with complicated urinary-tract infections 11. Pohl A. Modes of administration of antibiotics for symptomatic
mycin versus doxycycline for the treatment of mild scrub typhus. severe urinary tract infections. Available in The Cochrane Data-
associated with urinary-tract abnormalities or diseases base of Systematic Reviews; Issue 4. Chichester: John Wiley;
Clin Infect Dis 2004; 39: 1329–35.
6. Twartz JC, et al. Doxycycline prophylaxis for human scrub ty- such as diabetes mellitus may be at risk of kidney damage. 2007 (accessed 07/08/08).
12. Nicolle LE. Short-term therapy for urinary tract infection: suc-
phus. J Infect Dis 1982; 146: 811–18. Infections of the lower urinary tract in women generally cess and failure. Int J Antimicrob Agents 2008; 31 (suppl 1):
present as cystitis (inflammation of the bladder) and symp- S40–S45.
toms include dysuria, frequency, and urgency together 13. Nicolle LE. Uncomplicated urinary tract infection in adults in-
Urethritis cluding uncomplicated pyelonephritis. Urol Clin North Am
Urethritis or urethral inflammation can result from infec- with pyuria and significant bacteriuria; the urethral syn- 2008; 35: 1–12.
tious or noninfectious conditions. Infectious urethritis is a drome is similar, but there is no significant bacteriuria. In 14. Norris DL, Young JD. Urinary tract infections: diagnosis and
the upper urinary tract, acute pyelonephritis may occur as management in the emergency department. Emerg Med Clin
sexually transmitted disease seen most frequently in men. North Am 2008; 26: 413–30.
The most common causes are Neisseria gonorrhoeae and a complication of cystitis or, more rarely, may result from
Chlamydia trachomatis (termed nongonococcal urethritis septicaemia. Asymptomatic bacteriuria may progress to Catheter-related. References to catheter-related uri-
or non-specific urethritis). Other organisms implicated acute pyelonephritis in pregnant women and should there- nary-tract infections and their management.
have included Mycoplasma genitalium and Ureaplasma fore be treated. 1. Tambyah PA, Maki DG. The relationship between pyuria and in-
fection in patients with indwelling urinary catheters: a prospec-
urealyticum. Gonococcal and chlamydial infections fre- Urinary-tract infections in men are less common and are tive study of 761 patients. Arch Intern Med 2000; 160: 673–7.
quently occur together and if a specific clinical diagnosis often associated with abnormalities of the genito-urinary 2. Tambyah PA, Maki DG. Catheter-associated urinary tract infec-
cannot be made treatment for both infections should be tract such as prostatic hyperplasia. Acute bacterial prosta- tion is rarely symptomatic: a prospective study of 1497 catheter-
ized patients. Arch Intern Med 2000; 160: 678–82.
given together otherwise postgonococcal urethritis due to titis is usually caused by organisms similar to those re-
C. trachomatis may follow the cure of gonorrhoea. For the sponsible for cystitis in women. Chronic bacterial prosta- The elderly. References to urinary-tract infections in the
treatment of gonococcal urethritis see Gonorrhoea (p.191). titis is difficult to treat; the antibacterials used must be able elderly and their management.
For general management of chlamydial infections see to penetrate into the prostatic fluid. For other genito-uri- 1. Abrutyn E, et al. Does asymptomatic bacteriuria predict mortal-
p.166. nary infections in men, see under Epididymitis, p.170, and ity and does antimicrobial treatment reduce mortality in elderly
ambulatory women? Ann Intern Med 1994; 120: 827–33. Cor-
Guidelines produced by WHO,1 by an expert group in the under Urethritis, above. rection. ibid.; 121: 901.
UK,2 and by the CDC in the USA3 for the treatment of In preschool children, especially girls, asymptomatic bac- 2. Nicolle LE. Urinary tract infection in the elderly. J Antimicrob
urethritis are as follows: teriuria together with vesicoureteric reflux can result in re- Chemother 1994; 33 (suppl A): 99–109.
3. Ouslander JG, et al. Does eradicating bacteriuria affect the sever-
• WHO: for chlamydial urethritis: nal scarring and should be treated; the use of prophylactic ity of chronic urinary incontinence in nursing home residents?
• oral doxycycline 100 mg twice daily for 7 days, or antibacterials is complex and controversial. Long-term Ann Intern Med 1995; 122: 749–54.
follow-up of girls who have had asymptomatic bacteriuria 4. Abrutyn E, et al. Does treatment of asymptomatic bacteriuria in
• a single oral dose of azithromycin 1 g
older ambulatory women reduce subsequent symptoms of uri-
alternative regimens for 7 days, are: suggests that new kidney damage does not occur after 4 nary tract infection? J Am Geriatr Soc 1996; 44: 293–5.
• oral amoxicillin 500 mg three times daily years of age, but highlights the importance of diagnosis 5. Shortliffe LMD, McCue JD. Urinary tract infection at the age
• oral erythromycin 500 mg four times daily and treatment in younger children. extremes: pediatrics and geriatrics. Am J Med 2002; 113 (suppl
1A): 55S–66S.
• oral ofloxacin 300 mg twice daily The significance of asymptomatic bacteriuria in old age is 6. Lutters M, Vogt-Ferrier NB. Antibiotic duration for treating un-
• oral tetracycline 500 mg four times daily disputed, but most consider treatment to be unnecessary. complicated, symptomatic lower urinary tract infections in eld-
erly women. Available in The Cochrane Database of Systematic
Unless it can be excluded, patients should also be treated Infections associated with indwelling bladder catheters Reviews; Issue 3. Chichester: John Wiley; 2008 (accessed
concurrently for gonorrhoea (p.191) occur in both men and women and probably account for 19/08/08).
• UK: for nongonococcal urethritis: the majority of hospital-acquired urinary-tract infections.
Infants and children. References to urinary-tract infec-
• a single oral dose of azithromycin 1 g, or Treatment. Antibacterials used to treat urinary-tract infec- tions in infants and children, and their management.
• oral doxycycline 100 mg twice daily for 7 days tions need to be excreted in adequate concentrations in the 1. Anonymous. The management of urinary tract infection in chil-
alternative regimens are: urine. For acute uncomplicated infections oral amoxicillin, dren. Drug Ther Bull 1997; 35: 65–9.
• oral erythromycin 500 mg twice daily for 14 days ampicillin, co-trimoxazole, nalidixic acid, nitrofurantoin, 2. Williams G, et al. Antibiotics for the prevention of urinary tract
infection in children: a systematic review of randomized con-
• oral ofloxacin 400 mg daily in one single or two divided dos- or trimethoprim (preferred to co-trimoxazole in the UK) trolled trials. J Pediatr 2001; 138: 868–74.
es for 7 days have been given, although the choice will depend on local 3. Tran D, et al. Short-course versus conventional length antimi-
Persistent or recurrent nongonococcal urethritis should patterns of bacterial resistance; E. coli resistant to ampicil- crobial therapy for uncomplicated lower urinary tract infections
in children: a meta-analysis of 1279 patients. J Pediatr 2001;
be treated with: lin and amoxicillin is widespread. Alternatives when re- 139: 93–9.
• oral azithromycin 500 mg to start then 250 mg daily for 4 sistance is prevalent include amoxicillin with clavulanic 4. Shortliffe LMD, McCue JD. Urinary tract infection at the age
days plus oral metronidazole 400 mg twice daily for 5 days acid, oral cephalosporins, fluoroquinolones, or fosfomy- extremes: pediatrics and geriatrics. Am J Med 2002; 113 (suppl
1A): 55S–66S.
• oral erythromycin 500 mg four times daily for 21 days plus cin. In pregnant women, nitrofurantoin or a beta lactam 5. Michael M, et al. Short versus standard duration oral antibiotic
oral metronidazole 400 mg twice daily for 5 days can be used. Standard treatment schedules have been for 5 therapy for acute urinary tract infection in children. Available in
• oral moxifloxacin 400 mg once daily for 10 days to 7 days; 3-day or single-dose regimens can also be effec- The Cochrane Database of Systematic Reviews; Issue 1. Chich-
• USA: nongonococcal urethritis: ester: John Wiley; 2003 (accessed 16/05/05).
tive and may be preferred in women. Single-dose treat- 6. Williams GJ, et al. Long-term antibiotics for preventing recur-
• as for the UK ment may be associated with reduced efficacy compared rent urinary tract infection in children. Available in The Co-
alternative regimens for 7 days, are: with 3-day regimens. Urinary alkalinising agents such as chrane Database of Systematic Reviews; Issue 3. Chichester:
John Wiley; 2006 (accessed 07/08/08).
• oral erythromycin 500 mg four times daily potassium citrate and sodium citrate have been given by 7. Hodson EM, et al. Antibiotics for acute pyelonephritis in chil-
• oral erythromycin ethylsuccinate 800 mg four times daily mouth to relieve the pain of cystitis caused by lower uri- dren. Available in The Cochrane Database of Systematic Re-
• oral ofloxacin 300 mg twice daily nary-tract infections. Recurrent infections may require views; Issue 4. Chichester: John Wiley; 2007 (accessed
19/08/08).
• oral levofloxacin 500 mg once daily long-term low-dose antibacterial prophylaxis. 8. Beetz R, et al. Harnwegsinfektionen im Säuglings- und Kinde-
Persistent or recurrent nongonococcal urethritis should Acute pyelonephritis may require broad-spectrum salter: Konsensusempfehlungen zu Diagnostik, Therapie und
Prophylaxe. Urologe A 2007; 46: 112–23.
be treated with: parenteral treatment initially with, for example, aztreon- 9. Wolff O, Maclennan C. Evidence behind the WHO guidelines:
• a single oral dose of either metronidazole 2 g or tinidazole am, ceftazidime, cefuroxime, ciprofloxacin, or gen- hospital care for children: what is the appropriate empiric anti-
2 g plus oral azithromycin 1 g (if it was not used in the initial tamicin. biotic therapy in uncomplicated urinary tract infections in chil-
treatment regimen) dren in developing countries? J Trop Pediatr 2007; 53: 150–2.
Chronic bacterial prostatitis may require treatment for 10. Agence française de sécurité sanitaire des produits de santé. Di-
Sexual partners of patients with urethritis should be tested several weeks with trimethoprim, erythromycin, or a fluo- agnostic et antibiothérapie des infections urinaires bactériennes
and treated.2,3 roquinolone.
communautaires du nourrisson et de l’enfant. Med Mal Infect
1. WHO. Guidelines for the management of sexually transmitted 2007; 37: 645–63.
Catheter-related bladder infections may sometimes re- 11. Ochoa Sangrador C, Málaga Guerrero S. Recomendaciones de
in f e c tio ns . G e ne va : W HO , 20 03 . A l s o a v a i la b le a t : la Conferencia de Consenso "Manejo Diagnóstico y Terapéutico
http://whqlibdoc.who.int/publications/2003/9241546263.pdf spond to localised treatment with bladder washouts con- de las Infecciones del Tracto Urinario en la Infancia". An Pedi-
(accessed 23/03/07) taining chlorhexidine. atr (Barc) 2007; 67: 517–25.
2. Clinical Effectiveness Group (British Association for Sexual 12. Sedberry-Ross S, Pohl HG. Urinary tract infections in children.
Health and HIV - BASHH). National guideline on the manage- General references. Curr Urol Rep 2008; 9: 165–71.
ment of non-gonococcal urethritis (2007). Available at: 1. Kunin CM. Chemoprophylaxis and suppressive therapy in the
http://www.bashh.org/documents/89/89.pdf (accessed 19/08/08) management of urinary tract infections. J Antimicrob Chemoth- Men. References to urinary-tract infections in men and
3. CDC. Sexually transmitted diseases treatment guidelines 2006. er 1994; 33 (suppl A): 51–62.
MMWR 2006; 55(RR-11): 1–94. Also available at: http://
their management.
2. Reeves DS. A perspective on the safety of antibacterials used to 1. Lipsky BA. Prostatitis and urinary tract infection in men: what’s
www.cdc.gov/mmwr/PDF/rr/rr5511.pdf (accessed 23/03/07) treat urinary tract infections. J Antimicrob Chemother 1994; 33 new; what’s true? Am J Med 1999; 106: 327–34.
(suppl A): 111–20.
2. Joly-Guillou M-L, Lasry S. Practical recommendations for the
3. Brumfitt W, Hamilton-Miller JMT. Consensus viewpoint on drug treatment of bacterial infections of the male genital tract
Urinary-tract infections management of urinary infections. J Antimicrob Chemother
including urethritis, epididymitis and prostatitis. Drugs 1999;
Infections of the urinary tract are especially common in 1994; 33 (suppl A): 147–53.
57: 743–50.
women. They are frequently due to enteric bacteria, in par- 4. Maskell R. Management of recurrent urinary tract infections in
adults. Prescribers’ J 1995; 35: 1–11. 3. Ulleryd P. Febrile urinary tract infection in men. Int J Antimicrob
ticular Escherichia coli, although a common cause in Agents 2003; 22 (suppl 2): 89–93.
5. Ronald A, Sanche SE. Antimicrobial management of urinary
young women is Staphylococcus saprophyticus, a coagu- tract infections. Curr Opin Infect Dis 1995; 8: 420–3. Pregnancy. References to urinary-tract infections in
lase-negative staphylococcus. Other urinary pathogens in- 6. Nicolle LE. A practical guide to the management of complicat-
ed urinary tract infection. Drugs 1997; 53: 583–92. pregnancy and their management.
clude Staph. epidermidis, enterococci, and Pseudomonas 7. Preston SL, et al. Empiric treatment of uncomplicated urinary 1. Maclean AB. Urinary tract infection in pregnancy. Int J Antimi-
spp. An arbitrary definition of urinary-tract infection has tract infections. Ann Pharmacother 1998; 32: 1231–3. crob Agents 2001; 17: 273–6.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
200 Antibacterials
2. Krcmery S, et al. Treatment of lower urinary tract infection in Acediasulfone Sodium (rINN) soluble in water; practically insoluble in alcohol and in acetone;
pregnancy. Int J Antimicrob Agents 2001; 17: 279–82. slightly soluble in methyl alcohol. A 1% solution in water has a
3. Wing DA. Pyelonephritis in pregnancy: treatment options for op- Acediasulfona sódica; Acédiasulfone Sodique; Acediasulfonnatri-
um; Acediasulfonum Natricum; Asediasulfoninatrium; Sodium pH of 9.5 to 11.5.
timal outcomes. Drugs 2001; 61: 2087–96.
USP 31 (Amikacin). A white crystalline powder. Sparingly sol-
4. Smaill F. Antibiotics for asymptomatic bacteriuria in pregnancy. Diaphenylsulphonacetate. N-p-Sulphanilylphenylglycine sodium.
Available in The Cochrane Database of Systematic Reviews; Is- uble in water. pH of a 1% solution in water is between 9.5 and
sue 2. Chichester: John Wiley; 2001 (accessed 16/05/05).
Ацедиасульфон Натрий 11.5. Store in airtight containers.
5. Mittal P, Wing DA. Urinary tract infections in pregnancy. Clin C 14 H 13N 2 NaO 4 S = 328.3.
Perinatol 2005; 32: 749–64. C AS — 127-60-6. Amikacin Sulfate (USAN, rINNM)
6. Macejko AM, Schaeffer AJ. Asymptomatic bacteriuria and
symptomatic urinary tract infections during pregnancy. Urol Amikacin Sulphate (BANM); Amikacin-disulfát; Amikacine, sulfate
Clin North Am 2007; 34: 35–42. O O d’; Amikacini Disulfas; Amikacini sulfas; Amikacino sulfatas; Ami-
7. Smaill F, Vazquez JC. Antibiotics for asymptomatic bacteriuria kacinsulfat; Amikacin-szulfát; Amikacyny siarczan; Amikasiinisul-
in pregnancy. Available in The Cochrane Database of Systematic S
faatti; Amikasin Sülfat; BB-K8; Sulfato de amikacina.
Reviews; Issue 2. Chichester: John Wiley; 2007 (accessed
07/08/08). Амикацина Сульфат
O C 22 H 43N 5 O 13 ,2H 2 SO 4 = 781.8.
Women. References to urinary-tract infections in wom- H 2N N Na C AS — 39831-55-5.
en and their management. H ATC — D06AX12; J01GB06; S01AA21.
O
1. Warren JW, et al. Guidelines for antimicrobial treatment of un- ATC Vet — QD06AX12; QJ01GB06; QS01AA21.
complicated acute bacterial cystitis and acute pyelonephritis in Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US.
women. Clin Infect Dis 1999; 29: 745–58. Profile
Acediasulfone sodium is reported to have antibacterial properties Ph. Eur. 6.2 (Amikacin Sulphate). A white or almost white pow-
2. Hooton TM. Recurrent urinary tract infection in women. Int J
Antimicrob Agents 2001; 17: 259–68. and is an ingredient of preparations used topically in the treat- der. It loses not more than 13.0% of its weight on drying. Freely
3. Fihn SD. Acute uncomplicated urinary tract infection in women. ment of local infections of the ear. soluble in water; practically insoluble in alcohol and in acetone.
N Engl J Med 2003; 349: 259–66. The pH of a 1% solution in water is between 2.0 and 4.0. Store
Preparations in airtight containers.
4. Milo G, et al. Duration of antibacterial treatment for uncompli-
cated urinary tract infection in women. Available in The Co- Proprietary Preparations (details are given in Part 3) USP 31 (Amikacin Sulfate). Amikacin sulfate having a molar ra-
chrane Database of Systematic Reviews; Issue 2. Chichester: Multi-ingredient: Austria: Ciloprin cum Anaesthetico†; Fin.: Ciloprin tio of amikacin to H2SO4 of 1:2 contains the equivalent of not
John Wiley; 2005 (accessed 07/08/08). cum Anaesthetico†; India: Otogesic; Switz.: Ciloprin ca†. less than 674 micrograms and not more than 786 micrograms of
5. Nicolle L, et al. Uncomplicated urinary tract infection in women:
current practice and the effect of antibiotic resistance on empiric
amikacin per mg, calculated on the dried basis. Amikacin sulfate
treatment. Can Fam Physician 2006; 52: 612–8. having a molar ratio of amikacin to H2SO4 of 1:1.8 contains the
6. Foster RT. Uncomplicated urinary tract infections in women. Alatrofloxacin Mesilate (rINNM) equivalent of not less than 691 micrograms and not more than
Obstet Gynecol Clin North Am 2008; 35: 235–48. Alatrofloxacin Mesylate (USAN); Alatrofloxacine, Mésilate d’; Ala- 806 micrograms of amikacin per mg, calculated on the dried ba-
7. André M, Mölstad S. Nya riktlinjer för urinvägsinfektion hos
trofloxacini Mesilas; CP-116517-27; Mesilato de alatrofloxacino. sis.
kvinnor. Lakartidningen 2008; 105: 1107–9. A white crystalline powder. Freely soluble in water. pH of a 1%
7-{(1R,5S,6s)-6-[(S)-2-((S)-2-Aminopropionamido)propionami-
solution in water is between 2.0 and 4.0 (1:2 salt) and 6.0 to 7.3
do]-3-azabicyclo[3.1.0]hex-3-yl}-1-(2,4-difluorophenyl)-6-fluoro-
(1:1.8 salt). Store in airtight containers.
Whipple’s disease 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid mono-
Whipple’s disease is a rare chronic systemic condition as- methanesulphonate. Incompatibility. For discussion of the incompatibility of
sociated with infection with Tropheryma whippelii.1-4 It aminoglycosides, including amikacin, with beta lactams, see un-
Алатрофлоксацина Мезилат
was once considered to be a disease predominantly involv- der Gentamicin Sulfate, p.282. Amikacin is also reported to be
C 26 H 25F 3 N 6 O 5 ,CH 3 SO 3 H = 654.6. incompatible with various other drugs. However, reports are con-
ing the small intestine and resulting in malabsorption, but C AS — 157182-32-6 (alatrofloxacin); 157605-25-9 (ala-
tradictory in many cases, and other factors, such as the strength
may affect virtually all organs. There is probably CNS in- trofloxacin mesilate).
and composition of the vehicles used, may play a role.
volvement in all patients with Whipple’s disease, although
it may only be evident in 10 to 20%. Before the use of an- Stability. Solutions may darken from colourless to pale yellow
F but this does not indicate a loss of potency.
tibacterial therapy the disease was invariably fatal. The
treatment generally recommended is either benzylpenicil- O CH3 H
lin (sometimes given as procaine benzylpenicillin) and H Adverse Effects, Treatment, and Precau-
H2N N tions
streptomycin, or ceftriaxone, parenterally for two weeks, N F
followed by co-trimoxazole orally for at least one CH3 H O
As for Gentamicin Sulfate, p.282. Peak plasma con-
N N N
year.2,3,5,6 Such long-term treatment with co-trimoxazole, H centrations of amikacin greater than 30 to
a drug that crosses the blood-brain barrier, is advisable be- 35 micrograms/mL or trough concentrations greater
cause of the relatively high frequency and seriousness of F COOH than 5 to 10 micrograms/mL should be avoided. Ami-
CNS relapse. These relapses respond less well to antibac- O kacin affects auditory (cochlear) function to a greater
terial treatment; chloramphenicol has been used in those extent than gentamicin.
(alatrofloxacin)
not responding to the above regimen and a patient with
CNS relapse improved on ceftriaxone given intravenous- Effects on the eyes. A report of retinal damage after intravit-
Profile real injection of amikacin.1
ly.7 Further alternatives may be a tetracycline8 or cefixi-
Alatrofloxacin is a prodrug of the fluoroquinolone antibacterial 1. Jackson TL, Williamson TH. Amikacin retinal toxicity. Br J
me.6 A patient intolerant of co-trimoxazole was given phe- trovafloxacin (p.357) and has been used intravenously as the Ophthalmol 1999; 83: 1199–1200.
noxymethylpenicillin and probenecid after the initial 14- mesilate in the treatment of susceptible infections.
day course of benzylpenicillin and streptomycin.9 There Alatrofloxacin and trovafloxacin preparations were withdrawn Interactions
has also been a report of benefit in a penicillin-allergic pa- worldwide after reports of unpredictable severe hepatic adverse As for Gentamicin Sulfate, p.283.
tient treated with erythromycin.10 A combination of doxy- effects, including some fatalities.
cycline with hydroxychloroquine may be tried in patients Preparations Antimicrobial Action
without neurological involvement.3 Proprietary Preparations (details are given in Part 3) As for Gentamicin Sulfate, p.283. Amikacin is active
1. Relman DA, et al. Identification of the uncultured bacillus of Canad.: Trovan†; USA: Trovan†.
Whipple’s disease. N Engl J Med 1992; 327: 293–301. against a similar range of organisms although it is also
2. Marth T, Raoult D. Whipple’s disease. Lancet 2003; 361: reported to have some activity against Nocardia aster-
239–46.
3. Fenollar F, et al. Whipple’s disease. N Engl J Med 2007; 356:
oides, Mycobacterium tuberculosis, and some atypical
55–66. Amikacin (BAN, rINN) mycobacterial strains. Amikacin is not degraded by
4. Schneider T, et al. Whipple’s disease: new aspects of pathogen- many of the common enzymes often responsible for
esis and treatment. Lancet Infect Dis 2008; 8: 179–90. Amicacina; Amikacina; Amikacinas; Amikacine; Amikacinum;
5. Singer R. Diagnosis and treatment of Whipple’s disease. Drugs Amikacyna; Amikasiini. 6-O-(3-Amino-3-deoxy-α-D-glucopyran- acquired aminoglycoside resistance. In consequence,
1998; 55: 699–704. osyl)-4-O-(6-amino-6-deoxy-α-D-glucopyranosyl)-N1-[(2S)-4- cross-resistance with gentamicin and other aminogly-
6. Maiwald M, Relman DA. Whipple’s disease and Tropheryma amino-2-hydroxybutyryl]-2-deoxystreptamine.
whippelii: secrets slowly revealed. Clin Infect Dis 2001; 32: cosides is infrequent and amikacin may be effective
457–63. Амикацин against strains resistant to other aminoglycosides.
7. Adler CH, Galetta SL. Oculo-facial-skeletal myorhythmia in C 22 H 43N 5 O 13 = 585.6. However, resistant strains of Gram-negative bacteria
Whipple disease: treatment with ceftriaxone. Ann Intern Med C AS — 37517-28-5.
1990; 112: 467–9. and staphylococci have been reported, and it is gener-
ATC — D06AX12; J01GB06; S01AA21.
8. Abramowicz M, ed. The choice of antibacterial drugs. In: Hand- ally reserved for infections resistant to other aminogly-
book of antimicrobial therapy. 18th ed. New Rochelle NY: The ATC Vet — QD06AX12; QJ01GB06; QS01AA21.
Medical Letter, 2008: 72. cosides, although reports differ as to the extent and
9. Rickman LS, et al. Brief report: uveitis caused by Tropheryma speed of the development of amikacin resistance where
whippelii (Whipple’s bacillus). N Engl J Med 1995; 332: 363–6.
10. Bowles KM, et al. A 35-year-old with swollen knees who had
OH it has been widely used.
recurrent fever and pericarditis, then diarrhoea before getting NH2 O ◊ References.
better. Lancet 1996; 348: 1356. HO
H 2N 1. Ho YII, et al. In-vitro activities of aminoglycoside-aminocyclit-
O O ols against mycobacteria. J Antimicrob Chemother 1997; 40:
HO OH
HO 27–32.
Yaws O
NH2
See under Syphilis, p.192. OH HO N
O H Pharmacokinetics
H 2N OH
As for Gentamicin Sulfate, p.284.
Yersinia enteritis On intramuscular injection, peak plasma-amikacin
See p.174. Pharmacopoeias. In Chin., Eur. (see p.vii), Int., and US.
Ph. Eur. 6.2 (Amikacin). An antimicrobial substance obtained concentrations of about 20 micrograms/mL are
from kanamycin A. A white or almost white powder. Sparingly achieved 1 hour after a 500-mg dose, reducing to about
 Acediasulfone Sodium/Aminosalicylic Acid 201
2 micrograms/mL 10 hours after injection. A plasma A 0.25% solution has been instilled into body cavities Pharmacopoeias. In Chin., Eur. (see p.vii), and US.
concentration of 38 micrograms/mL has been reported in adults. Ph. Eur. 6.2 (Sodium Aminosalicylate Dihydrate). A slightly hy-
groscopic, white or almost white, crystalline powder, or white or
after the intravenous infusion of 500 mg over 30 min- A liposomal formulation of amikacin is under investi- almost white crystals. Freely soluble in water; sparingly soluble
utes, reducing to 18 micrograms/mL 1 hour later. Ami- gation. in alcohol, practically insoluble in dichloromethane. A 2% solu-
kacin has been detected in body tissues and fluids after Preparations tion in water has a pH of 6.5 to 8.5. Store in airtight containers.
injection; it crosses the placenta but does not readily BP 2008: Amikacin Injection;
Protect from light.
penetrate into the CSF, although substantial penetra- USP 31: Amikacin Sulfate Injection. USP 31 (Aminosalicylate Sodium). A white to cream-coloured,
practically odourless crystalline powder. Soluble 1 in 2 of water;
tion of the blood-brain barrier has been reported in chil- Proprietary Preparations (details are given in Part 3)
sparingly soluble in alcohol; very slightly soluble in chloroform
Arg.: Biklin; Greini; Riklinak; Austral.: Amikin; Austria: Biklin; Belg.:
dren with meningitis. Amukin; Braz.: Amicacil†; Amicalin†; Amicilon; Aminocina†; Bactomicin†; and in ether. Its solutions decompose slowly and darken in col-
A plasma half-life of about 2 to 3 hours has been re- Klebicil; Novamin; Canad.: Amikin†; Cz.: Amikin; Amikozit†; Miacin†; Fin.: our. Prepare solutions within 24 hours of use. Under no circum-
Biklin; Fr.: Amiklin†; Ger.: Biklin; Gr.: Amicagel†; Amicasil; Amikan; Biorisan; stances should a solution be used if its colour is darker than that
ported in patients with normal renal function. Most of Briklin; Cinegel; Durocin; Farcyclin; Flexelite; Fromentyl; Kancin-Gap; Lano-
mycin; Lifermycin; Likacin; Micalpha; Orlobin; Remikin; Rovericlin; Selaxa; of a freshly prepared solution. pH of a 2% solution in water is be-
a dose is excreted by glomerular filtration in the urine tween 6.5 and 8.5. Store in airtight containers at a temperature
Uzix; Hong Kong: Amikin; Apalin; Selemycin†; Hung.: Amikin; Likacin; In-
within 24 hours. dia: Amcin; Amicin; Amicip; Mikacin; Indon.: Alostil; Amikin; Mikasin; Irl.: not exceeding 40°. Protect from light.
Amikin; Israel: Amikin†; Ital.: Amicasil; Amik; Amikan; BB-K8; Chemacin;
◊ References. Dramigel; Likacin; Lukadin; Mediamik; Migracin; Mikan; Mikavir; Nekacin; Stability. Aqueous solutions of aminosalicylates are unstable
1. Vanhaeverbeek M, et al. Pharmacokinetics of once-daily ami- Pierami; Malaysia: Amikin†; Selemycin†; Mex.: Agnicin; Akacin; Amicina; and should be freshly prepared.
kacin in elderly patients. J Antimicrob Chemother 1993; 31: Amikafur; Amikalem; Amikasons; Amikavi; Amikayect; Amikin; Amiyec;
185–7. AMK; Baxi-K†; Beramikin; Biclin; Biokacin; Gamikal; Kafran; Kana; Karmikin; Solutions of sodium aminosalicylate in sorbitol or syrup degrad-
2. Gaillard J-L, et al. Cerebrospinal fluid penetration of amikacin Libamic; Lisobac; Mikazul; Oprad; Plokim; Sermicina; Yectamid; Neth.: ed more quickly to m-aminophenol than those in glycerol or pro-
in children with community-acquired bacterial meningitis. Anti- Amukin; NZ: Amikin; Philipp.: Amikacide; Amikin; Cidacid; Cinmik; Kamin; pylene glycol.1 Colour developed in all solutions but was not
microb Agents Chemother 1995; 39: 253–5. Kormakin; Nica; Pol.: Amikin; Biodacyna; Port.: Amic; Biclin; Kamina; Rus.:
Amikozit (Амикозит); Selemycin (Селемицин); S.Afr.: Amikin; Kacinth-A; found to be an accurate indicator of decomposition of sodium
3. Bressolle F, et al. Population pharmacokinetics of amikacin in Singapore: Amikin; Spain: Biclin; Kanbine; Swed.: Biklin; Switz.: Amikin; aminosalicylate as it reflected only oxidation of m-aminophenol.
critically ill patients. Antimicrob Agents Chemother 1996; 40: Thai.: Akacin; Akicin; Amikasol†; Amikin; Anbikin; Siamik; Tipkin; Tybikin;
1682–9. 1. Blake MI, et al. Effect of vehicle on the stability of sodium ami-
Turk.: Amiketem; Amiklin; Amikozit; Mikasin; UAE: Mikacin; UK: Amikin; nosalicylate in liquid dosage forms. Am J Hosp Pharm 1973; 30:
4. Canis F, et al. Pharmacokinetics and bronchial diffusion of sin- USA: Amikin; Venez.: Amikavax; Amikayect†; Behkacin; Biklin; Likacin.
gle daily dose amikacin in cystic fibrosis patients. J Antimicrob 441–3.
Chemother 1997; 39: 431–3. Adverse Effects and Treatment
5. Tod M, et al. Population pharmacokinetic study of amikacin ad- Aminosalicylic acid and its salts may cause the adverse effects of
ministered once or twice daily to febrile, severely neutropenic Aminosalicylic Acid salicylates (see Aspirin, p.20).
adults. Antimicrob Agents Chemother 1998; 42: 849–56.
6. Tréluyer JM, et al. Nonparametric population pharmacokinetic Acidum Aminosalicylicum; Aminosalicílico, ácido; 4-Aminosalicyl- Gastrointestinal effects are common and include nausea, vomit-
analysis of amikacin in neonates, infants, and children. Antimi- ic Acid; Aminosalicylsyra; Aminosalisyylihappo; Aminosalylum; ing, and diarrhoea; they may be reduced by giving doses with
crob Agents Chemother 2002; 46: 1381–7. Para-aminosalicylic Acid; PAS; Pasalicylum. 4-Amino-2-hydroxy- food or with an antacid but occasionally may be severe enough
benzoic acid. that therapy has to be withdrawn. Alteration of gastrointestinal
Uses and Administration Аминосалициловая Кислота function may lead to malabsorption of vitamin B12, folate, and
Amikacin is a semisynthetic aminoglycoside antibiotic C 7 H 7 NO 3 = 153.1. lipids.
derived from kanamycin and is used similarly to gen- C AS — 65-49-6. Hypersensitivity reactions have been reported in 5 to 10% of
tamicin (p.284) in the treatment of severe Gram-nega- ATC — J04AA01. adults, usually during the first few weeks of treatment, and in-
ATC Vet — QJ04AA01. clude fever, skin rashes; less commonly, arthralgia, lymphaden-
tive and other infections. It is given as the sulfate, and opathy, and hepatosplenomegaly may occur and, rarely, a syn-
is generally reserved for the treatment of severe infec- drome resembling infectious mononucleosis. Other adverse
tions caused by susceptible bacteria that are resistant to COOH effects which have been attributed to a hypersensitivity reaction
gentamicin and tobramycin. Amikacin has also been OH
to aminosalicylate include jaundice and encephalitis. Blood dis-
given with antimycobacterials in the treatment of non- orders reported include haemolytic anaemia in patients with
G6PD deficiency, agranulocytosis, eosinophilia, leucopenia, and
tuberculous mycobacterial infections (p.181). As with thrombocytopenia. Psychosis may occasionally occur. Pro-
gentamicin, amikacin may be used with penicillins and longed treatment may induce goitre and hypothyroidism. Crys-
with cephalosporins; the injections should be given at talluria may occur.
NH2
separate sites. Effects on the liver. Drug-induced hepatitis occurred in 0.32%
Doses of amikacin sulfate are expressed in terms of NOTE. Distinguish from 5-aminosalicylic acid (Mesalazine, of 7492 patients receiving antituberculous drugs; aminosalicylic
amikacin base; 1.3 g of amikacin sulfate is equivalent p.1745). acid was the most common cause.1
to about 1 g of amikacin. Adults and children may be Pharmacopoeias. In US. 1. Rossouw JE, Saunders SJ. Hepatic complications of antitubercu-
USP 31 (Aminosalicylic Acid). A white or practically white, lous therapy. Q J Med 1975; 44: 1–16.
given 15 mg/kg daily in equally divided doses every 8
bulky powder that darkens on exposure to light and air; it is Precautions
or 12 hours by intramuscular injection. In life-threaten- odourless or has a slight acetous odour. Slightly soluble in water Aminosalicylic acid and its salts should be used with great care
ing infections, the dose may be increased in adults up and in ether; soluble in alcohol; practically insoluble in benzene. in patients with hepatic or renal impairment and in patients with
to a maximum of 500 mg every 8 hours. A dose of Under no circumstances should a solution be used if its colour is gastric ulcer. They should be given with caution to patients with
7.5 mg/kg daily in two divided doses (equivalent to darker than that of a freshly prepared solution. pH of a saturated G6PD deficiency. The sodium salt should be used with caution
250 mg twice daily in adults) may be given for the solution in water is between 3.0 to 3.7. Store in airtight containers in patients with heart failure.
at a temperature not exceeding 30°. Protect from light. Aminosalicylates interfere with tests for glycosuria using copper
treatment of uncomplicated urinary-tract infections.
The same doses may be given by slow intravenous in- reagents and for urobilinogen using Ehrlich’s reagent.
Calcium Aminosalicylate
jection over 2 to 3 minutes, or by intravenous infusion. Breast feeding. Small amounts of aminosalicylic acid are
Aminosalicilato cálcico; Aminosalicylate calcium; Aminosalylcalci- present in breast milk. A maximum concentration of
In adults, 500 mg in 100 to 200 mL of diluent has been um; Aminosalylkalcium; Aminosalyylikalsium; Calcii Aminosalicy- 1.1 microgram/mL has been reported in the breast milk of a lac-
infused over 30 to 60 minutes; proportionately less las; Calcii Para-aminosalicylas; Calcium PAS; Kalciumaminosali- tating woman 3 hours after a 4-g dose of aminosalicylic acid.1
fluid should be given to children. cylat; Kalsiumaminosalisylaatti. Calcium 4-amino-2-hydroxyben- 1. Holdiness MR. Antituberculosis drugs and breast feeding. Arch
Neonates may be given 10 mg/kg as a loading dose, zoate trihydrate. Intern Med 1984; 144: 1888.
followed by 15 mg/kg daily in two divided doses. If Аминосалицилат Кальция Pregnancy. The use of aminosalicylic acid or its salts is not rec-
given by intravenous infusion, an infusion period of 1 (C 7 H 6 NO 3 ) 2 Ca,3H 2 O = 398.4. ommended in pregnant patients due to gastrointestinal intoler-
C AS — 133-15-3 (anhydrous calcium aminosalicylate). ance.1 In addition it has been noted that, a study published in
to 2 hours is recommended. It has been suggested that ATC — J04AA03. 1964 suggested that first-trimester exposure may be associated
doses may need to be adjusted in preterm neonates. ATC Vet — QJ04AA03. with congenital defects although other studies had not found sim-
Treatment should preferably not continue for longer Pharmacopoeias. Jpn includes the heptahydrate. ilar effects.2
than 7 to 10 days, and the total dose given to adults 1. Snider D. Pregnancy and tuberculosis. Chest 1984; 86: 10S–13S.
should not exceed 15 g. Peak plasma concentrations Sodium Aminosalicylate 2. Briggs GG, et al. Drugs in pregnancy and lactation. 7th ed. Phil-
adelphia: Lippincott Williams and Wilkins, 2005: 59.
greater than 30 to 35 micrograms/mL or trough plasma Aminosalicilato sódico; Aminosalicylan sodný dihydrát; Aminosal-
concentrations greater than 5 to 10 micrograms/mL icylate Sodium; Aminosalylnatrium; Monosodium 4-Aminosali- Interactions
cylate Dihydrate; Natrii Aminosalicylas; Natrii aminosalicylas di- The adverse effects of aminosalicylates and salicylates may be
should be avoided. Dosage should be adjusted in all pa- additive. Probenecid may also increase toxicity by delaying renal
hydricus; Natrii Paraaminosalicylas; Natrii Para-aminosalicylas;
tients according to plasma-amikacin concentrations, excretion and enhancing plasma concentrations of aminosali-
Natrio aminosalicilatas dihidratas; Natriumaminosalicylat; Natriu-
and this is particularly important where factors such as maminosalicylatdihydrat; Natriumaminosalisylaatti; Natriumami- cylate. The activity of aminosalicylic acid may be antagonised
age, renal impairment, or prolonged therapy may pre- by ester-type local anaesthetics such as procaine.
nosalisylaattidihydraatti; Pasalicylum Solubile; Sodium (aminosali-
dispose to toxicity, or where there is a risk of subthera- cylate de) dihydraté; Sodium Para-aminosalicylate; Sodium PAS; Antimicrobial Action
peutic concentrations. For discussion of the methods of Sodu aminosalicylan. Sodium 4-amino-2-hydroxybenzoate dihy- Aminosalicylic acid is bacteriostatic and is active against M. tu-
calculating aminoglycoside dosage requirements, see drate. berculosis. Other mycobacteria are usually resistant. It has a rel-
atively weak action compared with other antituberculous drugs.
Administration and Dosage, under Gentamicin, p.284. Аминосалицилат Натрия
Resistance develops quickly if aminosalicylic acid is used alone.
As with some other aminoglycosides, once-daily dos- C 7 H 6 NNaO 3 ,2H 2 O = 211.1.
age has been used successfully with amikacin without C AS — 133-10-8 (anhydrous sodium aminosalicylate); ◊ References.
6018-19-5 (sodium aminosalicylate dihydrate). 1. Rengarajan J, et al. The folate pathway is a target for resistance
increasing toxicity, but local guidelines should be con- ATC — J04AA02. to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol
sulted (see also Once-daily Dosage, p.285). ATC Vet — QJ04AA02. Microbiol 2004; 53: 275–82.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
202 Antibacterials
Pharmacokinetics mained well on prolonged follow-up. Other cases of benefit had Adverse Effects and Precautions
When given orally, aminosalicylic acid and its salts are readily been reported in the Chinese literature. As for Ampicillin, p.204.
absorbed, and peak plasma concentrations occur after about 1 to 1. Jiang Y-M, et al. Effective treatment of manganese-induced oc-
4 hours. cupational Parkinsonism with p-aminosalicylic acid: a case of The incidence of diarrhoea is less with amoxicillin than
Aminosalicylate diffuses widely through body tissues and fluids, 17-year follow-up study. J Occup Environ Med 2006; 48: 644–9. ampicillin.
although diffusion into the CSF occurs only if the meninges are Preparations Hepatitis and cholestatic jaundice have been reported
inflamed. About 15% of the sodium salt, and 50 to 70% of the USP 31: Aminosalicylate Sodium Tablets; Aminosalicylic Acid Tablets. with amoxicillin plus clavulanic acid; the clavulanic
acid, is bound to plasma proteins. acid component has been implicated. Erythema multi-
Proprietary Preparations (details are given in Part 3)
Aminosalicylate is metabolised in the intestine and liver prima- Canad.: Nemasol†; Chile: Aflogol; Cz.: Quadrasa†; Fr.: Quadrasa; Ger.: forme, Stevens-Johnson syndrome, toxic epidermal
rily by acetylation. Urinary excretion is rapid, and 80% or more Pas-Fatol N; Ital.: Quadrasa†; Salf-Pas; Port.: Paramino-Corazida; Rus.:
of a dose is excreted within 24 hours; 50% or more of the dose is Pask-Akri (Паск-Акри); Switz.: Perfusion de PAS†; Thai.: PAS Sodium; necrolysis, and exfoliative dermatitis have also been at-
excreted as the acetylated metabolite. The half-life of aminosali- Turk.: PAS; USA: Paser. tributed occasionally to the use of amoxicillin with cla-
cylic acid is about 1 hour. Multi-ingredient: India: Inapas. vulanic acid.
Aminosalicylate is distributed into breast milk (see under Pre- Breast feeding. Although amoxicillin is excreted in breast milk
cautions, above, for more details). in small amounts,1 the American Academy of Pediatrics consid-
Uses and Administration ers that it is usually compatible with breast feeding.2
Aminosalicylic acid and its salts are second-line antimycobacte-
Amoxicillin (BAN, rINN) 1. Kafetzis DA, et al. Passage of cephalosporins and amoxicillin
into the breast milk. Acta Paediatr Scand 1981; 70: 285–8.
rials given orally in the treatment of multidrug-resistant tubercu- Amoksisilin; Amoksisilliini; Amoxicilina; Amoxicilline; Amoxicilli- 2. American Academy of Pediatrics. The transfer of drugs and oth-
losis (p.196). They should always be given with other antituber- num; Amoxycillin. (6R)-6-[α-D-(4-Hydroxyphenyl)glycylami- er chemicals into human milk. Pediatrics 2001; 108: 776–89.
culous drugs. no]penicillanic acid. Correction. ibid.; 1029. Also available at:
Aminosalicylic acid may be given as the acid or as the sodium http://aappolicy. aap publicatio n s . org/cg i / c o nt e n t /f ul l /
Амоксициллин pediatrics%3b108/3/776 (accessed 24/05/04)
salt. Sodium aminosalicylate 1.38 g is equivalent to about 1 g of
aminosalicylic acid. However, a usual daily oral dose is 12 g in 3 C 16 H 19N 3 O 5 S = 365.4. Effects on the liver. Hepatitis and cholestatic jaundice associ-
divided doses and has been recommended for products contain- C AS — 26787-78-0. ated with the combination amoxicillin with clavulanic acid (co-
ing the acid as well as for those containing the sodium salt. ATC — J01C A04. amoxiclav) have been reported1-4 and by 1993 the UK CSM had
received 138 reports of hepatobiliary disorders, 3 of which were
For details of doses in infants, children, and adolescents, see be- ATC Vet — QG51AX01; QJ01C A04. fatal.5 It warned that, although usually reversible, the reaction of-
low.
ten occurred after stopping therapy with a delay of up to 6 weeks.
Aminosalicylate sodium is also given rectally in the treatment of It appeared that the clavulanic acid was probably responsible.
ulcerative colitis in a usual dose of 2 g once daily. HO Retrospective analysis of cases reported in Australia6 and a co-
Attempts have been made in formulation to overcome the bulk O hort study in the UK7 found increasing age and prolonged treat-
H H
and exceedingly unpleasant taste of the aminosalicylates. The ment to be major risk factors for jaundice after co-amoxiclav;
salts appear to be better tolerated than the free acid and solutions S male sex is also a risk factor. By 1997 the CSM considered that
N CH3
in iced water prepared immediately before use may be less un- H cholestatic jaundice occurred with a frequency of about 1 in 6000
pleasant to take. NH2 N CH3 adult patients and that the risk of acute liver injury was about 6
O times greater with co-amoxiclav than with amoxicillin alone.
Administration. A small study suggested that giving ami- COOH Therefore it recommended that co-amoxiclav should be reserved
nosalicylic acid in a dose of 4 g twice daily produced adequate for bacterial infections likely to be caused by amoxicillin-resist-
serum concentrations (well in excess of 1 microgram/mL, a typ- ant strains, and that treatment should not usually exceed 14
ical MIC against Mycobacterium tuberculosis) for up to 12 hours days.8
after each dose.1 The drug was taken with an acidic beverage Amoxicillin Sodium (BANM, USAN, rINNM)
1. Stricker BHC, et al. Cholestatic hepatitis due to antibacterial
such as fruit juice to prevent early release in the stomach. A sin- Amoksicilino natrio druska; Amoksisilin Sodyum; Amoksisilliini- combination of amoxicillin and clavulanic acid (Augmentin).
gle 4-g dose was not sufficient to maintain serum concentrations natrium; Amoksycylina sodowa; Amoxicilin sodná sůl; Amoxicili- Dig Dis Sci 1989; 34: 1576–80.
for the full 24-hour dosage interval. The authors had subsequent- na sódica; Amoxicilline sodique; Amoxicillinnatrium; Amoxicillin- 2. Wong FS, et al. Augmentin-induced jaundice. Med J Aust 1991;
ly changed their practice to use a twice-daily regimen for ami- 154: 698–701.
nátrium; Amoxicillinum natricum; Amoxycillin Sodium; BRL- 3. Larrey D, et al. Hepatitis associated with amoxycillin-clavulanic
nosalicylic acid in patients with multidrug-resistant tuberculosis. 2333AB-B; Natrii Amoxicillinum. acid combination report of 15 cases. Gut 1992; 33: 368–71.
1. Peloquin CA, et al. Once-daily and twice-daily dosing of p-ami- 4. Hebbard GS, et al. Augmentin-induced jaundice with a fatal out-
nosalicylic acid granules. Am J Respir Crit Care Med 1999; 159: Натрий Амоксициллин come. Med J Aust 1992; 156: 285–6.
932–4. C 16 H 18N 3 NaO 5 S = 387.4. 5. Committee on Safety of Medicines/Medicines Control Agency.
C AS — 34642-77-8. Cholestatic jaundice with co-amoxiclav. Current Problems
Administration in children. For the treatment of drug-resist- 1993; 19: 2. Also available at: http://www.mhra.gov.uk/home/
ant tuberculosis in infants, children, and adolescents the Ameri- ATC — J01C A04. idcplg?IdcService=GET_FILE&dDocName=CON2024454&
can Academy of Pediatrics (AAP) and WHO suggest an oral ATC Vet — QJ01C A04. RevisionSelectionMethod=LatestReleased (accessed 28/07/08)
dose of para-aminosalicylic acid 200 to 300 mg/kg 2 to 4 times 6. Thomson JA, et al. Risk factors for the development of amoxy-
Pharmacopoeias. In Chin. and Eur. (see p.vii). cillin-clavulanic acid associated jaundice. Med J Aust 1995; 162:
daily, to a maximum dose of 10 g daily. Ph. Eur. 6.2 (Amoxicillin Sodium). A white or almost white, very 638–40.
Administration in renal impairment. It has been recom- hygroscopic powder. Very soluble in water; sparingly soluble in 7. Rodríguez LAG, et al. Risk of acute liver injury associated with
mended that aminosalicylic acid should be avoided in patients dehydrated alcohol; very slightly soluble in acetone. A 10% so- the combination of amoxicillin and clavulanic acid. Arch Intern
lution in water has a pH of 8.0 to 10.0. Store in airtight contain- Med 1996; 156: 1327–32.
with renal impairment.1 An increase in plasma clearance of ami- 8. Committee on Safety of Medicines/Medicines Control Agency.
nosalicylic acid (attributed to increased hepatic metabolism) has ers. Revised indications for co-amoxiclav (Augmentin). Current
been noted in patients with renal impairment, hence attempting P ro b l e m s 1 9 9 7 ; 2 3 : 8 . A l s o a v a i l a b l e a t : h t t p : / /
to give aminosalicylate in reduced doses to such patients may Amoxicillin Trihydrate (BANM, rINNM) www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&
lead to subtherapeutic serum concentrations.2 dDocName=CON2023230&RevisionSelectionMethod=
Amoksicilinas trihidratas; Amoksisilin Trihidrat; Amoksisilliinitrihy- LatestReleased (accessed 11/07/06)
1. Appel GB, Neu HC. The nephrotoxicity of antimicrobial agents
(first of three parts). N Engl J Med 1977; 296: 663–70. draatti; Amoksycylina trójwodna; Amoxicilin trihydrát; Amoxicili- Effects on the teeth. A report of tooth discoloration in 3 chil-
2. Holdiness MR. Clinical pharmacokinetics of the antituberculosis na trihidrato; Amoxicillin (USAN); Amoxicilline trihydratée; Amox- dren associated with the use of amoxicillin with clavulanic acid.1
drugs. Clin Pharmacokinet 1984; 9: 511–44. icillin-trihidrát; Amoxicillintrihydrat; Amoxicillinum trihydricum; 1. Garcia-López M, et al. Amoxycillin-clavulanic acid-related
Amoxycillin Trihydrate; BRL-2333. tooth discoloration in children. Pediatrics 2001; 108: 819–20.
Inflammatory bowel disease. Together with corticosteroids,
derivatives of 5-aminosalicylic acid are one of the mainstays of Амоксициллин Тригидрат Sodium content. Each g of amoxicillin sodium contains about
the treatment of inflammatory bowel disease (p.1697). However, C 16 H 19N 3 O 5 S,3H 2 O = 419.4. 2.6 mmol of sodium.
aminosalicylic acid (4-aminosalicylic acid) has also been inves- C AS — 61336-70-7.
tigated, and beneficial results have been reported with both ATC — J01C A04. Interactions
enemas1-4 and oral dose forms5 in ulcerative colitis. Three pa- ATC Vet — QJ01C A04. As for Ampicillin, p.204.
tients who developed acute pancreatitis while taking mesalazine
(5-aminosalicylic acid) for inflammatory bowel disease, later tol- NOTE. Compounded preparations of amoxicillin may be repre- Antimicrobial Action
erated treatment with 4-aminosalicylic acid enemas.6 sented by the following names:
As for Ampicillin, p.204.
1. Campieri M, et al. 4-Aminosalicylic acid (4-ASA) and 5-ami- • Co-amoxiclav x/y (BAN)—amoxicillin (as the trihydrate or
nosalicylic acid (5-ASA) in topical treatment of ulcerative colitis the sodium salt) and potassium clavulanate; x and y are the Amoxicillin has been reported to be more active in vit-
patients. Gastroenterology 1984; 86: 1039. ro than ampicillin against Enterococcus faecalis, Heli-
strengths in milligrams of amoxicillin and clavulanic acid re-
2. Ginsberg AL, et al. Treatment of left-sided ulcerative colitis with spectively
4-aminosalicylic acid enemas: a double-blind, placebo-control- cobacter pylori, and Salmonella spp., but less active
led trial. Ann Intern Med 1988; 108: 195–9. • Co-amoxiclav (PEN)—amoxicillin trihydrate and potassium against Shigella spp.
3. Sharma MP, Duphare HV. 4-Aminosalicylic acid enemas for ul- clavulanate.
cerative colitis. Lancet 1989; i: 450.
Amoxicillin is inactivated by beta lactamases and com-
4. O’Donnell LJD, et al. Double blind, controlled trial of 4-ami- Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and plete cross-resistance has been reported between
nosalicylic acid and prednisolone enemas in distal ulcerative col- Viet. amoxicillin and ampicillin. The spectrum of activity of
itis. Gut 1992; 33: 947–9. Ph. Eur. 6.2 (Amoxicillin Trihydrate). A white or almost white,
5. Beeken W, et al. Controlled trial of 4-ASA in ulcerative colitis. crystalline powder. Slightly soluble in water; very slightly solu- amoxicillin may be extended by use with a beta-lacta-
Dig Dis Sci 1997; 42: 354–8. ble in alcohol; practically insoluble in fatty oils. It dissolves in di- mase inhibitor such as clavulanic acid (p.250). As well
6. Daniel F, et al. Tolerance of 4-aminosalicylic acid enemas in pa- lute acids and in dilute solutions of alkali hydroxides. A 0.2% so- as reversing resistance to amoxicillin in beta-lacta-
tients with inflammatory bowel disease and 5-aminosalicylic-in- lution in water has a pH of 3.5 to 5.5. Store in airtight containers.
duced acute pancreatitis. Inflamm Bowel Dis 2004; 10: 258–60. mase-producing strains of species otherwise sensitive,
USP 31 (Amoxicillin). A white, practically odourless crystalline clavulanic acid has also been reported to enhance the
Manganese toxicity. Intravenous aminosalicylic acid, given in powder. Slightly soluble in water and in methyl alcohol; insolu-
a course of 6 g daily for 4 days a week, for fifteen courses, pro- ble in carbon tetrachloride, in chloroform, and in benzene. pH of activity of amoxicillin against several species not gen-
duced significant benefit in a patient with parkinsonism induced a 0.2% solution in water is between 3.5 and 6.0. Store in airtight erally considered sensitive. These have included
by chronic occupational manganese exposure.1 The patient re- containers. Bacteroides, Legionella, and Nocardia spp., Haemo-
 Amoxicillin 203
philus influenzae, Moraxella catarrhalis (Branhamella less than 3 months old, the maximum dose should be na†; Amoxipen†; Amoxitan; Amplal†; Amplamox†; Ariproxina†; Bimoxin†;
Camoxin†; Duzimicin†; Farmoxil; Flemoxon†; Hiconcil; Hincomox; Ibamox-
catarrhalis), and Burkholderia pseudomallei (Pseu- 30 mg/kg daily in divided doses every 12 hours. il†; Licilon; Lifamox†; Moxiplus; Nemoxil†; Neo Moxicilin; Novacil†; Novo-
domonas pseudomallei). However, Ps. aeruginosa, Higher oral doses of amoxicillin, either as a single dose cilin; Novoxil†; Ocylin; Penvicilin†; Pharmox; Polibac†; Polimoxil; Probenil;
Prodoxil; Respicilin†; Trimox; Ultramox†; Uni Amox; Velamox; Canad.:
Serratia marcescens, and many other Gram-negative or in short courses, are used in some conditions. For Apo-Amoxi; Lin-Amox†; Novamoxin; Nu-Amoxi; Chile: Abiolex; Amobi-
bacteria remain resistant. Transferable resistance has example, a dose of 3 g repeated once after 8 hours may otic; Amoval; Amoval Duo; Amoxipenil; Moxilanic; Optamox; Cz.: Amo-
clen; Amogal†; Amoxihexal; Apo-Amoxi†; Duomox; Gonoform†; Gru-
been reported in H. pylori. be used for dental abscesses. A 3-g dose may be given namox†; InfectoMox†; Ospamox; Denm.: Flemoxin; Imacillin; Imadrax;
for uncomplicated acute urinary-tract infections, and Fin.: Amorion; Amoxin; Clamox†; Flemoxin†; Penalta†; Fr.: A-Gram; Amo-
dex; Bactox; Bristamox; Clamoxyl; Flemoxine†; Gramidil†; Hiconcil; Ger.:
Pharmacokinetics repeated once after 10 to 12 hours. Amagesan; Amc-Puren†; Amoxi; Amoxi-Diolan; Amoxi-Hefa; Amoxi-
Amoxicillin is resistant to inactivation by gastric acid. A high-dose regimen of 3 g twice daily may be used in Puren†; Amoxi-Tablinen; Amoxi-Wolff; Amoxibeta; Amoxidoc; Amoxihex-
al; Amoxillat†; Amoximerck; Amoxypen; Clamoxyl†; espa-moxin†; Flui-
It is more rapidly and more completely absorbed than patients with severe or recurrent infections of the respi- Amoxicillin; InfectoMox; Jutamox; Phamoxi†; Sigamopen†; Gr.: Amospes†;
ampicillin when given orally. Peak plasma-amoxicillin ratory tract. If necessary, children aged 3 to 10 years Amoxil; Aproxal; Flemoxin; Ospamox; Paradroxil†; Stevencillin; Triodanin†;
Hong Kong: Amolin; Amoxa†; Amoxapen; Apo-Amoxi; Aroxin; Betamox;
concentrations of about 5 micrograms/mL have been with otitis media may be given 750 mg twice daily for Edamox; Hamoxillin; Moxilen; Moxlin; Ospamox; Promox; Ranoxyl; Rei-
observed 1 to 2 hours after a dose of 250 mg, with de- 2 days. Amoxicillin has also been given as a single chamox; Unimox; Hung.: Clonamox; Duomox; Humamoxin†; Ospamox;
India: Amoxil; Amoxivan; Aristomox; Biomoxil; Damoxy†; Flemoxin; Gen-
tectable amounts present for up to 8 hours. Doubling dose of 3 g, with probenecid 1 g, in the treatment of mox; Hipen; Imox; Loxyn; Mokcan; Mox; Moxycarb; Novamox; Ronemox†;
the dose can double the concentration. The presence of uncomplicated gonorrhoea in areas where gonococci Symoxyl; Indon.: Abdimox; Aclam; Amobiotic; Amosine; Amoxil; Amoxil-
lin; Amoxsan; Arcamox; Bellacid; Bintamox; Bioxyllin; Corsamox; Danoxilin;
food in the stomach does not appear to diminish the remain sensitive. Dexymox; Erphamoxy; Ethimox; Farmoxyl; Ikamoxyl; Intermoxil; Kalmoxil-
total amount absorbed. lin; Kimoxil; Lapimox; Leomoxyl; Medimox; Medocyl; Mestamox; Mexylin;
For the prophylaxis of endocarditis in patients at risk, Mokbios; Moxlin; Moxtid; Nufamox; Opimox; Ospamox; Penmox; Primoxil;
Concentrations of amoxicillin after intramuscular in- amoxicillin 2 or 3 g is given about 1 hour before dental Pritamox; Robamox; Scannoxyl; Silamox; Solpenox; Supramox; Topcillin; Vi-
jection are similar to those achieved with oral doses. bramox; Wiamox; Widecillin; Xiltrop; Irl.: Amoxil; Clonamox; Galena-
procedures. mox†; Geramox; Oramox; Pinamox; Israel: Amoxi; Hiconcil†; Moxypen;
About 20% is bound to plasma proteins and plasma For the eradication of H. pylori, amoxicillin is given Moxyvit; Ital.: Alfamox; Amocrin†; Amoflux; Amosol; Amox; Amoxillin;
Amoxina; Bradimox; Dodemox†; Erremox†; Genimox†; Hydramox; Ib-
half-lives of 1 to 1.5 hours have been reported. The with either metronidazole or clarithromycin and a pro- iamox†; Isimoxin†; Majorpen†; Mopen; Moxiren; Neo-Ampiplus; Neotetra-
half-life may be prolonged in neonates, the elderly, and ton pump inhibitor; usual doses of amoxicillin are 0.75 nase; Oralmox; Pamocil; Progemox†; Sievert; Simoxil†; Simplamox†; Sinto-
pen; Velamox; Zimox; Jpn: Pasetocin; Malaysia: Beamoxy; Moxacil†;
patients with renal impairment; in severe renal impair- or 1 g twice daily or 500 mg three times daily. Moxilen; Moxipen†; Ospamox; Setmoxil†; Mex.: Acimox; Acroxil; Amecli-
ment the half-life may be 7 to 20 hours. Amoxicillin is An extended release formulation containing 775 mg of na; Amicil; Amobay; Amoxifur; Amoxil; Amoxinovag; Amoxisol; Amoxivet;
Ampliron; Amsaxilina; AMX†; Ardine†; Armoxin; Betabiot; Bimoxan; Biovi-
widely distributed at varying concentrations in body amoxicillin as the trihydrate is available in the USA for cam; Brenoxil; Dimopen; Doxamil; Examolin; Flemoxon; Gimalxina; Grunic-
tissues and fluids. It crosses the placenta; small the treatment of tonsillitis and pharyngitis due to Strep- ina; Hidramox; Limoxin; Lorexil M; Lumox; Micro Mox; Mocimed; Moxiclina;
Moxlin; Penamox; Penticlox; Polymox; Prodomix; Servamox; Servamox-F;
amounts are distributed into breast milk. Little amoxi- tococcus pyogenes in patients aged 12 years or older. It Solciclina; Vandix; Xalyn-Or; Xiprocan†; Neth.: Amoxi; Amoxilag; Clam-
cillin passes into the CSF unless the meninges are in- is given orally in a dose of 775 mg daily for 10 days. oxyl; Flemoxin; Norw.: Amoxillin; Imacillin; NZ: Alpha-Amoxi; Amoxil;
Apo-Amoxi; Flemoxin; Ibiamox; Ospamox; Philipp.: Amelox; Amoxil;
flamed. Amusa; Bactigent; Bradoxil; Cartrimox; Cilamox; Cilfam; Clearamox;
Amoxicillin is given by intramuscular or slow intrave- Daisamox; Eleomox; Essenmox; Gexcil; Globamox; Globapen; Himox;
Amoxicillin is metabolised to a limited extent to peni- nous injection in doses of 500 mg every 8 hours. In se- Kramollex; Lewixin; Littmox; Maelenoxyl; Medimoxil; Medvox; Megamox;
cilloic acid which is excreted in the urine. About 60% vere infections, 1 g of amoxicillin may be given every Montramox; Moxillin; Moxiped; Neomox; Novamox; Pediamox; Penbiosyn;
of an oral dose of amoxicillin is excreted unchanged in Promox; Roddexil; Sumoxil; Syncloxil; Telsimox; Teramoxyl; Termox; Trexil;
6 hours by slow intravenous injection over 3 to 4 min- Valmox; Vastamox; Vaxman; Westfimox; Yugoxil; Zerrsox; Zymoxyl; Pol.:
the urine in 6 hours by glomerular filtration and tubular utes or by infusion over 30 to 60 minutes. Children up Amotaks; Apo-Amoxi; Duomox; Grunamox†; Hiconcil; Novamox; Os-
secretion. Urinary concentrations above pamox; Port.: Amplamox; Bodisan†; Cipamox; Clamoxyl; Flemoxin; Mox-
to 10 years of age may be given 50 to 100 mg/kg daily adent; Moxipen†; Oraminax; Ospamox; Penamox†; Rus.: Amosin
300 micrograms/mL have been reported after a dose of by injection in divided doses. (Амосин); Flemoxin (Флемоксин); Hiconcil (Хиконцил); Ospamox
250 mg. Probenecid reduces renal excretion. Amoxi- (Оспамокс); S.Afr.: A-Lennon; Acucil; Amocillin; Amoxil; Amoxyfizz; Beta-
Doses may need to be reduced in moderate to severe mox; C-Mox; Ipcamox; Maxcil; Moxan; Moxypen; Penmox†; Promoxil; Ran-
cillin is removed by haemodialysis. High concentra- moxy; Spectramox; Xeracil; Zoxil; Singapore: Amoxa†; Amoxapen;
renal impairment (see below). Amoxicap; Amoxigran; Amoxil; Apo-Amoxi; Aroxin; Moxilen; Moxipen;
tions have been reported in bile; some may be excreted
in the faeces. Amoxicillin with clavulanic acid. Amoxicillin com- Ospamox; Unimox; Spain: Actimoxi†; Agerpen; Amitron; Amoflamisan;
Amoxaren; Amoxi Gobens; Amoxibacter; Amoximedical†; Apamox; Ar-
bined with clavulanic acid (co-amoxiclav) is given by dine; Blenox; Bolchipen†; Borbalan; Britamox; Brondix; Clamoxyl; Co
Amoxicillin with clavulanic acid. The pharmacokinet-
mouth in a ratio of amoxicillin (as the trihydrate) 2, 4, Amoxin; Dobriciclin; Edoxil†; Eupen; Flubiotic NF; Hosboral; Inexbron†;
ics of amoxicillin and clavulanic acid are broadly sim- Morgenxil†; Reloxyl†; Remisan; Salvapen; Tolodina†; Swed.: Amimox; Ima-
7, or 14 parts to 1 part of clavulanic acid (as the potas- cillin; Switz.: amoxi-basan†; Amoxi-Cophar†; Amoxi-Mepha; Amoximex;
ilar and neither appears to affect the other to any great
sium salt), or intravenously in a ratio of 5 parts of Antiotic†; Azilline; Clamoxyl; Escamox; Flemoxin†; Penimox†; Spectroxyl;
extent. Supramox†; Thai.: Acticillin†; Amacin; Amox; Amoxa; Amoxcillin; Amoxi;
amoxicillin (as the sodium salt) to 1 part of clavulanic Amoxil; Amoxy; Amoxylin; Asiamox; Coamox†; Ibiamox; Kamoxin; Kenya-
Uses and Administration acid (as the potassium salt). Doses of the combination, Mox†; Manmox; Meixil; Milamox; Moxapen; Moxcil; Moxcin; Moxilcap†;
Moxilin; Moximed; Moxipan†; Moxitab; Pondnoxcill; Pulmoxyl; Rancil; Ran-
Amoxicillin is the 4-hydroxy analogue of ampicillin calculated on amoxicillin content, are similar to those oxyl; Samox; Samoxin; Servamox; Sia-Mox; Sil-A-Mox†; TVMox; Unimox;
(p.205) and is used similarly in susceptible infections. for amoxicillin used alone. Turk.: Alfoxil; Amoksilav; Amoksilin; Amoksina; Amosin; Atoksilin; Demok-
sil; Largopen; Moksilin; Remoxil; Topramoxin; UAE: Julphamox; UK: Amix;
These include actinomycosis, anthrax, biliary-tract in- ◊ References. Amoram; Amoxident; Amoxil; Galenamox; Rimoxallin; USA: Amoxil; Dis-
1. Speller DCE, et al., eds. Clavulanate/β-lactam antibiotics: fur- perMox; Moxatag; Trimox; Venez.: Amitrexyl; Amofar; Amoxal; Amoxid-
fections, bronchitis, endocarditis (particularly for ther experience. J Antimicrob Chemother 1989; 24 (suppl B): uo; Amoxiga; Amoxilan; Amoxipen†; Amoxival; Amylin; Bactamox†; Fi-
prophylaxis), gastro-enteritis (including salmonella en- 1–226. bramox†; Flemoxon†; Ofamix†; Ospamox; Sentapen; Strimox; Sumopen;
2. Todd PA, Benfield P. Amoxicillin/clavulanic acid: an update of Trimoxal.
teritis, but not shigellosis), gonorrhoea, Lyme disease, its antibacterial activity, pharmacokinetic properties and thera-
mouth infections, otitis media, pneumonia, spleen dis- peutic use. Drugs 1990; 39: 264–307. Multi-ingredient: Arg.: Acemuk Biotic; Aclav; Albesine Biotic; Amixen
3. Easton J, et al. Amoxicillin/clavulanic acid: a review of its use Clavulanico; Amixen Plus; Amoclav; Amox-G Bronquial; Amoxi Plus; Amoxi
orders (pneumococcal infection prophylaxis), typhoid Respiratorio†; Amoxidal Respiratorio; Amoxidal Respiratorio Duo; Amox-
in the management of paediatric patients with acute otitis media.
and paratyphoid fever, and urinary-tract infections. Drugs 2003; 63: 311–40. igrand Bronquial; Amoxigrand Compuesto; Amoxipenil Bronquial; Amox-
itenk Plus; Amoxitenk Respiratorio†; Aseptobron Respiratorio; Bi Moxal; Bi
The beta-lactamase inhibitor clavulanic acid (p.250) 4. McCormack PL, Keating GM. Amoxicillin/clavulanic acid Moxal Duo; Bioclavid; Bioxilina Plus; Clavulox; Clavulox Duo; Cloximar Duo;
2000mg/125mg extended release (XR): a review of its use in the
widens amoxicillin’s antimicrobial spectrum and a treatment of respiratory tract infections in adults. Drugs 2005;
Darzitil Plus; Darzitil SB; Desinflam Biotic†; Dibional; Fluimucil Biotic†; Full-
cilina Plus†; Glifapen; Grinsil Clavulanico; Grinsil Respiratorio; Heliklar†;
combined preparation (co-amoxiclav) can be used 65: 121–36. Klonalmox; Lertus Biotic†; Muco Dosodos Biotic; No-Tos Biotic; Nobactam
when resistance to amoxicillin is prevalent, for exam- Administration in renal impairment. Doses of amoxicillin Bronquial; Oximar Respiratorio; Rodinac Biotic; Trexirol NF†; Trifamox
Bronquial; Trifamox Bronquial Duo; Trifamox IBL; Austral.: Augmentin;
ple in respiratory-tract infections due to Haemophilus should be reduced in patients with moderate to severe renal im- Ausclav†; Clamohexal; Clamoxyl; Clavulin; Curam; Klacid HP 7; Losec Hp 7;
influenzae or Moraxella catarrhalis (Branhamella ca- pairment according to creatinine clearance (CC): Nexium Hp; Pylorid-KA; Somac-MA; Austria: Amoclan; Amoxicillin comp;
• CC 10 to 30 mL/minute: 250 to 500 mg every 12 hours AmoxiClavulan; Amoxicomp; Amoxiplus; Amoxistad plus; Augmentin; Ben-
tarrhalis), in the empirical treatment of animal bites, or clav; Benomox; Betamoclav; Clavamox; Clavex; Clavolek; Clavoplus; Clavu-
• CC less than 10 mL/minute: 250 to 500 mg every 24 hours
in melioidosis. For details of these infections and their lanex; CombAmox; Curam; Helicocin; Helipac; Lanoclav; Lekamoxiclav;
• haemodialysis patients: 250 to 500 mg every 24 hours and an Oxyclav; Xiclav; Belg.: Amoclane; Augmentin; Clavucid; Co-Amoxi; Co-
treatment, see under Choice of Antibacterial, p.162. additional dose both during and after the dialysis session. Amoxilan†; Docamoclaf; Braz.: Anzopac†; Augmentin; Betaclav; Bronco-
Amoxicillin is also given as part of treatment regimens Amoxil†; Bronco-Polimoxil; Clav-Air†; Clavoxil†; Clavulin; Erradic; H-Bacter;
Preparations Helicocid Triplice†; Helicopac; Heliklar; Novamox; Omepramix; Policlavu-
to eradicate Helicobacter pylori infection in patients BP 2008: Amoxicillin Capsules; Amoxicillin Injection; Amoxicillin Oral Sus-
moxil; Pylorikit; Pyloripac; Pyloritrat; Sigma Clav; Sulbamox; Trifamox; Ca-
with peptic ulcer disease (p.1702). nad.: Apo-Amoxi Clav; Clavulin; Hp-Pac; Losec 1-2-3 A; Novo-Clavamox-
pension; Co-amoxiclav Injection; Co-amoxiclav Tablets; in; ratio-Aclavulanate; Chile: Ambilan; Ambilan Bid; Amolex; Augmentin;
USP 31: Amoxicillin and Clavulanate Potassium for Oral Suspension;
Administration and dosage. Amoxicillin is given oral- Amoxicillin and Clavulanate Potassium Tablets; Amoxicillin Capsules; Amox-
Augmentin Bid; Clavinex; Clavinex Duo; Clavoxilina Bid; Sulbamox; Cz.:
Amoksiklav; Augmentin; Augmentin-Duo; Betaklav; Curam; Enhancin; For-
ly as the trihydrate and by injection as the sodium salt. icillin for Oral Suspension; Amoxicillin Tablets; Amoxicillin Tablets for Oral cid; Klamoxin†; Megamox; Denm.: Bioclavid; Spektramox; Fin.: Amoxin
Suspension.
Doses are expressed in terms of the equivalent amount Comp; Augmentin; Bioclavid; Clapharin Comp; Clavurion; Clavuxal; Forcid;
Proprietary Preparations (details are given in Part 3) Helipak A; Helipak K; Losec Helira†; Spektramox†; Fr.: Augmentin; Ciblor;
of amoxicillin; 1.06 g of amoxicillin sodium and Arg.: Abiotyl†; Almorsan; Amixen; Amox-G; Amoxi; Amoxibiot; Amoxicili- Ger.: Abiclav; Amoclav; Amoxclav; Amoxi-Clavulan; Amoxi-saar plus;
1.15 g of amoxicillin trihydrate are each equivalent to na Duo†; Amoxicina; Amoxicler; Amoxidal; Amoxidal Duo; Amoxigrand; Amoxicillin comp; Amoxiclav; Amoxidura Plus; Amoxillat-Clav†; Amuclan†;
Amoxipenil; Amoxipoten; Amoxitenk; Amoxol; Antiamox; Antibiocilina†; Augmentan; Flanamox; ZacPac; Gr.: Augmentin; Bioclavid; Forcid; Frolicin;
about 1 g of amoxicillin. Antiobiocilina†; Apracur Biotic†; Ardine†; Atrival†; Biotamoxal; Bioxilina; Fugentin; Moxiclav; Tenervan; Hong Kong: Amoksiklav; Augmentin; Clam-
The usual oral dose is 250 to 500 mg every 8 hours, or Clofamox; Darzitil; Dunox; Fabamox; Flemoxon; Fullcilina; Fullcilina Duo†; ovid; Curam; Fleming; Moxiclav; Quali-Mentin; Hung.: Aktil; Amoclan†;
Grinsil; Grinsil Duo; Mixcilin; Moxitral; Nobactam; Optamox; Oximar; Plam- Amoclav; Augmentin; Augmentin-Duo; Augmentin-Extra; Clavumox†; Co-
500 to 875 mg every 12 hours. Children up to 10 years ox; Telmox; Trifamox; Trifamox Duo; Xalotina†; Austral.: Alphamox; Amo- Amoxi; Curam; Enhancin; Forcid; India: ABClox; Amclo†; Augmentin; Bi-
of age may be given 125 to 250 mg every 8 hours; for hexal; Amoxil; Bgramin; Cilamox; Fisamox; Ibiamox; Maxamox; Moxacin; cidal Plus; Biomoxil-LB; Boostim; Bromolin; Carbomox; Helipac; Hipenox;
Austria: Amoxal; Amoxihexal; Amoxilan; Amoxistad; Antibiostad; Clam- Imox-Clo; Imox-Clo LB; LMX; Moxycarb-DT†; Novaclav; Novaclox; Nova-
those under 40 kg, a dose of 20 to 40 mg/kg daily in oxyl; Eramox†; Ospamox; Supramox; Belg.: Amoxi†; Amoxypen; Bac- clox LB; Novamox AX; Novamox LB; Nuclav; Rapiclav†; Respimox; Supri-
divided doses every 8 hours, or 25 to 45 mg/kg daily in timed; Clamoxyl; Docamoxici; Flemoxin; Hiconcil; Moxaline†; Moxitop; No- mox; Symbiotik; Symoxyl-LB; Indon.: Amocomb; Ancla; Augmentin; Aus-
vabritine; Braz.: Amoflux†; Amox; Amoxadene; Amoxi-Ped; Amoxibron; pilic; Bellamox; Betaclav; Biditin; Capsinat; Clabat; Claneksi; Clavamox;
divided doses every 12 hours, may be used; in infants Amoxicap†; Amoxicom†; Amoxidil; Amoxifar; Amoxil; Amoximed; Amoxi- Comsikla; Danoclav; Daxet; Dexyclav; Improvox; Lansiclav; Nufaclav; Nuvo-

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
204 Antibacterials
clav; Prafamoc; Protamox; Surpas; Syneclav; Viaclav; Vulamox; Zumafen; Irl.: Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US. Precautions
Augmentin; Clavamel; Germentin; Pinaclav; Israel: Amoxiclav; Augmentin; Ph. Eur. 6.2 (Ampicillin Sodium). A white or almost white hy-
Clavamox; Ital.: Abba; Anival; Augmentin; Clavulin; Neoduplamox; Xi- As for Benzylpenicillin, p.214.
namod; Malaysia: Augmentin; Cavumox; Clamovid; Curam; Enhancin; groscopic powder. Freely soluble in water; sparingly soluble in
Klacid HP 7; Moxiclav; Vestaclav†; Mex.: Acarbixin; Acimox AC; Acimox- acetone; practically insoluble in liquid paraffin and in fatty oils. Ampicillin should be stopped if a skin rash occurs. It
Ex; Acroxil-C; Alvi-Tec; Ambrexin; Amobay CL; Amoxibron; Amoxiclav; A 10% solution in water has a pH of 8.0 to 10.0. Store in airtight should preferably not be given to patients with infec-
Amoxiclide; Apoclavox; Augmentin; Avuxilan; Biovicam Ex; Bolbamox†; containers. tious mononucleosis since they are especially suscepti-
Bromel; Bromixen; Bromoxil; Broxolim-AM†; Brumax; Cibronal; Clambusil;
Clamoxin; Clavant; Clavucyd; Clavulin; Clavuser; Enhancin; Esteclin Bac; Fer- USP 31 (Ampicillin Sodium). A white to off-white, odourless or ble to ampicillin-induced skin rashes; patients with
lex; Gimabrol; Gramaxin; Hidramox-M; Loexom FC; Loexom FS; Lumox- practically odourless, hygroscopic, crystalline powder. Very sol-
bron S; Maxint†; Megamox; Moxlin CLV; Mucovibrol Amoxi; Mucoxina; uble in water and in isotonic sodium chloride and glucose solu-
lymphatic leukaemia or possibly HIV infection may
Penamox M; Penbritin Ex; Pentibroxil; Pylopac; Ravotaf; Riclasip; Sekretovit tions. pH of a solution in water containing the equivalent of amp- also be at increased risk of developing skin rashes.
Amoxi; Septacin Amoxi; Sermoxol; Servamox CLV; Sinufin; Solcibrol; Toxol;
Trifamox IBL; Valclan; Vanmoxol; Neth.: Amoclan; Amuclan; Augmentin; icillin 1% is between 8.0 and 10.0. Store in airtight containers. Myasthenia gravis. The symptoms of a woman with myasthe-
Bioclavid; Forcid; PantoPAC; Norw.: Bremide†; NZ: Alpha-Amoxyclav;
Incompatibility. The incompatibility of ampicillin sodium and nia gravis were exacerbated when she was given ampicillin.1
Augmentin; Klacid HP 7†; Losec Hp 7; Synermox; Philipp.: Amoclav; Aug- 1. Argov Z, et al. Ampicillin may aggravate clinical and experi-
mentin; Augmex; Augurcin; Bactiv; Bactoclav; Bioclavid; Clamovid; Claneksi; aminoglycosides is well established. Incompatibilities have also mental myasthenia gravis. Arch Neurol 1986; 43: 255–6.
Claventin; Clavoxel; Clovimax; Enhancin; Exten; Klavic; Natravox; OAC Hp7; been reported with a wide range of other drugs, including other
Proxiclav; Sullivan; Suplentin; Valmocel; Xilanic; Pol.: Amoksiklav; Augmen- antibacterials, and appear to be more pronounced at higher con- Sodium content. Each g of ampicillin sodium contains about
tin; Curam; Forcid; Ramoclav; Taromentin; Port.: Amoclavam; Amplamox 2.7 mmol of sodium.
Plus; Augmentin; Betamox; Clavamox; Clavepen; Forcid; Noprilam; Penilan; centrations and in solutions also containing glucose.
Rus.: Amoclan (Амоклан); Amoksiklav (Амоксиклав); Augmentin
(Аугментин); Flemoclav (Флемоклав); Medoclav (Медоклав); Panklav Stability. The stability of solutions of ampicillin sodium is de- Interactions
(Панклав); Rapiclav (Рапиклав); Trifamox IBL (Трифамокс ИБЛ); S.Afr.: pendent on many factors including concentration, pH, tempera-
Adco-Amoclav; Augmaxcil; Augmentin; Bio-Amoksiclav; Clamentin; Clavu- ture, and the nature of the vehicle. Stability decreases in the pres- As for Benzylpenicillin, p.214.
mox; Co-Amoxyclav; Curam; Forcid; Hiconcil-NS; Losec 20 Triple†; Macro- ence of glucose, fructose, invert sugar, dextrans, hetastarch, Allopurinol. An increased frequency of skin rashes has been
pen; Megapen; Moxyclav†; Ranclav; Rolab-Amoclav; Suprapen; Singapore: sodium bicarbonate, and lactate. It is recommended that reconsti-
Amocla; Augmentin; Augmex†; Clamonex; Clamovid; Curam; Enhancin; Fu- reported in patients receiving ampicillin or amoxicillin, with al-
gentin; Moxiclav; Spain: Amo Resan†; Amoclave; Amoxi Gobens Mucolit- tuted solutions of ampicillin sodium for injection should be given lopurinol, compared with those receiving the antibacterial
ico; Amoxyplus; Ardine Bronquial†; Ardineclav; Augmentine; Bigpen†; within 24 hours of preparation, and should be stored at 2° to 8° alone,1 but this could not be confirmed in a subsequent study.2
Bronco Tonic; Burmicin; Clamoxyl Mucolitico; Clavepen; Clavucid; Clavu- but should not be frozen. Solutions for infusion are stable for var- 1. Jick H, Porter JB. Potentiation of ampicillin skin reactions by
mox; Duonasa; Edoxil Mucolitico†; Eupeclanic†; Eupen Bronquial; Inmu- ying periods and details are given in licensed product informa- allopurinol or hyperuricemia. J Clin Pharmacol 1981; 21:
pen†; Kelsopen; Pulmo Borbalan; Reloxyl Mucolitico†; Remisan Mucolitico;
Salvapen Mucolitico; Swed.: Bioclavid; Nexium Hp; Spektramox; Switz.: tion. 456–8.
Amicosol; Augmentin; Aziclav; Clavamox; clavu-basan†; Co-Amoxi; Co- 2. Hoigné R, et al. Occurrence of exanthems in relation to ami-
References. nopenicillin preparations and allopurinol. N Engl J Med 1987;
Amoxicilline; Thai.: Amocla; Amoksiklav; Augclav; Augmentin; Augpen; Ca-
vumox; Curam; Klamoks; Moxiclav; Moxicle; Pencla; Ranclav; Turk.: Amok- 1. Lynn B. The stability and administration of intravenous penicil- 316: 1217.
lavin; Augmentin; Bioment; Croxilex; Helipak; Klamoks; Klavunat; Klavupen; lins. Br J Intraven Ther 1981; 2(Mar): 22–39. Chloroquine. The absorption of ampicillin has been reduced in
UAE: Julmentin; UK: Amiclav†; Augmentin; Augmentin-Duo; Heliclear†;
USA: Amoclan; Augmentin; Prevpac; Venez.: Augmentin; Augmentin Bid†; healthy subjects taking chloroquine.1
Clavumox; Curam; Fulgram. Ampicillin Trihydrate (BANM, rINNM) 1. Ali HM. Reduced ampicillin bioavailability following oral coad-
ministration with chloroquine. J Antimicrob Chemother 1985;
Ampicilin trihydrát; Ampicilina trihidrato; Ampicilinas trihidratas; 15: 781–4.
Ampicillin; Ampicilline trihydratée; Ampicillin-trihidrát; Ampicil-
lintrihydrat; Ampicillinum trihydricum; Ampicylina trójwodna; Antimicrobial Action
Ampicillin (BAN, USAN, rINN) Ampisilliinitrihydraatti. Ampicillin is a beta-lactam antibiotic. It is bactericidal
Aminobenzylpenicillin; Ampicilin; Ampicilina; Ampicilinas, bev- Ампициллин Тригидрат and has a similar mode of action to that of benzylpeni-
andenis; Ampicillin, vattenfritt; Ampicilline; Ampicilline anhydre; C 16 H 19N 3 O 4 S,3H 2 O = 403.5. cillin (p.214), but as an aminopenicillin with an amino
Ampicillinum; Ampicillinum anhydricum; Ampicylina bezwodna; C AS — 7177-48-2.
Ampisilin; Ampisilliini; Ampisilliini, vedetön; Anhydrous Ampicillin; group side-chain attached to the basic penicillin struc-
ATC — J01C A01; S01AA19. ture, ampicillin is better able to penetrate the outer
AY-6108; BRL-1341; NSC-528986; P-50; Vízmentes ampicillin.
ATC Vet — QJ01C A01; QS01AA19. membrane of some Gram-negative bacteria and has a
(6R)-6-(α-D-Phenylglycylamino)penicillanic acid.
Ампициллин Pharmacopoeias. In Eur. (see p.vii) and Viet. In Chin. and Jpn broader spectrum of activity.
under the title Ampicillin. Int. and US permit anhydrous or the
C 16 H 19 N 3 O 4 S = 349.4. trihydrate under the title Ampicillin.
Spectrum of activity. Ampicillin resembles benzylpen-
C AS — 69-53-4. Ph. Eur. 6.2 (Ampicillin Trihydrate). A white or almost white, icillin in its action against Gram-positive organisms,
ATC — J01CA01; S01AA19. crystalline powder. Slightly soluble in water; practically insolu- including Streptococcus pneumoniae and other strepto-
ATC Vet — QJ01C A01; QJ51CA01; QS01AA19. ble in alcohol and in fatty oils. It dissolves in dilute solutions of cocci, but, with the possible exception of activity
acids and of alkali hydroxides. A 0.25% solution in water has a against Enterococcus faecalis, it is slightly less potent
pH of 3.5 to 5.5. Store in airtight containers.
USP 31 (Ampicillin). It is anhydrous or contains three molecules
than benzylpenicillin. Listeria monocytogenes is high-
O of water of hydration. A white, practically odourless crystalline ly sensitive. The Gram-negative cocci Moraxella ca-
H H powder. Slightly soluble in water and in methyl alcohol; insolu- tarrhalis (Branhamella catarrhalis), Neisseria gonor-
N S ble in carbon tetrachloride, in chloroform, and in benzene. pH of rhoeae, and N. meningitidis are sensitive. Ampicillin is
CH3
H a 1% solution in water is between 3.5 and 6.0. Store in airtight more active than benzylpenicillin against some Gram-
NH2 N CH3 containers.
negative bacilli, including Haemophilus influenzae
O and Enterobacteriaceae such as Escherichia coli, Pro-
COOH Adverse Effects teus mirabilis, Salmonella and Shigella spp. It is inac-
As for Benzylpenicillin, p.213. tive against Pseudomonas aeruginosa. Ampicillin also
NOTE. Compounded preparations of ampicillin may be represent-
ed by the following names: Skin rashes are among the most common adverse ef- has activity similar to benzylpenicillin against other or-
fects and are generally either urticarial or maculopapu- ganisms including many anaerobes and Actinomyces
• Co-fluampicil (BAN)—flucloxacillin 1 part and ampicillin 1
part (w/w). lar; the urticarial reactions are typical of penicillin hy- spp.
Pharmacopoeias. In Eur. (see p.vii), Jpn, and Viet. persensitivity, while the erythematous maculopapular Activity with other antimicrobials. There is synergy
Int. and US permit anhydrous or the trihydrate. eruptions are characteristic of ampicillin and amoxicil- against some beta-lactamase-producing organisms be-
Ph. Eur. 6.2 (Ampicillin, Anhydrous; Ampicillin BP 2008). A lin and often appear more than 7 days after commenc- tween ampicillin and beta-lactamase inhibitors such as
white or almost white, crystalline powder. It exhibits polymor- ing treatment. Such rashes may be due to hypersensi- clavulanic acid or sulbactam, and also penicillinase-
phism. Sparingly soluble in water; practically insoluble in alco- tivity to the beta-lactam moiety or to the amino group
hol, in acetone, and in fatty oils. It dissolves in dilute solutions of stable drugs such as cloxacillin or flucloxacillin. Syn-
acids and of alkali hydroxides. A 0.25% solution in water has a in the side-chain, or to a toxic reaction. The occurrence ergy has also been shown between ampicillin and
pH of 3.5 to 5.5. Store at a temperature not exceeding 30° in air- of a maculopapular rash during ampicillin use does not aminoglycosides against a range of organisms, includ-
tight containers. necessarily preclude the subsequent use of other peni- ing enterococci. Variable effects ranging from synergy
USP 31 (Ampicillin). It is anhydrous or contains three molecules cillins. However, since it may be difficult in practice to to antagonism have been reported between ampicillin
of water of hydration. A white, practically odourless crystalline distinguish between hypersensitive and toxic respons-
powder. Slightly soluble in water and in methyl alcohol; insolu- and other beta lactams, bacteriostatic drugs such as
ble in carbon tetrachloride, in chloroform, and in benzene. pH of es, skin testing for hypersensitivity may be advisable chloramphenicol, and rifampicin.
a 1% solution in water is between 3.5 and 6.0. Store in airtight before another penicillin is used in patients who have Resistance. Like benzylpenicillin, ampicillin is inacti-
containers. had ampicillin rashes. Most patients with infectious vated by beta lactamases, although other mechanisms
mononucleosis develop a maculopapular rash when may be responsible for resistance in some species.
Ampicillin Sodium (BANM, USAN, rINNM) treated with ampicillin, and patients with other lym- There are geographical variations in the incidence of
Aminobenzylpenicillin Sodium; Ampicilin sodná sůl; Ampicilina phoid disorders such as lymphatic leukaemia, and pos- resistance, but most staphylococci and many strains of
sódica; Ampicilino natrio druska; Ampicilline sodique; Ampicillin- sibly those with HIV infection, also appear to be at E. coli, H. influenzae, M. catarrhalis, N. gonorrhoeae,
natrium; Ampicillin-nátrium; Ampicillinum natricum; Ampicylina higher risk. More serious skin reactions may occur and
sodowa; Ampisilliininatrium; Natrii Ampicillinum; Sodyum Ampi- and Salmonella and Shigella spp. are resistant.
erythema multiforme associated with ampicillin has
silin. occasionally been reported.
Натрий Ампициллин
Pharmacokinetics
C 16 H 18 N 3 NaO 4 S = 371.4.
Gastrointestinal adverse effects, particularly diarrhoea Ampicillin is relatively resistant to inactivation by gas-
C AS — 69-52-3. and nausea and vomiting, occur quite often, usually af- tric acid and is moderately well absorbed from the gas-
ATC — J01CA01; S01AA19. ter oral use. Pseudomembranous colitis has also been trointestinal tract after oral doses. Food can interfere
ATC Vet — QJ01C A01; QS01AA19. reported. with the absorption of ampicillin so doses should pref-
 Ampicillin/Apramycin 205
erably be taken at least 30 minutes before meals. Peak 3 to 5 minutes or by infusion. Again, children may be Amplital; Amplizer; Ibimicyn†; Pentrexyl; Malaysia: Ampilin; Biocil†;
Pamecil; Setcillin†; Standacillin; Mex.: Acilmed; Alphapen; Alvedrin; Am-An;
concentrations in plasma are attained in about 1 to 2 given half the adult dose. Ambidrin; Ambiosol; Ampex; Ampi-Quim; Ampi-Tecno; Ampibal†; Ampi-
hours and after a 500-mg oral dose are reported to cidar†; Ampidrat†; Ampigrin; Ampilon†; Ampimex; Ampiset†; Amprexyn;
For urinary-tract infections, ampicillin 500 mg is given Amsapen; Anglopen; Azpencil; Bestcilina-A; Binotal; Bremecina; Brupen;
range from 3 to 6 micrograms/mL. Deamcilina; Dibacilina; Diferin; Expicin; Flamicina; Gramipen-F; Iqfacilina;
orally every 8 hours. Lampicin; Marovilina; Meprizina; Mexapin; Mibiot; Omnipen; Pebiot; Penbri-
Peak plasma concentrations of ampicillin after a 500- tin; Pentiver; Pentrexyl; Procilina; Prodifer; Promecilina; Rayepen†; Sinaplin;
For typhoid and paratyphoid fever where Salmonella Tronex; Yapamicin; Zumorin; Neth.: Pentrexyl†; Norw.: Pentrexyl;
mg intramuscular dose given as the sodium salt occur typhi strains remain sensitive to ampicillin, an oral Philipp.: Aldribid; Ampicin; Ampinex; Bactimed; Clovillin; Eurocin; Excillin;
Gramcil; Obocil; Panacta; Penbritin; Pentrexyl; Picaplin; Polypen; Rotocin;
within about 1 hour and are reported to range from 7 to dose of 1 to 2 g may be given every 6 hours for 2 weeks Shinapen; Vatacil; Port.: Amplifar; Cilin†; Estreptobroncol; Hiperbiotico; Hi-
14 micrograms/mL. for acute infections, and for 4 to 12 weeks in carriers. perbiotico Retard; S.Afr.: Ampimax; Ampipen; Be-Ampicil; Penbritin; Pen-
rite; Petercillin; Ranamp; Spectracil; Singapore: Ampilin; Dhacillin; Pamecil†;
An intramuscular dose of 10 mg/kg (maximum dose Pricillin†; Standacillin; Spain: Ampiplus; Antibiopen; Britapen; Gobemicina;
Ampicillin is widely distributed and therapeutic con- 250 mg) every 6 hours for 4 to 6 weeks has been sug- Nuvapen; Swed.: Doktacillin; Thai.: Amcillin†; Amilin; Ampicyn; Ampilin;
centrations can be achieved in ascitic, pleural, and joint gested for children who are chronic carriers.
Ampillin†; Ampra; Amprexyl; Ampro†; Eracillin; Penbritin; Pencotrex; Pen-
trexyl; Siampicil; Sumapen; Vacillin; Viccillin; Turk.: Alfasilin; Ampisid; Amp-
fluids. It crosses the placenta and small amounts are isina; Neosilin; Penbisin; Silina; UAE: Julphapen; UK: Magnapen; Penbritin;
distributed into breast milk. There is little diffusion into Ampicillin 2 g given with probenecid 1 g, as a single Rimacillin; USA: Principen; Venez.: Alampen; Ampen†; Ampenina; Ampi-
ga†; Ampilan; Arcocilin; Fibrapen†; Intrapen†; Neoampicil†.
the CSF except when the meninges are inflamed. oral dose, has been used in the treatment of uncompli-
About 20% is bound to plasma proteins and the plasma cated gonorrhoea in areas where gonococci remain Multi-ingredient: Arg.: Aminoxidin Sulbactam; Ampi-Bis Plus; Ampigen
SB; Amplibenzatin Bronquial; Aseptobron Ampicilina†; Cronopen Balsami-
half-life is about 1 to 1.5 hours, but this may be in- sensitive; repeated doses are recommended in females. co; Grampenil Bronquial†; Meticil; Prixin; Unasyna; Unsayna†; Austria: Un-
creased in neonates, the elderly, and patients with renal asyn; Braz.: Ambezetal; Amplotal; Benzotal; Combactan; Durapen; Optaci-
In meningitis, higher parenteral doses of 2 to 3 g given lin; Parenzyme Ampicilina; Sulbacter†; Unasyn; Urobiotic†; Uropielon;
impairment; in severe renal impairment half-lives of 7 Chile: Unasyn; Cz.: Ampiclox†; Unasyn; Fr.: Unacim; Ger.: Unacid; Gr.:
intravenously every 4 or 6 hours have been suggested. Begalin-P; Hong Kong: Ampiclox†; APT-Ampicloxa; Pamedox; Roscilox;
to 20 hours have been reported. For infants and children with meningitis, an intrave- Unasyn; Hung.: Unasyn; India: Adilox; Ampilox; Ampilox-LB; Amplus;
Ampoxin; Ampoxin-LB; Campicillin Plus; Campilox; Clax; Megaclox; Mega-
Ampicillin is metabolised to some extent to penicilloic nous dose of 150 mg/kg daily in divided doses may be clox LB; Megapen; Sulbacin; Irl.: Ampiclox†; Israel: Unasyn; Ital.: Ampi-
acid which is excreted in the urine. given; a dose of 50 mg/kg (maximum 3 g) every 4 to 6 plus†; Amplium; Bethacil; Diamplicil†; Loricin; Unasyn; Jpn: Sulperazon†;
Unasyn-S†; Malaysia: Sulbacin; Unasyn; Mex.: Ampiclox-D; Anglotex; Bi-
hours has also been suggested. Neonates may be given solvon A; Brucilina; Brupen Compuesto; Diamprex; Doxapen; Mucolin A;
Renal clearance of ampicillin occurs partly by glomer- a dose of 50 mg/kg every 12 hours for those under 1 Panac; Panac K; Pentibrom; Pentidix; Pentrexyl Expec; Unasyna; Philipp.:
Unasyn; Pol.: Unasyn; Rus.: Oxamp (Оксамп)†; Sultasin (Сультасин); Un-
ular filtration and partly by tubular secretion; it is re- week of age, or every 8 hours for older neonates. asyn (Уназин); S.Afr.: Ampiclox; Apen; Cloxam; Megamox; Ranclosil†; Sin-
duced by probenecid. About 20 to 40% of an oral dose gapore: Unasyn; Spain: Ampilevel; Espectral†; Espectrosira†; Gobemicina
For intrapartum prophylaxis against group B strepto- Retard; Maxicilina; Penisintex Bronquial†; Pulminflamatoria†; Pulmosterin
may be excreted unchanged in the urine in 6 hours; uri- coccal infection in the neonate, a maternal dose of 2 g Retard; Retarpen; Retarpen Balsamico†; Retarpen Mucolitico†; Ultrapenil;
nary concentrations have ranged from 0.25 to Unasyn; Thai.: Ampiclox; Sulam; Unasyn; Viccillin-S; Turk.: Azosilin; Com-
by intravenous injection initially then 1 g every 4 hours bicid; Duobak; Duobaktam; Duocid; Nobecid; Sulbaksit; Sulcid; Sultasid;
1 mg/mL after a dose of 500 mg. After parenteral use until delivery has been suggested. UK: Magnapen; USA: Unasyn; Venez.: Ampibactan; Ampitren†; Fipexiam;
about 60 to 80% is excreted in the urine within 6 hours. Sinif; Unasyn.
Ampicillin is removed by haemodialysis. High con- Ampicillin may also be given by other routes, usually
centrations are reached in bile; it undergoes enterohe- as a supplement to systemic therapy. Intraperitoneal or
patic recycling and some is excreted in the faeces. intrapleural injections are given in a dose of 500 mg
Apramycin (BAN, USAN, rINN)
daily dissolved in 5 to 10 mL of water. For intra-artic-
Ampicillin with sulbactam. The pharmacokinetics of ular injection, ampicillin 500 mg daily is given dis- 47657; Apramicina; Apramycine; Apramycinum; EL-857; EL-
ampicillin and sulbactam are broadly similar and nei- solved in up to 5 mL of water or a solution of procaine 857/820; Nebramycin Factor 2. 4-O-[(2R,3R,4aS,6R,7S,8R,8aR)-3-
ther appears to affect the other to any great extent. hydrochloride 0.5%. Amino-6-(4-amino-4-deoxy-α-D-glucopyranosyloxy)-8-hy-
droxy-7-methylaminoperhydropyrano[3,2-b]pyran-2-yl]-2-de-
Ampicillin benzathine has also been given by intra- oxystreptamine.
Uses and Administration muscular injection. Апрамицин
Ampicillin is used in the treatment of a variety of infec-
tions due to susceptible organisms (see Antimicrobial Ampicillin with sulbactam. The sodium salts of ampi- C 21 H 41 N 5 O 11 = 539.6.
Action, above). They include biliary-tract infections, cillin and sulbactam (p.335) may be given intramuscu- C AS — 37321-09-8.
bronchitis, endocarditis, gastro-enteritis (including sal- larly or intravenously in the treatment of infections due
ATC Vet — QA07AA92; QJ01GB90; QJ51GB90.
monella enteritis and shigellosis), gonorrhoea, listerio- to beta-lactamase-producing organisms. Doses are ex-
pressed in terms of the equivalent amounts of ampicil-
sis, meningitis, perinatal streptococcal infections (in-
lin and sulbactam; available injections contain ampicil-
trapartum prophylaxis against group B streptococci), HO
lin and sulbactam in the ratio 2:1, respectively. The H N
peritonitis, pneumonia, septicaemia, typhoid and para-
usual dose is ampicillin 1 g with sulbactam 500 mg O
typhoid fever, and urinary-tract infections. Resistance
every 6 hours; doses may be doubled in severe infec-
to ampicillin is increasingly a problem in some infec- HO HO H C
tions.
tions, for example, gonorrhoea, pneumococcal infec- O NH
OH
tions, respiratory-tract infections due to Haemophilus For oral use sultamicillin (p.344), a mutual prodrug of O
influenzae or Moraxella catarrhalis (Branhamella ca- ampicillin and sulbactam, may be given.
O OH
tarrhalis), Salmonella infections, shigellosis, and in-
fections due to Escherichia coli. For details of these in- Administration in renal impairment. The dose of ampicil- H N
OH
lin should be reduced, or the dose interval increased, in severe O
fections and their treatment, see under Choice of renal impairment (creatinine clearance less than 10 mL/minute). H N NH
Antibacterial, p.162. If beta-lactamase-producing or- Patients undergoing dialysis should receive an additional dose
ganisms are present, ampicillin can be given with a after the session.
beta-lactamase inhibitor such as sulbactam (see below) Apramycin Sulfate (rINNM)
or a penicillinase-resistant drug such as cloxacillin, di- Preparations
cloxacillin, or flucloxacillin (known as co-fluampicil). BP 2008: Ampicillin Capsules; Ampicillin Injection; Ampicillin Oral Suspen- Apramycin Sulphate (BANM); Apramycine, Sulfate d’; Apramycini
It may also be used with an aminoglycoside to increase sion; Co-fluampicil Capsules; Co-fluampicil Oral Suspension; Sulfas; Apramycinsulfat; Apramysiinisulfaatti; Sulfato de apramici-
USP 31: Ampicillin and Probenecid for Oral Suspension; Ampicillin and na.
the spectrum of organisms covered; it is advisable to Sulbactam for Injection; Ampicillin Capsules; Ampicillin for Injectable Sus-
pension; Ampicillin for Injection; Ampicillin for Oral Suspension; Ampicillin
give the injections separately. Tablets. Апрамицина Сульфат
C 21 H 41 N 5 O 11 ,2 ⁄ H 2 SO 4 = 784.8.
Administration and dosage. The dosage of ampicillin Proprietary Preparations (details are given in Part 3)
will depend on the severity of the disease, the age of the Arg.: Alpovex; Aminoxidin†; Ampi-Bis; Ampi†; Ampicler; Ampigen; Ampi- C AS — 41194-16-5.
grand; Ampinox; Ampitenk; Ampixen; Atecilina; Bactilina; Decilina†; Fabop-
patient, and renal function. Ampicillin is usually given cilina; Galciclina†; Grampenil†; Histopen; Poenbiotico†; Trifacilina; Trimicro; Pharmacopoeias. In BP(Vet).
orally as the trihydrate and by injection as the sodium Welticilina; Austral.: Alphacin; Ampicyn; Austrapen; Ibimicyn; Austria: BP(Vet) 2008 (Apramycin Sulphate). The sulfate of an antibiot-
Standacillin; Belg.: Pentrexyl; Braz.: Ampi; Ampiciflan; Ampiciklyna†; Amp- ic produced by certain strains of Streptomyces tenebrarius or by
salt. Doses are expressed in terms of the equivalent icil; Ampicilab; Ampicilase; Ampicilib†; Ampicilil; Ampicilon; Ampicimax†;
amount of ampicillin; 1.06 g of ampicillin sodium and Ampicinal†; Ampifar†; Ampigran; Ampilozin; Ampitrat†; Ampival†; Ampix- other means. The potency is not less than 430 units per mg, cal-
in†; Amplacilina; Amplacin; Amplibac; Amplofen†; Bacterinil†; Binotal; Bi- culated with reference to the anhydrous substance. A light brown
1.15 g of ampicillin trihydrate are each equivalent to pencil†; Cilinon; Cilipen; Emicilin; Expectocilin; Gonol; Gramcilina; Lifacilina†; hygroscopic powder or granular material. Freely soluble in wa-
about 1 g of ampicillin. Notacilin†; Praticilin†; Tandrexin†; Canad.: Apo-Ampi; Nu-Ampi; Cz.: ter; practically insoluble in alcohol, in acetone, in ether, and in
Apo-Ampi†; Penstabil†; Standacillin†; Denm.: Doktacillin†; Pentrexyl; Fin.:
A-Pen; Fr.: Totapen; Ger.: Binotal; Gr.: Copercilex; Isticilline; Pentrexyl; methyl alcohol.
The usual adult oral dose is 0.25 to 1 g every 6 hours Hong Kong: Amprexyl; Dhacillin†; Pamecil; Penbritin†; Penodil; Pentrexyl;
taken at least 30 minutes before or 2 hours after food. Hung.: Penstabil†; Semicillin; Standacillin; India: Ampilin; Ampipen; Amp- Profile
isyn; Aristocillin; Biocilin; Campicillin; Ipacillin†; Roscillin; Synthocilin; Indon.: Apramycin is an aminoglycoside antibiotic used as the sulfate in
Children may be given half the adult dose. The usual Ambiopi; Amcillin; Ampi; Arcocillin; Binotal; Biopensyn; Cetacillin; Corsacil- veterinary practice for the treatment of susceptible infections.
adult dose by injection is 500 mg every 4 to 6 hours lin; Kalpicilin; Opicillin; Parpicillin; Penbiotic; Penbritin; Polypen; Primacillin;
Sanpicillin; Standacillin; Ultrapen; Viccillin; Xepacillin; Irl.: Clonamp; Novap-
intramuscularly or by slow intravenous injection over en; Penbritin; Israel: Penibrin; Ital.: Ampilisa†; Ampilux; Ampiplus Simplex;

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
206 Antibacterials
Arbekacin Sulfate (rINNM) Profile
Avilamycin is an antibacterial that has been used in veterinary
ABK (arbekacin); AHB-DBK (arbekacin); Arbekacin Sulphate; Ar- HO medicine as a growth promotor.
békacine, Sulfate d’; Arbekacini Sulfas; HABA-Dibekacin (ar- O
bekacin); Sulfato de arbekacina. O-3-Amino-3-deoxy-α-D-glu- H H
copyranosyl-(1→4)-O-[2,6-diamino-2,3,4,6-tetradeoxy-α-D- S
N CH3
erythro-hexopyranosyl-(1→6)]-N′-[(2S)-4-amino-2-hydroxybu- H Avoparcin (BAN, USAN, rINN)
tyryl]-2-deoxy-L-streptamine sulphate. O NH N CH3 Avoparcina; Avoparcine; Avoparcinum; Compound 254.
Арбекацина Сульфат O O Авопарцин
C 22 H 44 N 6 O 10 ,xH 2S0 4 . H 3C COOH
C AS — 37332-99-3.
C AS — 51025-85-5 (arbekacin). N NH2
H Profile
Avoparcin is a glycopeptide antibiotic usually produced by Amy-
Pharmacopoeias. Jpn includes the trihydrate. colatopsis coloradensis (Streptomyces candidus). It has been in-
OH corporated into animal feedstuffs to promote growth.
NH2 OH Profile
Aspoxicillin is a ureidopenicillin that has been given intrave- ◊ There is evidence of cross-resistance between avoparcin and
nously in the treatment of susceptible infections. vancomycin.1 Suggestions that vancomycin-resistant organisms
could enter the human population from the food chain as a result
O OH O NH2 of the use of avoparcin as a growth promotor in animals2,3 were
O disputed by the manufacturers of avoparcin.4,5 After a ban in the
Astromicin Sulfate (USAN, pINNM) EU on the use of avoparcin as a growth promotor in animals
H2N H2N O OH
there has been some evidence6 of a decrease in the occurrence of
H 2N Abbott-44747; Astromicin Sulphate; Astromicine, Sulfate d’; As- vancomycin-resistant enterococci in poultry meat.
tromicini Sulfas; Fortimicin A Sulphate; KW-1070; Sulfato de as- 1. Klare I, et al. vanA-mediated high-level glycopeptide resistance
NH tromicina. 4-Amino-1-(2-amino-N-methylacetamido)-1,4-dide- in Enterococcus faecium from animal husbandry. FEMS Micro-
oxy-3-O-(2,6-diamino-2,3,4,6,7-pentadeoxy-β-L-lyxo-hepto- biol Lett 1995; 125: 165–72.
pyranosyl)-6-O-methyl-L-chiro-inositol sulphate. 2. Howarth F, Poulter D. Vancomycin resistance: time to ban
HO O avoparcin? Lancet 1996; 347: 1047.
Астромицина Сульфат 3. Wise R. Avoparcin and animal feedstuff. Lancet 1996; 347:
(arbekacin) C 17 H 35N 5 O 6 ,2H 2 SO 4 = 601.6. 1835.
C AS — 55779-06-1 (astromicin); 72275-67-3 (astromicin 4. Mudd A. Vancomycin resistance and avoparcin. Lancet 1996;
Pharmacopoeias. In Jpn. 347: 1412.
sulfate); 66768-12-5 (xH 2 SO 4 ).
5. Mudd AJ. Is it time to ban all antibiotics as animal growth-pro-
Profile moting agents? Lancet 1996; 348: 1454–5.
Arbekacin is an aminoglycoside derived from dibekacin and has 6. Pantosti A, et al. Decrease of vancomycin-resistant enterococci
general properties similar to those of gentamicin (p.282). It has CH3 in poultry meat after avoparcin ban. Lancet 1999; 354: 741–2.
been used as the sulfate in the treatment of serious infections due H 2N
to meticillin-resistant Staphylococcus aureus.
Azidamfenicol (BAN, rINN)
HO H2N O
Azidamfénicol; Azidamfenicolum; Azidamphenicol; Azidanfeni-
Arsanilic Acid (BAN, rINN) col; Azidoamphenicol; Bayer-52910. 2-Azido-N-[(αR,βR)-β-hy-
O O NH2 droxy-α-hydroxymethyl-4-nitrophenethyl]acetamide.
Acide Arsanilique; Ácido arsanílico; Acidum Arsanilicum; Ami-
narsonic Acid; AS-101. p-Aminobenzenearsonic acid; 4-Ami- H3C Азидамфеникол
nophenylarsonic acid. C 11 H 13N 5 O 5 = 295.3.
H3 C N OH C AS — 13838-08-9.
Арсаниловая Кислота
ATC — S01AA25.
C 6 H 8 AsNO 3 = 217.1.
O NH2 ATC Vet — QS01AA25.
C AS — 98-50-0.
(astromicin)
OH
OH
H 2N As O Pharmacopoeias. In Jpn.
OH
OH Profile
Astromicin is an aminoglycoside antibiotic produced by Micro- HN N+
monospora spp. and with actions and uses similar to those of O2N N N-
NOTE. The code AS-101 has also been used for an immunomod- gentamicin (p.282). Astromicin sulfate has been given by intra-
ulator investigated as an antineoplastic and antiviral. O
muscular injection or intravenous infusion. Dosage should be ad-
Pharmacopoeias. In US for veterinary use only. justed based on serum-astromicin concentration monitoring.
USP 31 (Arsanilic Acid). A white to off-white crystalline pow- Profile
der. Soluble in hot water, in amyl alcohol, and in solutions of al- Preparations Azidamfenicol is an antibiotic that is related structurally to chlo-
kali carbonates; slightly soluble in cold water, in alcohol, and in Proprietary Preparations (details are given in Part 3) ramphenicol (p.239). It is used as 1% eye drops or eye ointment
acetic acid; insoluble in acetone, in chloroform, in ether, in ben- Jpn: Fortimicin. in the treatment of bacterial eye infections.
zene, and in dilute mineral acids; sparingly soluble in concentrat- Preparations
ed mineral acids.
Proprietary Preparations (details are given in Part 3)
Avilamycin (BAN, USAN, rINN) Cz.: Ophthalmo-Azaphenicol†; Ger.: Berlicetin; Posifenicol; Thilocanfol;
Sodium Arsanilate (BANM, rINNM) Gr.: Thilocof.
Avilamicina; Avilamycine; Avilamycinum; LY-048740 (avilamycin
Arsanilate de Sodium; Arsanilato sódico; Natrii Arsanilas; Sodi- or avilamycin A).
um Aminarsonate; Sodium Anilarsonate. Sodium 4-aminophe-
Авиламицин
nylarsonate. Azidocillin Sodium (BANM, rINNM)
C 61 H 88Cl 2 O 32 (avilamycin A) = 1404.2.
Натрий Арсанилат Azidobenzylpenicillin Sodium; Azidocilina sódica; Azidocilline
C AS — 11051-71-1 (avilamycin); 69787-79-7 (avilamycin
C 6 H 7 AsNNaO 3 = 239.0. A); 69787-80-0 (avilamycin C). Sodique; Natrii Azidocillinum. Sodium (6R)-6-(D-2-azido-2-phe-
C AS — 127-85-5. nylacetamido)penicillanate.
Pharmacopoeias. Fr. includes the anhydrous substance and Натрий Азидоциллин
the trihydrate. C 16 H 16N 5 NaO 4 S = 397.4.
C AS — 17243-38-8 (azidocillin); 35334-12-4 (azidocillin
Profile sodium).
Arsanilic acid and sodium arsanilate are used in veterinary med- ATC — J01CE04.
icine for the prophylaxis and treatment of enteric infections in
pigs and also as growth-promoting agents. ATC Vet — QJ01CE04.

O
Aspoxicillin (rINN) H H
Aspoxicilina; Aspoxicilline; Aspoxicillinum; TA-058. (2S,5R,6R)-6- S
N CH3
{(2R)-2-[(2R)-2-Amino-3-(methylcarbamoyl)propionamido]-2- H
(p-hydroxyphenyl)acetamido}-3,3-dimethyl-7-oxo-4-thia-1- N3 N CH3
azabicyclo[3.2.0]-heptane-2-carboxylic acid. O
Аспоксициллин COOH
C 21 H 27 N 5 O 7 S = 493.5. (azidocillin)
C AS — 63358-49-6.
 Arbekacin Sulfate/Azithromycin 207
Profile Effects on the ears. Reversible sensorineural hearing loss was Pharmacokinetics
Azidocillin is a semisynthetic penicillin with actions and uses reported in 3 patients given oral azithromycin 500 mg daily with Azithromycin given orally is rapidly absorbed and
similar to those of phenoxymethylpenicillin (p.314). It is given clofazimine and ethambutol for the treatment of disseminated
orally as the sodium salt; doses, expressed in terms of the base, Mycobacterium avium complex infection.1 Irreversible hearing about 40% bioavailable. Absorption from capsules, but
are 750 mg twice daily in the treatment of susceptible infections. loss has also been reported after low-dose exposure to oral azi- not tablets or suspension, is reduced by food. Peak
The potassium salt has also been used. thromycin.2,3 A patient who had had 8 days of treatment with plasma concentrations occur 2 to 3 hours after an oral
Preparations intravenous azithromycin 500 mg daily for pneumonia reported dose and 1 to 2 hours after intravenous dosage. How-
complete deafness, which had resolved 20 days after stopping ever, azithromycin is extensively distributed into the
Proprietary Preparations (details are given in Part 3)
Ger.: InfectoBicillin H. the drug.4
See also Incidence of Adverse Effects, above.
tissues, and tissue concentrations subsequently remain
1. Wallace MR, et al. Ototoxicity with azithromycin. Lancet 1994; much higher than those in the blood; in contrast to most
343: 241. other antibacterials, plasma concentrations are there-
Azithromycin (BAN, USAN, rINN) 2. Ress BD, Gross EM. Irreversible sensorineural hearing loss as a
result of azithromycin ototoxicity: a case report. Ann Otol Rhinol
fore of little value as a guide to efficacy. High concen-
Atsitromysiini; Azithromycine; Azithromycinum; Azitromicina; Laryngol 2000; 109: 435–7. trations are taken up into white blood cells. There is
Azitromicinas; Azitromisin; Azitromycin; Azytromycyna; CP- 3. Mick P, Westerberg BD. Sensorineural hearing loss as a probable little diffusion into the CSF when the meninges are not
serious adverse drug reaction associated with low-dose oral azi-
62993; XZ-450. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(2,6- thromycin. J Otolaryngol 2007; 36: 257–63. inflamed. Data from animal studies indicate that azi-
Dideoxy-3-C-3-O-dimethyl-α-L-ribo-hexopyranosyloxy)-2-ethyl- 4. Bizjak ED, et al. Intravenous azithromycin-induced ototoxicity. thromycin crosses the placenta. Small amounts of azi-
3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-(3,4,6-tride- Pharmacotherapy 1999; 19: 245–8. thromycin are demethylated in the liver, and it is ex-
oxy-3-dimethylamino-β-D-xylo-hexopyranosyloxy)-1-oxa-6-aza- Effects on fluid and electrolyte homoeostasis. The syn- creted in bile mainly as unchanged drug and a number
cyclopentadecan-15-one dihydrate; 9-Deoxo-9a-aza-9a-methyl- drome of inappropriate antidiuretic hormone secretion was asso- of inactive metabolites have also been detected. About
9a-homoerythromycin A dihydrate. ciated with azithromycin treatment in a patient.1,2
1. Cadle RM, et al. Symptomatic syndrome of inappropriate anti-
6% of an oral dose (representing about 20% of the
Азитромицин
C 38 H 72N 2 O 12,2H 2 O = 785.0. diuretic hormone secretion associated with azithromycin. Ann amount in the systemic circulation) is excreted in the
Pharmacother 1997; 31: 1308–10. urine. The terminal elimination half-life is about 68
C AS — 83905-01-5 (anhydrous azithromycin); 117772- 2. Kintzel PE. Correction: symptomatic syndrome of inappropriate
70-0 (azithromycin dihydrate). antidiuretic hormone secretion associated with azithromycin. hours.
Ann Pharmacother 1998; 32: 388.
ATC — J01FA10; S01AA26. ◊ Reviews and references.
ATC Vet — QJ01FA10; QS01AA26. Effects on the kidneys. Acute interstitial nephritis leading to 1. Lalak NJ, Morris DL. Azithromycin clinical pharmacokinetics.
irreversible renal failure has been reported1 in a patient who re- Clin Pharmacokinet 1993; 25: 370–4.
ceived azithromycin for 9 days. A later report2 described a pa- 2. Luke DR, et al. Safety, toleration, and pharmacokinetics of intra-
tient who developed recurrent acute interstitial nephritis after venous azithromycin. Antimicrob Agents Chemother 1996; 40:
H 3C 2577–81.
courses of azithromycin. Repeated exposure resulted in persist- 3. Rapp RP. Pharmacokinetics and pharmacodynamics of intrave-
H 3C N ent renal damage; leucocytosis and eosinophilia were still nous and oral azithromycin: enhanced tissue activity and mini-
CH3 present 1 year later. mal drug interactions. Ann Pharmacother 1998; 32: 785–93.
H 3C 1. Mansoor GA, et al. Azithromycin-induced acute interstitial ne- 4. Chandra R, et al. Clinical pharmacokinetics and gastrointestinal
OH OH tolerability of a novel extended-release microsphere formulation
phritis. Ann Intern Med 1993; 119: 636–7.
H 3C OH CH3 N CH3 2. Soni N, et al. Recurrent acute interstitial nephritis induced by of azithromycin. Clin Pharmacokinet 2007; 46: 247–59.
HO azithromycin. Pediatr Infect Dis J 2004; 23: 965–6.
H 3C H 3C O O CH3 Uses and Administration
O Eosinophilia. A syndrome characterised by eosinophilia, ar-
thralgia, fever, and rash was associated with azithromycin or rox- Azithromycin is a nitrogen-containing macrolide (aza-
ithromycin treatment in a patient on separate occasions.1 The lide) with actions and uses similar to those of erythro-
O O original authors believed the condition represented the Churg-
OCH3 mycin (p.272). It is given in the treatment of respirato-
CH3 St rau ss sy n dro m e , a l t ho u gh th i s w a s d is p ut e d in
correspondence2 and attributed to the eosinophilia-myalgia syn- ry-tract infections (including otitis media), in skin and
CH3 drome. soft-tissue infections, and in uncomplicated genital in-
O OH
CH3
1. Hübner C, et al. Macrolide-induced Churg-Strauss syndrome in fections. Azithromycin may also be used for the proph-
a patient with atopy. Lancet 1997; 350: 563. ylaxis, and as a component of regimens in the treat-
2. Kränke B, Aberer W. Macrolide-induced Churg-Strauss syn-
Pharmacopoeias. In Chin. and Jpn. drome in patient with atopy. Lancet 1997; 350: 1551–2. ment, of Mycobacterium avium complex (MAC)
Eur. (see p.vii) includes the anhydrous form. Overdosage. Bradycardia with complete heart block was infections. It is used in some countries for the prophy-
US includes the monohydrate and the dihydrate. reported1 in a 9-month-old infant who had been inadvertently laxis of endocarditis in at-risk patients unable to take
Ph. Eur. 6.2 (Azithromycin). A white or almost white powder. given about 50 mg/kg of azithromycin intravenously. penicillin. It is also used in the management of tracho-
Practically insoluble in water; freely soluble in dehydrated alco- 1. Tilelli JA, et al. Life-threatening bradyarrhythmia after massive ma and typhoid.
hol and in dichloromethane. A 0.2% solution in a mixture of me- azithromycin overdose. Pharmacotherapy 2006; 26: 147–50.
thyl alcohol and water (1:1) has a pH of 9.0 to 11.0. Store in air- For details of all these infections and their treatment,
tight containers. Interactions see under Choice of Antibacterial, p.162.
USP 31 (Azithromycin). It is anhydrous or contains one or two For a discussion of drug interactions of macrolide anti- Azithromycin has been tried in protozoal infections
molecules of water of hydration. pH of a 0.2% solution in a mix- such as babesiosis (below), crytosporidiosis (p.823),
ture of methyl alcohol and water (1:1) is between 9.0 and 11.0.
bacterials, see Erythromycin, p.271.
Store in airtight containers. Giving azithromycin with antacids containing alumin- and toxoplasmosis (p.826).
ium or magnesium salts can reduce the rate, but not the It is given orally or by intravenous infusion usually as
Adverse Effects and Precautions extent, of its absorption; azithromycin should be given the dihydrate; doses are expressed in terms of the anhy-
As for Erythromycin, p.270. at least 1 hour before or 2 hours after the antacid. drous substance. Azithromycin dihydrate 524 mg is
Gastrointestinal disturbances are the most frequent ad- Nelfinavir. Azithromycin serum concentrations are markedly equivalent to about 500 mg of anhydrous azithromy-
verse effect of azithromycin but are usually mild and increased when it is given with nelfinavir,1 but the clinical signif- cin. The capsule formulation should be given at least 1
less frequent than with erythromycin. Headache, som- icance of this is uncertain. US licensed product information for hour before, or 2 hours after, meals.
nolence, and taste disturbances may occur. Severe hy- azithromycin states that dosage adjustment is not required al- The usual oral adult dose of azithromycin is 500 mg as
though the patient should be closely monitored for adverse ef-
persensitivity reactions occur rarely but may be pro- fects. a single dose daily for 3 days. Alternatively, an initial
longed. Thrombocytopenia and mild transient 1. Amsden GW, et al. A study of the pharmacokinetics of azithro- dose of 500 mg may be followed by 250 mg daily for
neutropenia have been rarely reported in patients re- mycin and nelfinavir when coadministered in healthy volunteers. a further 4 days.
J Clin Pharmacol 2000; 40: 1522–7.
ceiving azithromycin. Pain and inflammation may oc- For uncomplicated genital infections caused by
cur at the site of intravenous infusions particularly at Antimicrobial Action Chlamydia trachomatis and for chancroid, 1 g of azi-
high concentrations. As for Erythromycin, p.271. Azithromycin is less ac- thromycin is given as a single dose. A single dose of
Licensed product information states that azithromycin tive than erythromycin against streptococci and sta- 2 g has been given for uncomplicated gonorrhoea. For
should be used with caution in patients with hepatic or phylococci, but has greater activity than erythromycin the treatment of granuloma inguinale, an initial dose of
renal impairment. It should not be given to those with in vitro against some Gram-negative organisms such as 1 g followed by 500 mg daily may be given, or 1 g may
severe hepatic impairment as safety has not been estab- Haemophilus influenzae and Moraxella catarrhalis be given once a week for at least 3 weeks, until all le-
lished. Although plasma concentrations may be in- (Branhamella catarrhalis), as well as having activity sions have completely healed.
creased in renal impairment dosage adjustment is not against some of the Enterobacteriaceae such as Es- In the USA, a modified-release preparation given as an
usually required. cherichia coli and Salmonella and Shigella spp. Azi- oral suspension is available. The product delivers a sin-
Incidence of adverse effects. In patients receiving azithro- thromycin is also more active than erythromycin gle dose of 2 g and should also be taken on an empty
mycin daily long-term for mycobacterial infections,1 gastrointes- against Chlamydia trachomatis and Ureaplasma urea- stomach. It is licensed for the treatment of acute bacte-
tinal disorders occurred in 32 of 39 patients (82%), hearing im- rial sinusitis or community-acquired pneumonia in
pairment in 10 patients (26%), tinnitus in 18 patients (46%), and
lyticum, and some opportunistic mycobacteria, includ-
poor balance or dizziness in 11 patients (28%). In general, ad- ing Mycobacterium avium complex. It has activity adults.
verse effects were associated with higher serum-azithromycin against the protozoa Toxoplasma gondii and Plasmodi- For prophylaxis of disseminated MAC infections, azi-
concentrations. um falciparum. thromycin 1.2 g may be given once weekly. For treat-
1. Brown BA, et al. Relationship of adverse events to serum drug ment or secondary prophylaxis, 500 mg once daily
levels in patients receiving high-dose azithromycin for mycobac- Resistance. The pattern of resistance to azithromycin is similar
terial lung disease. Clin Infect Dis 1997; 24: 958–64. to that seen with clarithromycin (p.249). should be given with other antimycobacterials.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
208 Antibacterials
For mild or moderate typhoid caused by multidrug- sia microti infections. Immunocompromised patients may be found that azithromycin 1 g daily for 3 days resulted in an 88%
resistant strains, 500 mg once daily may be given for 7 given higher doses of azithromycin (600 to 1000 mg daily). Chil- clinical response rate by day 7, but with a slower onset of action,
dren may be given azithromycin 12 mg/kg once daily, or when compared with chloroquine 600 mg daily for 2 days then
days. 10 mg/kg on day 1 followed by 5 mg/kg once daily thereafter, 300 mg on day 3 which resulted in a rate of 99%.
For details of doses in infants and children, see below. with atovaquone 20 mg/kg twice daily, both orally for 7 to 10 Azithromycin in a dose of 0.5 g once daily up to 1.5 g daily in
days. Azithromycin with quinine was reported to be effective in divided doses together with other antimalarials, such as artesuna-
Azithromycin dihydrate may also be given initially by 2 patients who had not responded to quinine plus clindamycin.4,5 te 200 mg daily2,7 or quinine 10 mg/kg 3 times daily,6,7 given for
intravenous infusion to adults in doses equivalent to 1. Krause PJ, et al. Atovaquone and azithromycin for the treatment 3 days was found to be effective in the treatment of uncomplicat-
500 mg of azithromycin as a single daily dose in the of babesiosis. N Engl J Med 2000; 343: 1454–8. ed multidrug-resistant P. falciparum malaria.
treatment of community-acquired pneumonia and pel- 2. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New
Rochelle NY: The Medical Letter, 2007. However, further studies are warranted, especially in children
vic inflammatory disease; treatment should be changed 3. Wormser GP, et al. The clinical assessment, treatment, and pre- and pregnant women.
to the oral route after at least 2 days in pneumonia and vention of Lyme disease, human granulocytic anaplasmosis, and 1. Taylor WR, et al. Malaria prophylaxis using azithromycin: a
babesiosis: clinical practice guidelines by the Infectious Diseas- double-blind, placebo-controlled trial in Irian Jaya, Indonesia.
after 1 or 2 days in pelvic inflammatory disease. It may es Society of America. Clin Infect Dis 2006; 43: 1089–1134. Clin Infect Dis 1999; 28: 74–81.
be given either in a solution containing 1 mg/mL over Al so availabl e at: http://www.journals.uchicago.edu/ 2. Krudsood S, et al. A randomized clinical trial of combinations of
3 hours or in a solution containing 2 mg/mL over 1 doi/pdf/10.1086/508667 (accessed 12/08/08) artesunate and azithromycin for treatment of uncomplicated
4. Shaio MF, Yang KD. Response of babesiosis to a combined reg- Plasmodium falciparum malaria in Thailand. Southeast Asian J
hour. imen of quinine and azithromycin. Trans R Soc Trop Med Hyg Trop Med Public Health 2000; 31: 801–7.
In the USA, azithromycin is available as 1% eye drops 1997; 91: 214–15. 3. Taylor WR, et al. Tolerability of azithromycin as malaria proph-
5. Shih C-M, Wang C-C. Ability of azithromycin in combination ylaxis in adults in Northeast Papua, Indonesia. Antimicrob
for the topical treatment of conjunctivitis caused by with quinine for the elimination of babesial infection in humans. Agents Chemother 2003; 47: 2199–2203.
susceptible strains of bacteria. Am J Trop Med Hyg 1998; 59: 509–12.
4. Heppner DG, et al. Randomized, controlled, double-blind trial of
◊ Reviews. Cholera. Azithromycin has been tried1-3 in the treatment of daily oral azithromycin in adults for the prophylaxis of Plasmo-
cholera (p.172). A single dose of 10 or 20 mg/kg was found to be dium vivax malaria in Western Thailand. Am J Trop Med Hyg
1. Peters DH, et al. Azithromycin: a review of its antimicrobial 2005; 73: 842–9.
activity, pharmacokinetic properties and clinical efficacy. Drugs effective in children1,2 and 1 g in adults.3
5. Dunne MW, et al. A double-blind, randomized study of azithro-
1992; 44: 750–99. 1. Khan WA, et al. Comparison of single-dose azithromycin and mycin compared to chloroquine for the treatment of Plasmodium
2. Langtry HD, Balfour JA. Azithromycin: a review of its use in 12-dose, 3-day erythromycin for childhood cholera: a ran- vivax malaria in India. Am J Trop Med Hyg 2005; 73: 1108–11.
paediatric infectious disease. Drugs 1998; 56: 273–97. domised, double-blind trial. Lancet 2002; 360: 1722–7. 6. Miller RS, et al. Effective treatment of uncomplicated Plasmodi-
3. Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, 2. Bhattacharya MK, et al. Azithromycin in the treatment of chol- um falciparum malaria with azithromycin-quinine combinations:
clarithromycin, and azithromycin. Mayo Clin Proc 1999; 74: era in children. Acta Paediatr 2003; 92: 676–8. a randomized, dose-ranging study. Am J Trop Med Hyg 2006; 74:
613–34. 3. Saha D, et al. Single-dose azithromycin for the treatment of 401–6.
4. Garey KW, Amsden GW. Intravenous azithromycin. Ann Phar- cholera in adults. N Engl J Med 2006; 354: 2452–62. 7. Noedl H, et al. Azithromycin combination therapy with artesu-
macother 1999; 33: 218–28. nate or quinine for the treatment of uncomplicated Plasmodium
5. Ioannidis JPA, et al. Meta-analysis of randomized controlled tri- Hyperplasia. For reference to the use of azithromycin to con-
falciparum malaria in adults: a randomized, phase 2 clinical trial
als on the comparative efficacy and safety of azithromycin trol ciclosporin-induced gingival hyperplasia, see p.1824. in Thailand. Clin Infect Dis 2006; 43: 1264–71.
against other antibiotics for upper respiratory tract infections. J
Antimicrob Chemother 2001; 48: 677–89. Ischaemic heart disease. Macrolide antibacterials, including Respiratory disorders. For reference to the use of azithromy-
6. Contopoulos-Ioannidis DG, et al. Meta-analysis of randomized azithromycin,1-4 clarithromycin,5-9 and roxithromycin,10-14 have cin in the management of respiratory disorders, see under Eryth-
controlled trials on the comparative efficacy and safety of azi- been investigated in the prevention of ischaemic heart disease, romycin, p.273.
thromycin against other antibiotics for lower respiratory tract based on a suggested link between atherosclerosis and infection
infections. J Antimicrob Chemother 2001; 48: 691–703.
7. Zuckerman JM. Macrolides and ketolides: azithromycin, clari-
with Chlamydophila pneumoniae (Chlamydia pneumoniae) (see Preparations
thromycin, telithromycin. Infect Dis Clin North Am 2004; 18: p.166). Although preliminary results from some pilot studies
USP 31: Azithromycin Capsules.
621–49. were promising, longer-term studies in large numbers of patients
8. Law C, Amsden GW. Single-dose azithromycin for respiratory were disappointing and none of the three macrolides decreased Proprietary Preparations (details are given in Part 3)
tract infections. Ann Pharmacother 2004; 38: 433–9. ischaemic events or provided clinical benefit; indeed, in one Arg.: Arzomicin; Azitral; Azitrogal; Azitrolan; Azitrona; Azitrox; Clearsing;
9. Blumer JL. Evolution of a new drug formulation: the rationale study9 an unexpected increase in cardiovascular mortality was Cronopen; Doyle; Fabramicina; Finatres†; Macromax; Misultina; Naxocina;
for high-dose, short-course therapy with azithromycin. Int J An- Neblic; Nifostin; Novozitron; Orobiotic; Sitrox; Sumir†; Talcilina; Tanezox;
seen in those taking clarithromycin. Triamid; Tritab; Vectocilina; Zitromax; Austral.: Zithromax; Austria: Zi-
timicrob Agents 2005; 26 (suppl 3): S143–S147.
1. Anderson JL, et al. Randomized secondary prevention trial of thromax; Belg.: Zitromax; Braz.: Astro; Atromicin; Azatill; Azi; Azidromic†;
10. Swainston Harrison T, Keam SJ. Azithromycin extended re- Azimed; Azimix; Azitrax†; Azitrin; Azitrogran; Azitrolab; Azitromicil; Az-
lease: a review of its use in the treatment of acute bacterial si- azithromycin in patients with coronary artery disease and sero-
logical evidence for Chlamydia pneumoniae infection: the Azi- itromin†; Azitron; Azitronax†; Azitroxil; Biozitrom†; Clindal; Ems-Max; Mac
nusitis and community-acquired pneumonia in the US. Drugs Azi; Mazitrom; Novatrex; Selimax; Selimax Pulso; Siftromin†; Triazi†;
2007; 67: 773–92. thromycin in Coronary Artery Disease: Elimination of Myocar-
dial Infection with Chlamydia (ACADEMIC) study. Circulation Tromix; Trozyman; Zimicina†; Zitril; Zitromax; Zitromil; Zitroneo; Canad.:
11. Panpanich R, et al. Azithromycin for acute lower respiratory 1999; 99: 1540–7. Z-Pak; Zithromax; Chile: Abacten; Asipral†; Atizor; Azitrom; Ricilina; Trex;
tract infections. Available in The Cochrane Database of System- Zithromax; Cz.: Azibiot; Azitrox; Sumamed; Zitrocin; Denm.: Zitromax;
atic Reviews; Issue 1. Chichester: John Wiley; 2008 (accessed 2. Cercek B, et al. Effect of short-term treatment with azithromy-
cin on recurrent ischaemic events in patients with acute coro- Fin.: Zithromax; Fr.: Azadose; Zithromax; Ger.: Ultreon; Zithromax; Gr.:
18/06/08). Azibactron; Azifarm; Azirox; Azirutec; Azithral; Azithrin; Azitrolid; Azivirus;
nary syndrome in the Azithromycin in Acute Coronary Syn-
drome (AZACS) trial: a randomised controlled trial. Lancet Azytan; Bezanin; Disithrom; Figothrom; Goldamycin; Gramokil; Novozi-
Administration in children. Azithromycin is licensed for use thron; Zinfect; Zithro-Due; Zithromax; Zithropan; Zithrotel; Zithroxyn; Zi-
in infants and children and the usual oral dose in those over 6 2003; 361: 809–13.
3. O’Connor CM, et al. Azithromycin for the secondary preven- trax; Hong Kong: Zithromax; Hung.: Azi; Azicid; Sumamed; Zitrocin; In-
months of age is 10 mg/kg once daily for 3 days, or an initial dose tion of coronary heart disease events: the WIZARD study: a ran- dia: Azee; Azibact; Azifast; Azithral; Aziwok; Zithrocin; Zycin; Indon.:
of 10 mg/kg may be followed by 5 mg/kg daily for a further 4 domized controlled trial. JAMA 2003; 290: 1459–66. Aztrin; Binozyt; Mezatrin; Zarom; Zibramax; Zicho; Zifin; Zistic; Zithromax;
days; those who weigh over 45 kg may be given the usual adult Zycin; Irl.: Azromax; Zithromax; Israel: Azenil; Zeto; Zithromax; Ital.: Az-
4. Grayston JT, et al. Azithromycin for the secondary prevention itrocin; Ribotrex; Trozocina; Zitromax; Malaysia: Zithromax; Mex.: Am-
dose (see above). A single dose of 30 mg/kg may also be given of coronary events. N Engl J Med 2005; 352: 1637–45. sati; Azibiot; Aziphar; Azitrocin; Azitrohexal; Azo-Max; Koptin; Macrozit;
for acute otitis media. For pharyngitis or tonsillitis in children 5. Sinisalo J, et al. Effect of 3 months of antimicrobial treatment Medatz; Sicalan; Texis; Tromicina; Truxa; Zertalin; Zithran; Zitroken; Neth.:
aged over 2 years, 12 mg/kg once daily for 5 days may be given. with clarithromycin in acute non-Q-wave coronary syndrome. Azacleus; Azitro; Merckazitro; Nucaza; Zithromax; Norw.: Azitromax; NZ:
Circulation 2002; 105: 1555–60. Zithromax; Philipp.: Zithromax; ZMax; Pol.: Azibiot; Azimycin; Azitrox;
US official guidelines suggest that for prophylaxis of disseminat- 6. Berg HF, et al. Effect of clarithromycin on inflammatory mark- Macromax; Oranex; Sumamed; Port.: 3Z; Arzomicina†; Azimax; Aziton;
ed Mycobacterium avium complex infections, azithromycin ers in patients with atherosclerosis. Clin Diagn Lab Immunol Azitrix; Biozitra; Gigatrom; Lazitrom; Neofarmiz; Unizitro; Vascin; Zithro-
20 mg/kg (to a maximum of 1.2 g) once weekly or 5 mg/kg (to a 2003; 10: 525–8. max; Zitrozina; Rus.: Azithrox (Азитрокс); Azithrus (Азитрус); Azitral
maximum of 250 mg) once daily may be given.1 For treatment, 7. Berg HF, et al. Treatment with clarithromycin prior to coronary (Азитрал); Aziwok (Азивок); Hemomycin (Хемомицин); Sumamed
artery bypass graft surgery does not prevent subsequent cardiac (Сумамед); Zetamax (Зетамакс); ZI-Factor (ЗИ-фактор); Zithrocin
10 to 12 mg/kg (to a maximum of 500 mg) once daily should be events. Clin Infect Dis 2005; 40: 358–65. (Зитроцин); Zitrolid (Зитролид); S.Afr.: Zithrogen; Zithromax; Singa-
given with other antimycobacterials.2 8. Berg HF, et al. Effect of clarithromycin treatment on Chlamydia pore: Zithromax; Spain: Altezym; Goxil; Pefloden; Toraseptol; Vinzam;
In the UK, the BNFC suggests that azithromycin may be used in pneumoniae in vascular tissue of patients with coronary artery Zentavion; Zitromax; Swed.: Azitromax; Switz.: Zithromax; Thai.:
disease: a randomized, double-blind, placebo-controlled trial. J Binozyt; Zithromax; Turk.: Azacid; Azeltin; Azitro; Azomax; Azro; Tremac;
penicillin allergic children for the prevention of secondary cases Clin Microbiol 2005; 43: 1325–9. Zitromax; Zitrotek; UAE: Azomycin; UK: Zithromax; USA: AzaSite; Zi-
of group A streptococcal infection; those 6 months and older 9. Jespersen CM, et al. Randomised placebo controlled multicen- thromax; Zmax; Venez.: Amizin; Amovin; Aruzilina; Arzomidol; Atromizin;
may be given an oral dose of 12 mg/kg (to a maximum of tre trial to assess short term clarithromycin for patients with sta- Azigram; Azimakrol; Azitrom; Azitromin; Binozyt; Saver; Zitromax; Zival.
500 mg) once daily for 5 days. ble coronary heart disease: CLARICOR trial. BMJ 2006; 332: Multi-ingredient: India: Orflaz Kit; Safkit; Mex.: Zithroflam.
22–7. Correction. ibid.; 151.
The BNFC also suggests giving azithromycin 10 mg/kg once 10. Gurfinkel E, et al. Treatment with the antibiotic roxithromycin
daily for 7 days in the treatment of mild to moderate typhoid in patients with acute non-Q-wave coronary syndromes: the fi-
caused by multidrug-resistant strains in those aged 6 months and nal report of the ROXIS Study. Eur Heart J 1999; 20: 121–7.
over. 11. Wiesli P, et al. Roxithromycin treatment prevents progression of Azlocillin (BAN, USAN, rINN)
peripheral arterial occlusive disease in Chlamydia pneumoniae Atslosilliini; Azlocilina; Azlocilline; Azlocillinum. 6-[N-(2-Oxoimi-
1. CDC. Guidelines for preventing opportunistic infections among seropositive men: a randomized, double-blind, placebo-control-
HIV-infected persons—2002: recommendations of the US Pub- led trial. Circulation 2002; 105: 2646–52. dazolidin-1-ylcarbonyl)-D-phenylglycylamino]penicillanic acid.
lic Health Service and the Infectious Diseases Society of Amer-
ica. MMWR 2002; 51 (RR-8): 1–52. Also available at: 12. Zahn R, et al. Antibiotic therapy after acute myocardial infarc- Азлоциллин
tion: a prospective randomized study. Circulation 2003; 107:
http://www.cdc.gov/mmwr/PDF/rr/rr5108.pdf (accessed 1253–9. C 20 H 23N 5 O 6 S = 461.5.
01/05/07)
13. Sander D, et al. Progression of early carotid atherosclerosis is C AS — 37091-66-0.
2. CDC. Treating opportunistic infections among HIV-exposed and only temporarily reduced after antibiotic treatment of Chlamy-
infected children: recommendations from CDC, the National In- ATC — J01C A09.
dia pneumoniae seropositivity. Circulation 2004; 109: 1010–15.
stitutes of Health, and the Infectious Diseases Society of Amer- 14. Kaehler J, et al. A randomized trial in patients undergoing per- ATC Vet — QJ01C A09.
ica. MMWR 2004; 53 (RR-14): 1–63. Also available at: cutaneous coronary angioplasty: roxithromycin does not reduce
http://www.cdc.gov/mmwr/PDF/RR/RR5314.pdf (accessed clinical restenosis but angioplasty increases antibody concen-
01/05/07) trations against Chlamydia pneumoniae. Am Heart J 2005; 150: O
987–93. H
Babesiosis. In a prospective, randomised study1 involving 58 H H
patients with babesiosis (p.823), azithromycin with atovaquone 1-7
Malaria. Azithromycin has been studied in the management HN N N S
was found to be as effective as, and associated with fewer ad- of malaria. Studies1,4 have shown that an initial loading dose of N CH3
H
verse effects than, standard therapy with quinine and clindamy- 750 mg of azithromycin on the first day followed by 250 mg dai- O O N CH3
cin. Azithromycin 600 mg once daily, or 500 to 1000 mg on day ly thereafter for 20 weeks was effective in the prophylaxis of
1 followed by 250 mg once daily thereafter, with atovaquone Plasmodium vivax malaria; the drug was well tolerated and the O
COOH
750 mg twice daily, both orally for 7 to 10 days, has been recom- most frequently reported adverse effects were heartburn, paraes-
mended by some experts2,3 in the USA for the treatment of Babe- thesia, and itching.3 In the treatment of P. vivax malaria, a study5
 Azlocillin/Aztreonam 209
Azlocillin Sodium (BANM, rINNM) Administration in hepatic or renal impairment. The in- although the incidence of cross-sensitivity appears to
terval between doses of azlocillin may need to be increased to be low (but see below).
Azlocilina sódica; Azlocilline Sodique; Azlocillinum Natricum; every 12 hours in moderate to severe renal impairment (creati-
Azlocylina sodowa; Bay-e-6905; Natrii Azlocillinum. Sodium nine clearance less than 30 mL/minute); additional dosage re- Aztreonam should be used with caution in patients
(6R)-6-[D-2-(2-oxoimidazolidine-1-carboxamido)-2-phenyla- ductions may be needed in patients with both severe renal and with renal or hepatic impairment.
cetamido]penicillanate. hepatic impairment. Breast feeding. In a study in 12 healthy women given aztreon-
Натрий Азлоциллин am, peak concentrations in breast milk were found to be less than
C 20 H 22N 5 NaO 6 S = 483.5. 1% of those in serum and this was considered suggestive of a low
C AS — 37091-65-9. risk of adverse effects in breast-fed infants.1 The American
Aztreonam (BAN, USAN, rINN) Academy of Pediatrics states that no adverse effects have been
ATC — J01C A09.
Atstreonaami; Azthreonam; Aztréonam; Aztreonamum; SQ- seen in breast-fed infants whose mothers received aztreonam and
ATC Vet — QJ01C A09. considers it to be usually compatible with breast feeding,2 al-
26776. (Z)-2-{2-Aminothiazol-4-yl-[(2S,3S)-2-methyl-4-oxo-1-
Pharmacopoeias. In Pol. though UK licensed product information recommends that
sulphoazetidin-3-ylcarbamoyl]methyleneamino-oxy}-2-methyl-
mothers should refrain from breast feeding while receiving aztre-
Incompatibility. Azlocillin sodium has been reported to be in- propionic acid. onam.
compatible with aminoglycosides, ciprofloxacin, metronidazole, Азтреонам 1. Fleiss PM, et al. Aztreonam in human serum and breast milk. Br
and tetracyclines. C 13 H 17 N 5 O 8 S 2 = 435.4. J Clin Pharmacol 1985; 19: 509–11.
C AS — 78110-38-0. 2. American Academy of Pediatrics. The transfer of drugs and oth-
Adverse Effects and Precautions er chemicals into human milk. Pediatrics 2001; 108: 776–89.
As for Carbenicillin Sodium, p.216. ATC — J01DF01. Correction. ibid.; 1029. Also available at:
Prolongation of bleeding time has been less frequent and less se- ATC Vet — QJ01DF01. h t tp : // a a pp o l ic y. a a p p u bl i c a t i on s . o rg /c gi / c o n te nt / f u ll /
pediatrics%3b108/3/776 (accessed 25/05/04)
vere with azlocillin than with carbenicillin.
Hypersensitivity. Aztreonam is said to show little cross-reac-
Hypouricaemia. Reports of transient asymptomatic decreases S O tivity with other beta lactams,1,2 but there have been isolated re-
in serum-uric acid concentrations during treatment with azlocil- H CH3 ports of immediate hypersensitivity to aztreonam in patients with
lin.1,2 H 2N a history of hypersensitivity to penicillin.3,4
N N
1. Faris HM, Potts DW. Azlocillin and serum uric acid. Ann Intern H 1. Saxon A, et al. Lack of cross-reactivity between aztreonam, a
Med 1983; 98: 414. N N monobactam antibiotic, and penicillin in penicillin-allergic sub-
2. Ernst JA, Sy ER. Effect of azlocillin on uric acid levels in serum. jects. J Infect Dis 1984; 149: 16–22.
O O 2. Adkinson NF. Immunogenicity and cross-allergenicity of aztre-
Antimicrob Agents Chemother 1983; 24: 609–10. SO3H
onam. Am J Med 1990; 88 (suppl 3C): 12S–15S.
Sodium content. Each g of azlocillin sodium contains about CH3 3. Alvarez JS, et al. Immediate hypersensitivity to aztreonam. Lan-
HOOC cet 1990; 335: 1094.
2.1 mmol of sodium. As azlocillin sodium has a lower sodium CH3
4. Hantson P, et al. Immediate hypersensitivity to aztreonam and
content than carbenicillin sodium, hypernatraemia and hypoka- imipenem. BMJ 1991; 302: 294–5.
laemia are less likely to occur. Pharmacopoeias. In Jpn and US, which allows the anhydrous
or hydrated forms. Interactions
Interactions USP 31 (Aztreonam). A white, odourless crystalline powder.
As for Benzylpenicillin, p.214. Very slightly soluble in dehydrated alcohol; practically insoluble Caution is recommended in patients receiving aztreon-
Antibacterials. For the effect of azlocillin on the clearance of in chloroform, in ethyl acetate, and in toluene; soluble in dimethyl- am and oral anticoagulants because of the possibility of
cefotaxime, and a report of neurotoxicity, see p.228. For refer- formamide and in dimethyl sulfoxide; slightly soluble in methyl increased prothrombin time.
ence to azlocillin affecting the disposition of ciprofloxacin, see alcohol. Store in airtight containers.
p.246. Incompatibility and stability. Aztreonam has been reported Antimicrobial Action
Antimicrobial Action to be incompatible with cefradine, metronidazole, nafcillin, and Aztreonam is bactericidal and acts similarly to the pen-
Azlocillin has an antimicrobial action similar to that of piperacil- vancomycin. icillins by inhibiting synthesis of the bacterial cell wall;
lin (p.315). Its activity in vitro against Enterobacteriaceae is gen- References. it has a high affinity for the penicillin-binding protein 3
erally less than that of mezlocillin or piperacillin, but it has com- 1. Bell RG, et al. Stability of intravenous admixtures of aztreonam
and cefoxitin, gentamicin, metronidazole, or tobramycin. Am J (PBP-3) of Gram-negative bacteria. The activity of az-
parable activity to piperacillin against Pseudomonas aeruginosa.
Hosp Pharm 1986; 43: 1444–53. treonam is restricted to Gram-negative aerobic organ-
Pharmacokinetics 2. Riley CM, Lipford LC. Interaction of aztreonam with nafcillin in isms, including beta-lactamase-producing strains, with
Azlocillin is not absorbed from the gastrointestinal tract to any intravenous admixtures. Am J Hosp Pharm 1986; 43: 2221–4.
3. Belliveau PP, et al. Stability of aztreonam and ampicillin sodi- poor or no activity against Gram-positive aerobes or
significant extent. It has nonlinear dose-dependent pharmacoki- um-sulbactam sodium in 0.9% sodium chloride injection. Am J
netics. Doubling an intravenous dose results in more than double anaerobic organisms. It is active against most Entero-
Hosp Pharm 1994; 51: 901–4.
the plasma concentration. Between 20 and 46% of azlocillin in 4. Trissel LA, Martinez JF. Compatibility of aztreonam with select- bacteriaceae including Escherichia coli, Klebsiella,
the circulation is bound to plasma proteins. The plasma half-life ed drugs during simulated Y-site administration. Am J Health- Proteus, Providencia, Salmonella, Serratia, Shigella,
is usually about 1 hour, but is longer in neonates; in patients with Syst Pharm 1995; 52: 1086–90.
5. Trissel LA, et al. Compatibility and stability of aztreonam and
and Yersinia spp. Some strains of Enterobacter and
renal impairment half-lives of 2 to 6 hours have been reported.
vancomycin hydrochloride. Am J Health-Syst Pharm 1995; 52: Citrobacter spp. are resistant. Aztreonam has some ac-
Azlocillin is widely distributed in body tissues and fluids. It 2560–4. tivity against Pseudomonas aeruginosa, although most
crosses the placenta into the fetal circulation and small amounts
are distributed into breast milk. There is little diffusion into the strains of other Pseudomonas spp. are insensitive. Az-
Adverse Effects treonam has good activity against Haemophilus influ-
CSF except when the meninges are inflamed. The adverse effects of aztreonam are similar to those of
Azlocillin is metabolised to a limited extent. About 50 to 70% of enzae and Neisseria spp.
other beta lactams (see Benzylpenicillin, p.213, and
a dose is excreted unchanged in the urine by glomerular filtration
Cefalotin, p.219). Hypersensitivity reactions, includ- Synergy has been reported in vitro between aztreonam
and tubular secretion within 24 hours of a dose, resulting in high and aminoglycosides against Ps. aeruginosa and some
urinary concentrations. Azlocillin is partly excreted in the bile ing skin rashes, urticaria, angioedema, exfoliative der-
where it is also found in high concentrations. matitis, eosinophilia, bronchospasm, and rarely anaphy- Enterobacteriaceae.
Plasma concentrations are enhanced if probenecid is given. laxis and toxic epidermal necrolysis, may occur in Aztreonam is stable to hydrolysis by many beta-lacta-
patients receiving aztreonam, although it has been re- mases and appears to be a poor inducer of beta-lacta-
Azlocillin is removed by haemodialysis.
ported to be only weakly immunogenic. Gastrointesti- mase production. Acquired resistance has occasionally
Uses and Administration nal effects include diarrhoea, nausea, vomiting, mouth been reported.
Azlocillin is a ureidopenicillin and, like piperacillin (p.316), is
used mainly for the treatment of infections caused by Pseu- ulcer, and an abnormal taste.
Pharmacokinetics
domonas aeruginosa. It has been used particularly for septicae- Phlebitis or thrombophlebitis has been reported after
mia, and infections of the respiratory and urinary tracts, and also Aztreonam is poorly absorbed from the gastrointesti-
the intravenous use of aztreonam, and pain or swelling
for peritonitis; for details of these infections, see under Choice of nal tract and is therefore given parenterally. Absorption
after intramuscular injection.
Antibacterial, p.162. after intramuscular injection is good; peak plasma con-
Azlocillin is commonly used with an aminoglycoside; however, Use of aztreonam may result in the overgrowth of non- centrations of about 46 micrograms/mL have been
they should be given separately as they have been shown to be susceptible organisms, including Gram-positive cocci. achieved within 1 hour of a 1-g dose. Aztreonam has a
incompatible (see Incompatibility, above). Pseudomembranous colitis or gastrointestinal bleeding plasma half-life of about 1.7 hours. The half-life may
Administration and dosage. Azlocillin is given intravenously as may develop. be prolonged in neonates, in the elderly, in patients
the sodium salt. Doses are expressed in terms of the equivalent Other adverse effects that have been reported with az- with renal impairment, and to some extent in those
amount of azlocillin; 1.05 g of azlocillin sodium is equivalent to treonam include jaundice and hepatitis, increases in
about 1 g of azlocillin. A 10% solution in a suitable diluent is with hepatic impairment. Aztreonam is about 56%
given by slow injection for doses of 2 g or less; higher doses liver enzymes, and prolongation of prothrombin and bound to plasma proteins. It is widely distributed in
should be infused over 20 to 30 minutes. partial thromboplastin times. body tissues and fluids, including bile. Diffusion into
The usual adult dose is 5 g every 8 hours for life-threatening in- Effects on the skin. References. the CSF is poor unless the meninges are inflamed. It
fections, or 2 g every 8 hours for less severe infections and uri- 1. McDonald BJ, et al. Toxic epidermal necrolysis possibly linked crosses the placenta and enters the fetal circulation;
nary-tract infections. to aztreonam in bone marrow transplant patients. Ann Pharma-
small amounts are distributed into breast milk.
cother 1992; 26: 34–5.
The following doses may be used for children: premature infants, Aztreonam is not extensively metabolised. The princi-
50 mg/kg twice daily; neonates less than 7 days old, 100 mg/kg
twice daily; infants between 7 days and 1 year, 100 mg/kg three Precautions pal metabolite, SQ-26992, is inactive and is formed by
times daily; children up to 14 years, 75 mg/kg three times daily. Aztreonam should not be given to patients who are hy- opening of the beta-lactam ring; it has a much longer
Dosage of azlocillin may need to be adjusted in patients with he- persensitive to it and should be used with caution in half-life than the parent compound. Aztreonam is ex-
patic or renal impairment (see below). those known to be hypersensitive to other beta lactams, creted mainly in the urine, by renal tubular secretion
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
210 Antibacterials
and glomerular filtration; about 60 to 70% of a dose Preparations Bacitracin (BAN, rINN)
appears within 8 hours as unchanged drug with only USP 31: Aztreonam for Injection; Aztreonam Injection. Bacitracina; Bacitracinas; Bacitracine; Bacitracinum; Bacytracyna;
small quantities of metabolites. Only small amounts of Proprietary Preparations (details are given in Part 3) Basitrasiini; Basitrasin.
unchanged drug and metabolites are excreted in the Arg.: Azactam†; Austral.: Azactam; Austria: Azactam; Belg.: Azactam;
Бацитрацин
faeces. Braz.: Azactam; Chile: Azactam; Cz.: Azactam; Denm.: Azactam; Fin.:
Azactam; Fr.: Azactam; Ger.: Azactam; Gr.: Azactam; Aztreotic†; Hong C AS — 1405-87-4.
Aztreonam is removed by haemodialysis and to a less- Kong: Azactam; India: Azenam; Trezam†; Irl.: Azactam; Israel: Azactam†; ATC — D06AX05; R02AB04.
Ital.: Azactam; Primbactam; Jpn: Azactam; Mex.: Monobac; Norw.:
er extent by peritoneal dialysis. Azactam; NZ: Azactam; Philipp.: Azactam; Pol.: Azactam; Port.: ATC Vet — QA07AA93; QD06AX05; QR02AB04.
Azactam; S.Afr.: Azactam; Singapore: Azactam; Spain: Azactam; Uro-
◊ Reviews. bactam†; Swed.: Azactam; Switz.: Azactam; UK: Azactam; USA: Azactam;
1. Mattie H. Clinical pharmacokinetics of aztreonam: an update. Venez.: Azactam.
CH3
Clin Pharmacokinet 1994; 26: 99–106.
S
Uses and Administration Bacampicillin Hydrochloride (BANM, USAN, rINNM) H 3C
O
Aztreonam is a monobactam or monocyclic beta- H2N N
Ampicillin Ethoxycarbonyloxyethyl Hydrochloride; Bacampicil-
lactam antibacterial used parenterally as an alternative line, chlorhydrate de; Bacampicillini hydrochloridum; Bakampici-
His D-Asp Asn Leu
to aminoglycosides or third-generation cephalosporins lin-hydrochlorid; Bakampicilino hidrochloridas; Bakampicillin-hid-
for the treatment of infections caused by susceptible roklorid; Bakampicillinhydroklorid; Bakampisilin Hidroklorür; D-Phe ε D-Glu
Gram-negative aerobic organisms. These have includ- Bakampisilliinihydrokloridi; Carampicillin; EPC-272; Hidrocloruro
ed bone and joint infections, gonorrhoea, intra-abdom- de bacampicilina. 1-(Ethoxycarbonyloxy)ethyl (6R)-6-(α-D-phe- Ile D-Orn Lys α Ile
inal and pelvic infections, lower respiratory-tract infec- nylglycylamino)penicillanate hydrochloride.
(bacitracin A)
tions including pseudomonal infections in patients Бакампициллина Гидрохлорид
with cystic fibrosis, meningitis, septicaemia, skin and C 21 H 27N 3 O 7 S,HCl = 502.0.
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US.
soft-tissue infections, and urinary-tract infections. For C AS — 50972-17-3 (bacampicillin); 37661-08-8
Ph. Eur. 6.2 (Bacitracin). Mixture of antimicrobial polypeptides
details of these infections and their treatment, see under (bacampicillin hydrochloride).
produced by certain strains of Bacillus licheniformis or B. subti-
Choice of Antibacterial, p.162. To broaden the spec- ATC — J01C A06.
lis. The potency is not less than 60 units/mg, calculated with ref-
ATC Vet — QJ01C A06.
trum of activity for empirical treatment of infections, erence to the dried substance. A white or almost white hygro-
aztreonam should be used with other antibacterials. scopic powder. Freely soluble in water and in alcohol. A 1%
solution in water has a pH of 6.0 to 7.0. Store at a temperature of
Use with an aminoglycoside may be of benefit in seri- O 8° to 15° in airtight containers.
ous Pseudomonas aeruginosa infections. H H USP 31 (Bacitracin). A mixture of polypeptides produced by the
S
Aztreonam is usually given parenterally by deep intra- N CH3 growth of an organism of the licheniformis group of Bacillus
H subtilis (Bacillaceae). The main components are bacitracins A,
muscular injection, by slow intravenous injection over NH2 N CH3
O O O O CH3
B1, B2, and B3. It has a potency of not less than 65 units/mg, cal-
3 to 5 minutes, or by intravenous infusion over 20 to 60 culated with reference to the dried substance. It is a white to pale
minutes. It is given to adults, in usual doses ranging O buff, hygroscopic powder, odourless or having a slight odour.
CH3 O
from 1 to 8 g daily, in divided doses every 6 to 12 Freely soluble in water; soluble in alcohol, in glacial acetic acid,
hours, according to the severity of the infection. Single (bacampicillin) and in methyl alcohol, the solution in the organic solvents usually
doses over 1 g should be given by the intravenous showing some insoluble residue; insoluble in acetone, in chloro-
form, and in ether. Its solutions deteriorate rapidly at room tem-
route. Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. perature. It is precipitated from its solutions and is inactivated by
Ph. Eur. 6.2 (Bacampicillin Hydrochloride). A white or almost
UK licensed product information recommends that in- white hygroscopic powder or granules. Soluble in water and in
salts of many of the heavy metals. pH of a solution in water con-
fants older than one week and children be given aztre- taining 10 000 units/mL is between 5.5 and 7.5. Store in airtight
dichloromethane; freely soluble in alcohol. A 2% solution in wa- containers at a temperature of 8° to 15°.
onam 30 mg/kg every 6 or 8 hours. For severe infec- ter has a pH of 3.0 to 4.5. Store in airtight containers.
tions, children of 2 years or older may be given USP 31 (Bacampicillin Hydrochloride). A white or practically
white, hygroscopic, powder. Soluble in water and in dichlo- Bacitracin Zinc (BANM, rINNM)
50 mg/kg every 6 or 8 hours up to a maximum total
romethane; freely soluble in alcohol and in chloroform; very Bacitracin zinečnatý komplex; Bacitracina zinc; Bacitracin-cink;
daily dose of 8 g. Although not licensed in the UK for slightly soluble in ether. pH of a 2% solution in water is between Bacitracine Zincique; Bacitracine-zinc; Bacitracino cinko komple-
neonates less than one week old, the BNFC suggests a 3.0 and 4.5. Store in airtight containers. ksas; Bacitracins Zinc Complex; Bacitracinum Zincicum; Bacitrac-
dose of 30 mg/kg every 12 hours. In the USA the dose inum zincum; Bacytracyna cynkowa; Sinkkibasitrasiini; Zinc Baci-
Adverse Effects and Precautions
for children from 9 months of age is 30 mg/kg every 8 As for Ampicillin, p.204. Diarrhoea has been reported to occur tracin; Zinci Bacitracinum; Zinkbacitracin.
hours for mild to moderate infection, or every 6 to 8 less frequently with bacampicillin. Цинка Бацитрацин
hours in moderate to severe infection up to a maximum C AS — 1405-89-6.
Interactions ATC — D06AX05; R02AB04.
total daily dose of 120 mg/kg. As for Benzylpenicillin, p.214. ATC Vet — QD06AX05; QR02AB04.
For details of dosage in patients with renal impairment, Antimicrobial Action Pharmacopoeias. In Eur. (see p.vii), Int., and US.
see below. Bacampicillin has the antimicrobial action of ampicillin in vivo Ph. Eur. 6.2 (Bacitracin Zinc). The zinc complex of bacitracin.
A single intramuscular dose of 1 g has been recom- (p.204). It possesses no intrinsic activity and needs to be hydro- The potency is not less than 60 units/mg, calculated with refer-
lysed to ampicillin. ence to the dried substance. A white or light-yellowish-grey hy-
mended for the treatment of gonorrhoea or cystitis.
Pharmacokinetics groscopic powder. Slightly soluble in water and in alcohol. The
Aztreonam lysine is under investigation for inhalation- Bacampicillin is more rapidly and completely absorbed from the filtrate of a saturated solution has a pH of 6.0 to 7.5. Store in air-
al use in respiratory-tract infections. gastrointestinal tract than ampicillin, to which it is hydrolysed in tight containers.
the intestinal wall and plasma. Peak plasma-ampicillin concen- USP 31 (Bacitracin Zinc). The zinc complex of bacitracin, which
◊ General references. consists of a mixture of antimicrobial polypeptides, the main
trations occur about 30 to 60 minutes after oral doses, and are
1. Brogden RN, Heel RC. Aztreonam: a review of its antibacterial components being bacitracins A, B1, B2, and B3. It has a poten-
activity, pharmacokinetic properties and therapeutic use. Drugs about 2 to 3 times those after an equivalent dose of ampicillin.
The absorption of bacampicillin from tablets does not appear to cy of not less than 65 units/mg, calculated with reference to the
1986; 31: 96–130.
be affected by the presence of food in the stomach. About 75% dried substance. It contains not less than 4% and not more than
2. Neu HC. ed. Aztreonam’s role in the treatment of Gram-negative
infections. Am J Med 1990; 88 (suppl 3C): 1S–43S. of a dose is excreted in the urine as ampicillin within 8 hours. 6% of zinc, calculated with reference to the dried substance. A
3. Hellinger WC, Brewer NS. Carbapenems and monobactams: im- white or pale tan, hygroscopic powder, odourless or having a
ipenem, meropenem, and aztreonam. Mayo Clin Proc 1999; 74: Uses and Administration slight odour. Sparingly soluble in water. pH of a saturated solu-
420–34. Bacampicillin has actions and uses similar to those of ampicillin tion in water is between 6.0 and 7.5. Store in airtight containers
(p.205) to which it is rapidly hydrolysed in the body. It is given at a temperature of 8° to 15°.
Administration. References to the use of aztreonam (as aztre- orally as the hydrochloride in adult doses of 0.8 to 2.4 g daily, in
onam lysine) by inhalation in the treatment of airway infections 2 divided doses; children over 5 years of age have been given 25 Incompatibility. Bacitracin was slowly inactivated in bases
in patients with cystic fibrosis.1,2 to 50 mg/kg daily in 2 divided doses. containing stearyl alcohol, cholesterol, polyoxyethylene deriva-
1. Gibson RL, et al. Microbiology, safety, and pharmacokinetics of tives, and sodium laurilsulfate, and was rapidly inactivated in
aztreonam lysinate for inhalation in patients with cystic fibrosis.
In uncomplicated gonorrhoea a single dose of bacampicillin hy- bases containing water, macrogols, propylene glycol, glycerol,
Pediatr Pulmonol 2006; 41: 656–65. drochloride 1.6 g with probenecid 1 g may be given in areas cetylpyridinium chloride, benzalkonium chloride, ichthammol,
2. Retsch-Bogart GZ, et al. A phase 2 study of aztreonam lysine for where gonococci remain sensitive. phenol, and tannic acid.1
inhalation to treat patients with cystic fibrosis and Pseudomonas
aeruginosa infection. Pediatr Pulmonol 2008; 43: 47–58.
Preparations 1. Plaxco JM, Husa WJ. The effect of various substances on the
antibacterial activity of bacitracin in ointments. J Am Pharm As-
USP 31: Bacampicillin Hydrochloride for Oral Suspension; Bacampicillin soc (Sci) 1956; 45: 141–5.
Administration in renal impairment. Dosage of aztreonam Hydrochloride Tablets.
should be reduced in moderate to severe renal impairment. Pa- Stability. Bacitracin zinc was more stable than bacitracin and
Proprietary Preparations (details are given in Part 3)
tients with renal impairment may be given a usual initial dose could be stored for 18 months at temperatures up to 40° without
Austria: Penglobe; Belg.: Bacampicin†; Canad.: Penglobe†; Cz.: Pen-
followed by a maintenance dose adjusted according to creatinine globe†; Fr.: Bacampicine†; Penglobe†; Ger.: Ambacamp†; Hong Kong: appreciable loss of activity. Lozenges of bacitracin zinc and oint-
clearance (CC): Penglobe†; Hung.: Penglobe†; India: Penglobe; Ital.: Ampibac†; Bacacil; ments and tablets containing bacitracin zinc with neomycin were
• CC 10 to 30 mL/minute: half the initial dose Bacagen; Bacasint; Bacattiv†; Bacillin; Bakam; Campixen†; Penglobe; Polibiot- more stable than the corresponding bacitracin preparations.
ic†; Rebacil; Winnipeg; Malaysia: Penbaccin†; Penglobe†; Mex.: Pen- Bacitracin zinc was less bitter than bacitracin and the taste was
• CC less than 10 mL/minute: one-quarter of the initial dose globe†; Philipp.: Penglobe; Port.: Bacampicin†; Spain: Ambaxino†; Pen- more readily disguised.1
globe†; Swed.: Penglobe†; Thai.: Penglobe†; Turk.: Bakamsilin; Penbak.
• haemodialysis patients: a supplementary dose of one-eighth of 1. Gross HM, et al. Zinc bacitracin in pharmaceutical preparations.
the initial dose may be given after each dialysis session Drug Cosmet Ind 1954; 75: 612–13.
 Bacampicillin Hydrochloride/Bekanamycin Sulfate 211
Units 900 units/kg daily in 2 or 3 divided doses; those weighing more Bambermycin (BAN, pINN)
The second International Standard Preparation (1964) than 2.5 kg may be given 1000 units/kg daily in 2 or 3 divided
Bambermicina; Bambermycine; Bambermycins (USAN); Bamber-
doses.
of bacitracin zinc contains 74 units/mg. mycinum; Flavophospholipol.
Preparations Бамбермицин
Adverse Effects and Precautions BP 2008: Polymyxin and Bacitracin Eye Ointment; C 69 H 108 N 5 O 34 P = 1582.6 (moenomycin A).
Systemic bacitracin may produce severe nephrotoxici- USP 31: Bacitracin and Polymyxin B Sulfate Topical Aerosol; Bacitracin for C AS — 11015-37-5 (bambermycin); 76095-39-1 (moen-
Injection; Bacitracin Ointment; Bacitracin Ophthalmic Ointment; Bacitracin omycin A).
ty, resulting in renal failure due to tubular and glomer- Zinc and Polymyxin B Sulfate Ointment; Bacitracin Zinc and Polymyxin B
ular necrosis. Renal function should be determined be- Sulfate Ophthalmic Ointment; Bacitracin Zinc Ointment; Neomycin and
Polymyxin B Sulfates and Bacitracin Ointment; Neomycin and Polymyxin B
fore, and daily during, therapy. Fluid intake and urinary Sulfates and Bacitracin Ophthalmic Ointment; Neomycin and Polymyxin B CH
COOH
output should be maintained to avoid kidney toxicity. Sulfates and Bacitracin Zinc Ointment; Neomycin and Polymyxin B Sulfates HO O
and Bacitracin Zinc Ophthalmic Ointment; Neomycin and Polymyxin B Sul- O COOH
If renal toxicity occurs, bacitracin should be stopped. fates, Bacitracin Zinc, and Hydrocortisone Acetate Ophthalmic Ointment; O
O O
OH
O H
Use with other nephrotoxic drugs should be avoided Neomycin and Polymyxin B Sulfates, Bacitracin Zinc, and Hydrocortisone NH P OR
Ointment; Neomycin and Polymyxin B Sulfates, Bacitracin Zinc, and Hydro- HO O
(see Interactions, below). cortisone Ophthalmic Ointment; Neomycin and Polymyxin B Sulfates, Baci- H
N CH
tracin Zinc, and Lidocaine Ointment; Neomycin and Polymyxin B Sulfates, O
HO O
Nausea and vomiting may occur, as well as pain at the Bacitracin, and Hydrocortisone Acetate Ointment; Neomycin and Poly- HO O
O
site of injection. Hypersensitivity reactions, including myxin B Sulfates, Bacitracin, and Hydrocortisone Acetate Ophthalmic Oint- HO
ment; Neomycin and Polymyxin B Sulfates, Bacitracin, and Lidocaine Oint- OH OH
CH
rashes and anaphylaxis, have occurred with both sys- ment; Neomycin Sulfate and Bacitracin Ointment; Neomycin Sulfate and HO O O
O
Bacitracin Zinc Ointment; Polymyxin B Sulfate and Bacitracin Zinc Topical O HO
temic, and more rarely with topical, use. Aerosol; Polymyxin B Sulfate and Bacitracin Zinc Topical Powder. HN
HO
O
O
Proprietary Preparations (details are given in Part 3) NH H C
Interactions O
Austria: Rhinocillin B†; Canad.: Baciguent; Baciject; Bacitin; USA: Ak-Trac-
Additive nephrotoxicity would be anticipated if baci- in†; Baci-IM; Venez.: Baciderm. OH
tracin were given systemically with other nephrotoxic Multi-ingredient: Arg.: Biotaer an Caramelos; Biotaer Gamma†; Biotaer
drugs, particularly colistin, kanamycin, neomycin, Nebulizable; Biotaer Ultrason Nebulizable†; Butimerin; Carnot Colutorio;
CH CH
polymyxin B, and streptomycin; such use should be Cicatrex; Nebapol B†; Austral.: Cicatrin; Nemdyn; Neosporin; Austria:
Baneocin; Cicatrex; Eucillin; Nebacetin; Belg.: Nebacetine; Neobacitracine; R=
CH
avoided.. Bacitracin is reported to enhance the neu- Braz.: Anaseptil; Antiseptin†; Bacidermina; Bacigen; Bacinantrat†; Bacineo†;
Bactoderm; Belcetin†; Cicatrene; Cicatrizan†; Cutiderm; Dermacetin-Ped†; H C CH CH CH
romuscular blocking action of certain drugs, such as Dermase; Epicitrin; Ferid; Kindcetin; Nebacetin; Nebaciderme; Nebacimed;
neuromuscular blockers and anaesthetics, if given dur- Nebacitrin†; Nebactrina†; Nebalon†; Neobacina†; Neobacipan†; Ne-
(moenomycin A)
ing surgery or postoperatively. ocetrin; Neotop; Neotricin; Polysporin; Pomacetin†; Rinogerol†; Teut-
omicin; Canad.: Antibiotique Onguent; Bacimyxin; Band-Aid Antibiotic; Bi-
oderm; Cicatrin; Cortimyxin; Cortisporin; Johnson & Johnson First Aid
Ointment†; Neosporin; Neotopic†; Optimyxin; Ozonol Antibiotic Plus; Profile
Antimicrobial Action Polycidin†; Polyderm; Polysporin; Polysporin Complete Antibiotic; Bambermycin is an antibacterial complex containing mainly
Bacitracin interferes with bacterial cell wall synthesis Polysporin Triple Antibiotic; Polytopic; Chile: Bacitopic Compuesto; Baci- moenomycin A and moenomycin C and which may be obtained
topic†; Banedif; Banedif Oftalmico; Banedif Oftalmico con Prednisolona; Bi- from cultures of Streptomyces bambergiensis or by other means.
by blocking the function of the lipid carrier molecule odexin†; Dermabiotico; Grifoftal†; Monticina; Nasomin; Oftabiotico; Pensu- It is used as a growth promotor in veterinary practice.
that transfers cell wall subunits across the cell mem- lan; Polvos Antibioticos†; Rinobanedif; Unguento Dermico Antibiotico; Cz.:
Framykoin; Ophthalmo-Framykoin; Ophthalmo-Framykoin Compositum;
brane. It is active against many Gram-positive bacteria Pamycon; Fin.: Bacibact; Fr.: Bacicoline; Collunovar†; Oropivalone Bacitra-
including staphylococci, streptococci (particularly cine†; Ger.: Anginomycin†; Bivacyn†; Cicatrex†; Nebacetin; Neobac;
group A streptococci), corynebacteria, and clostridia. It Polyspectran; Polyspectran HC; Gr.: Apobacyn; Lysopaine; Nebacetin; Baquiloprim (BAN, rINN)
Sopain-Plus; Vioplex-T; Hong Kong: Bacimycin; Bivacyn; Nebacetin†; Ne-
is also active against Actinomyces, Treponema palli- osporin†; PMS-Baximycin†; Polyfax†; Prednitracin†; Hung.: Baneocin; Biva- Bakilopriimi; Bakiloprim; Baquiloprima; Baquiloprime; Baquilopri-
cyn; India: Nebasulf; Neosporin; Neosporin-H; Indon.: Nebacetin; Ne- mum; 138OU. 5-(8-Dimethylamino-7-methyl-5-quinolylme-
dum, and some Gram-negative species such as Neisse- tracin; Scanderma Plus; Tracetin; Irl.: Cicatrin; Polyfax; Israel: Bamyxin; thyl)pyrimidin-2,4-diyldiamine.
ria and Haemophilus influenzae, although most Gram- Ital.: Bimixin; Cicatrene; Enterostop; Orobicin; Malaysia: Bacitracin-N; Ba-
negative organisms are resistant. neocin; Mex.: Nebacetina; Neosporin; Polixin; Tribiot; Neth.: Bacicoline-B; Бахилоприм
Norw.: Bacimycin; Philipp.: BNP Ointment; Terramycin Plus; Trimycin;
Trimycin-H; Pol.: Baneocin; Bivacyn; Multibiotic; Neotopic; Tribiotic; Port.: C 17 H 20 N 6 = 308.4.
Acquired bacterial resistance to bacitracin rarely oc- Baciderma; Bacitracina Zimaia; Bacitracina-Neo†; Cicatrin; Davimicina†; C AS — 102280-35-3.
curs, but resistant strains of staphylococci have been Dermimade Bacitracina†; Dermobiotico†; Dimicina; Distop; Oralbiotico†;
Polisulfade; Rus.: Baneocin (Банеоцин); S.Afr.: Cicatrin; Neosporin†;
detected. Polysporin; Singapore: Baneocin; Batramycin; Fast Powder; Polybamycin;
Spain: Bacisporin; Banedif; Dermisone Tri Antibiotic; Dermo Hubber; Ed- CH3 N
ifaringen; Lizipaina; Neo Bacitrin; Oxidermiol Enzima†; Phonal; Pomada An-
Pharmacokinetics tibiotica; Rinobanedif; Tulgrasum Antibiotico; Switz.: Bacimycin; Baneopol;
Batramycine; Cicatrex; Lysopaine; Nebacetin; Neotracin; Oro-Pivalone; N N NH2
Bacitracin is not appreciably absorbed from the gas- H 3C
Prednitracin†; Thai.: Bacal; Banocin; Basina; Biochin†; Genquin; Izac†; Med-
trointestinal tract or from intact or denuded skin, cin; My-B; Mybacin; Mybacin Dermic; Turk.: Thiocilline; UK: Cicatrin†; Poly-
fax; USA: Ak-Poly-Bac; Ak-Spore; Betadine First Aid Antibiotics + Moistur- N
wounds, or mucous membranes; however, systemic H 3C
izer; Betadine Plus First Aid Antibiotics & Pain Reliever; Cortimycin;
absorption has been reported after peritoneal lavage. It Cortisporin†; Lanabiotic†; Mycitracin†; Neocin; Neosporin + Pain Relief;
is rapidly absorbed when given by intramuscular injec- Neosporin†; Neotricin HC; Ocu-Spor-B; Ocutricin; Polycin-B; Polymycin; NH2
Polysporin†; Polytracin; Spectrocin Plus†; Tri-Biozene; Venez.: Dermabiotic.
tion. Bacitracin readily diffuses into pleural and ascitic
fluids but little passes into the CSF. About 10 to 40% Profile
Baquiloprim is a diaminopyrimidine antibacterial used in veteri-
of a single injected dose is excreted slowly by glomer- nary medicine with sulfadimethoxine or sulfadimidine.
ular filtration and appears in the urine within 24 hours. Balofloxacin (rINN)
Balofloxacine; Balofloxacino; Balofloxacinum; Q-35. (±)-1-Cyclo-
Uses and Administration propyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-(methylamino)pip- Bekanamycin Sulfate (rINNM)
Bacitracin and bacitracin zinc are applied topically (as eridino]-4-oxo-3-quinolinecarboxylic acid.
Aminodeoxykanamycin Sulphate; Bekanamycin Sulphate; Békan-
a cream, ointment, dusting powder, or ophthalmic oint- Балофлоксацин amycine, Sulfate de; Bekanamycini Sulfas; Kanamycin B Sulphate;
ment), often with other antibacterials such as neomycin C 20 H 24 FN 3 O 4 = 389.4. KDM; NK-1006; Sulfato de bekanamicina. 6-O-(3-Amino-3-de-
and polymyxin B, and sometimes with corticosteroids, oxy-α-D-glucopyranosyl)-2-deoxy-4-O-(2,6-diamino-2,6-dide-
C AS — 127294-70-6.
in the treatment of local infections due to susceptible oxy-α-D-glucopyranosyl)-D-streptamine sulphate.
organisms. Typical concentrations of bacitracin or Беканамицина Сульфат
bacitracin zinc in such products are 250 to 500 units/g. C 18 H 37 N 5 O 10 ,2 ⁄ H 2 SO 4 = 728.7.
Absorption from open wounds and from the bladder or OCH3
C AS — 4696-76-8 (bekanamycin); 70550-99-1 (bekan-
peritoneal cavity may lead to adverse effects, although H amycin sulfate).
the dose-limiting toxicity of combined preparations is N N
considered to be due to neomycin. NH OH
H 3C HO
OH
Parenteral use of bacitracin is usually avoided be- F COOH O H2N
cause of nephrotoxicity but it may be given intramus- HO O NH2
O HO
cularly for the treatment of infants with staphylococcal H2N OH O
pneumonia and empyema due to susceptible organ- O
isms. For details of doses, see below. Profile H 2N NH2
Balofloxacin is a fluoroquinolone antibacterial used in the treat-
Bacitracin has been given orally in the treatment of an- ment of urinary-tract infections. (bekanamycin)
tibiotic-associated colitis due to Clostridium difficile. Preparations
Pharmacopoeias. In Jpn.
Administration in children. In the USA, bacitracin may be Proprietary Preparations (details are given in Part 3)
given intramuscularly for the treatment of infants with staphylo- Kor.: Q-Roxin. Profile
coccal pneumonia and empyema due to susceptible organisms. Bekanamycin is an aminoglycoside and is a congener of kan-
Infants weighing less than 2.5 kg may be given a dose of amycin. It has properties similar to those of gentamicin (p.282).
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
212 Antibacterials
It is given topically as the sulfate for the treatment of eye infec- Benzathine benzylpenicillin should not be injected in- although phenoxymethylpenicillin is usually preferred.
tions. It has also been given intramuscularly and orally. It is re- travascularly since ischaemic reactions may occur. Benzathine benzylpenicillin 900 mg is equivalent to
ported to be more toxic than kanamycin.
about 720 mg of benzylpenicillin (1.2 million units).
Preparations Interactions
Proprietary Preparations (details are given in Part 3) For early syphilis, a single dose of benzathine ben-
Port.: Kanacyl†.
As for Benzylpenicillin, p.214. zylpenicillin 1.8 g by deep intramuscular injection is
Multi-ingredient: Ital.: Visucloben Antibiotico; Visumetazone Antibioti- given, usually as 2 injections at separate sites. In late
co. Pharmacokinetics syphilis, 1.8 g is given at weekly intervals for 3 consec-
When benzathine benzylpenicillin is given by intra- utive weeks. Benzathine benzylpenicillin is not usually
muscular injection, it forms a depot from which it is recommended for the treatment of neurosyphilis be-
Benethamine Penicillin (BAN, rINN) slowly released and hydrolysed to benzylpenicillin. cause of reports of inadequate penetration into the CSF.
Bénéthamine Pénicilline; Benethaminum Penicillinum; Penicilina- Peak plasma concentrations are produced in about 24 Infants up to 2 years of age may be given a single intra-
benetamina. Benzyl(phenethyl)ammonium (6R)-6-(2-phenyla- hours and are lower than those after an equivalent dose muscular dose of 37.5 mg/kg for the treatment of con-
cetamido)penicillanate. of benzylpenicillin potassium or sodium. However, de- genital syphilis, provided there is no evidence of infec-
Бенетамин Пенициллин pending on the dose, benzylpenicillin is usually detect- tion in the CSF.
C 15 H 17 N,C 16 H 18 N 2 O 4S = 545.7. able in plasma for up to 4 weeks (but see below).
C AS — 751-84-8. For the treatment of other treponemal infections, such
Distribution into the CSF is reported to be poor. as yaws, pinta, and endemic syphilis (bejel), a single
Due to the slow absorption from the site of injection, intramuscular dose of benzathine benzylpenicillin
O benzylpenicillin has been detected in the urine for up to 900 mg is given; a dose of 450 mg may be used in chil-
H H H2N +
S
12 weeks after a single dose. dren.
N CH3
H Benzathine benzylpenicillin is relatively stable in the For streptococcal pharyngitis and the primary preven-
N CH3
O presence of gastric juice, but absorption from the gas- tion of rheumatic fever, the adult dose is a single intra-
COO- trointestinal tract is variable. Plasma concentrations of muscular injection of 900 mg; children under 30 kg
benzylpenicillin after an oral dose are lower than those may be given 225 to 675 mg. To prevent recurrences of
Profile from the same dose of a soluble penicillin; peak con- acute rheumatic fever, 900 mg is given intramuscularly
Benethamine penicillin is a poorly soluble derivative of ben- centrations are also produced less rapidly, but may per- every 3 or 4 weeks to adults; a dose of 450 mg has been
zylpenicillin (p.213) with similar actions and uses, although it is sist for longer.
not recommended for chronic, severe, or deep-seated infections. used for children under 30 kg.
After deep intramuscular injection it forms a depot from which it Plasma concentrations. Benzathine benzylpenicillin has
is slowly absorbed and hydrolysed to benzylpenicillin. been given every 4 weeks for secondary prophylaxis against
Preparations
Benethamine penicillin is usually given with benzylpenicillin so- rheumatic fever, although some advocate giving it every 3 weeks USP 31: Penicillin G Benzathine and Penicillin G Procaine Injectable Suspen-
dium and also sometimes procaine benzylpenicillin to produce to ensure adequate plasma concentrations of benzylpenicillin. sion; Penicillin G Benzathine Injectable Suspension; Penicillin G Benzathine
both an immediate and a prolonged effect; overall, the effect lasts Typical concentrations achieved after a single intramuscular in- Oral Suspension; Penicillin G Benzathine Tablets.
for 2 to 3 days. jection of benzathine benzylpenicillin 900 mg have been cited as Proprietary Preparations (details are given in Part 3)
Preparations about 100, 20, and 2 nanograms/mL on days 1, 14, and 32 re- Arg.: Benzetacil; Galtamicina; Pen di Ben; Retarpen; Austral.: Bicillin L-A;
spectively. In one study1 adequate concentrations (defined as Austria: Retarpen; Belg.: Penadur; Braz.: Bactopen; Benzatron; Benzetacil;
Proprietary Preparations (details are given in Part 3)
20 nanograms or more per mL) were seen in more than 80% of Bepeben; Longacilin; Neo Benzil†; Pencil B; Cz.: Pendepon Compositum;
Multi-ingredient: Fr.: Biclinocilline; Port.: Atralmicina. serum samples at 3 weeks, but in only 36% at 4 weeks. In a fur- Retarpen; Fr.: Extencilline; Ger.: Pendysin; Gr.: Penadur; Hung.: Re-
tarpen†; India: Pencom; Penidure; Israel: Durabiotic; Ital.: Diaminocillina;
ther study,2 in which single doses of 900 mg, 1.35 g and 1.8 g Wycillina; Malaysia: Retarpen; Mex.: Benacilina; Bencelin; Benzafur; Ben-
were compared, it appeared that doses higher than the 900-mg zanil Simple; Benzetacil; Ipenxin; Lentopenil; Unicil 6:3:3; Unicil L-A; Neth.:
dose of benzathine benzylpenicillin usually recommended might Penidural; NZ: Bicillin L-A; Philipp.: Penadur; Zalpen; Pol.: Debecylina;
Benzathine Benzylpenicillin (BAN, rINN) prolong the duration of protective plasma concentrations of ben- Port.: Lentocilin S; Penadur†; Rus.: Bicillin-1 (Бициллин-1); Extencilline
zylpenicillin (defined as above 25 nanograms/mL) and improve (Экстенциллин); S.Afr.: Bicillin L-A; Penilente LA†; Singapore: Retarpen;
Bensylpenicillinbensatin; Bensylpenicillinbenzatin; Bentsyylipenisil- Spain: Benzetacil; Cepacilina; Thai.: Penadur†; Turk.: Benzapen; Benzapen
the efficacy of dosing every 4 weeks for prophylaxis against 6.3.3; Deposilin; Deposilin 6.3.3; Penadur; Penadur 6.3.3; USA: Bicillin L-A;
liinibentsatiini; Benzathin-benzylpenicilin; Benzathine benzylpéni-
rheumatic fever. Permapen; Venez.: Benzetacil L-A; Silcopen†.
cilline; Benzathine Penicillin; Benzathini Benzylpenicillinum; Benza-
tin Penisilin; Benzatina bencilpenicilina; Benzethacil; Benzilpenicili- 1. Kaplan EL, et al. Pharmacokinetics of benzathine penicillin G: Multi-ingredient: Austria: Retarpen compositum; Chile: Karbasalin†;
serum levels during the 28 days after intramuscular injection of Ger.: Retacillin compositum; Tardocillin; Ital.: Tri-Wycillina†; Mex.: Bence-
nas benzatinas; Benzilpenicillina Benzatinica; Benzilpenicillin-benz- 1 200 000 units. J Pediatr 1989; 115: 146–50. lin Combinado; Benzanil Compuesto; Benzetacil Combinado; Pecivax;
antin; Benzylopenicylina benzatynowa; Benzylpenicillinum Ben- 2. Currie BJ, et al. Penicillin concentrations after increased doses Pendiben Compuesto; Neth.: Penidural D/F†; Port.: Lentocilin; Penadur
zanthinum; Benzylpenicillinum benzathinum; Penicillin G Benza- of benzathine penicillin G for prevention of secondary rheumatic 6.3.3†; Rus.: Bicillin-3 (Бициллин-3); Bicillin-5 (Бициллин-5); S.Afr.: Peni-
fever. Antimicrob Agents Chemother 1994; 38: 1203–4. lente Forte†; Ultracillin; Spain: Benzetacil Compuesta; Cepacilina 633; Pe-
thine; Penisilin G Benzatin; Penzaethinum G. NN′-Dibenzylethyl- nilevel Retard; USA: Bicillin C-R; Venez.: Benzetacil 3-3; Benzetacil 6-3-3.
enediammonium bis[(6R)-6-(2-phenylacetamido)penicillanate]. Pregnancy. The pharmacokinetics of benzathine benzylpenicil-
Бензатина Бензилпенициллин lin appear to be altered in late pregnancy. Of 10 healthy pregnant
C 16 H 20 N 2 (C 16 H 18N 2 O 4 S) 2 = 909.1. women given benzathine benzylpenicillin 1.8 g intramuscularly
C AS — 1538-09-6 (anhydrous benzathine benzylpenicil- before caesarean section, only 4 achieved adequate serum con- Benzathine Phenoxymethylpenicillin
centrations of benzylpenicillin (for syphilis, at least
lin); 5928-83-6 (benzathine benzylpenicillin monohydrate); Benzatin Fenoksimetil Penisilin; Benzatina fenoximetilpenicilina;
18 nanograms/mL) for 7 days.1
41372-02-5 (benzathine benzylpenicillin tetrahydrate). Penicillin V Benzathine (USAN); Phenoxymethylpenicillini Dibenzy-
1. Nathan L, et al. Penicillin levels following the administration of
ATC — J01CE08. benzathine penicillin G in pregnancy. Obstet Gynecol 1993; 82: laethylendiaminum. N,N′-Dibenzylethylenediammonium bis[(6R)-
ATC Vet — QJ01CE08. 338–42. 6-(2-phenoxyacetamido)penicillanate].
(C 16 H 18 N 2 O 5 S) 2 ,C 16 H 20 N 2 = 941.1.
Uses and Administration C AS — 5928-84-7 (anhydrous benzathine phenoxymeth-
O Benzathine benzylpenicillin has the same antimicrobi- ylpenicillin); 63690-57-3 (benzathine phenoxymethylpeni-
H H
S
+NH
2 al action as benzylpenicillin (p.214), to which it is hy- cillin tetrahydrate).
N CH3 drolysed gradually after deep intramuscular injection. ATC — J01CE10.
H
N CH3 +NH
2
This results in a prolonged effect, but because of the ATC Vet — QJ01CE10.
O
COO- 2
relatively low blood concentrations of benzylpenicillin
produced, its use should be restricted to micro-organ-
Pharmacopoeias. In Chin., Eur. (see p.vii), and Int.
isms that are highly susceptible to benzylpenicillin. In O
Jpn and US include the tetrahydrate. acute infections, and when bacteraemia is present, the H H +
NH2
S
Ph. Eur. 6.2 (Benzylpenicillin, Benzathine). It contains a variable initial treatment should be with benzylpenicillin by in- O N CH3
H
quantity of water. A white or almost white powder. Very slightly jection. N CH3 +NH
2
soluble in water; slightly soluble in alcohol; freely soluble in O
dimethylformamide and in formamide. Store in airtight contain- Infections treated with benzathine benzylpenicillin in- COO- 2
ers. clude diphtheria (asymptomatic carriers), pharyngitis
USP 31 (Penicillin G Benzathine). The tetrahydrate is a white, (Streptococcus pyogenes; Arcanobacterium haemo- Pharmacopoeias. In US.
odourless, crystalline powder. Soluble 1 in 5000 of water and 1 lyticum (Corynebacterium haemolyticum)), and syphi-
in 65 of alcohol. pH in a solution prepared by dissolving 50 mg USP 31 (Penicillin V Benzathine). A practically white powder
in 50 mL of dehydrated alcohol, and adding 50 mL of water is
lis (including non-venereal treponematoses). It is also having a characteristic odour. Soluble 1 in 3200 of water, 1 in 330
between 4.0 and 6.5. Store in airtight containers. used for primary and secondary prophylaxis of rheu- of alcohol, 1 in 37 of acetone, 1 in 42 of chloroform, and 1 in 910
matic fever. For details of these infections and their of ether. pH of a 3% suspension in water is between 4.0 and 6.5.
Store in airtight containers.
Adverse Effects and Precautions treatment, see under Choice of Antibacterial, p.162.
As for Benzylpenicillin, p.213. Administration and dosage. Benzathine benzylpenicil- Profile
Benzathine phenoxymethylpenicillin has actions and uses simi-
Non-allergic (embolic-toxic) reactions similar to those lin is given by deep intramuscular injection, sometimes lar to those of phenoxymethylpenicillin (p.314) and is given oral-
associated with procaine benzylpenicillin, p.319, have with procaine benzylpenicillin and benzylpenicillin ly in the treatment of susceptible mild to moderate infections.
been reported rarely with benzathine benzylpenicillin. itself. It has been given orally for mild infections, Doses are expressed in terms of phenoxymethylpenicillin.
 Benethamine Penicillin/Benzylpenicillin 213
Preparations white to slightly yellow crystalline powder. It is odourless or Some patients with syphilis and other spirochaete in-
USP 31: Penicillin V Benzathine Oral Suspension. practically so, and is moderately hygroscopic. Its solutions lose fections may experience a Jarisch-Herxheimer reaction
potency fairly rapidly at room temperature, but retain substan-
Proprietary Preparations (details are given in Part 3)
tially full potency for several days at temperatures below 15°. Its
shortly after starting treatment with penicillin, which is
Austral.: Abbocillin-V; Cilicaine V; Austria: Ospen; Canad.: Pen-Vee†; probably due to the release of endotoxins from the
Cz.: Ospen; Fr.: Oracilline; Ger.: InfectoBicillin; Gr.: Ospen; Hung.: Ospen; solutions are rapidly inactivated by acids, by alkali hydroxides,
Oxybion†; Pol.: Ospen; Rus.: Ospen (Оспен); Spain: Benoral; Switz.: by oxidising agents, and by penicillinase. pH of a 6% solution in killed treponemes and should not be mistaken for a hy-
Ospen; Phenocillin; Turk.: Pen-Os; Venez.: Ospen. water is between 5.0 and 7.5. Store in airtight containers. persensitivity reaction. Symptoms include fever, chills,
Incompatibility. Benzylpenicillin has been reported to be in- headache, and reactions at the site of the lesions. The
compatible with metal ions and some rubber products. Its stabil- reaction can be dangerous in cardiovascular syphilis,
Benzylpenicillin (BAN, rINN) ity may be affected by ionic and nonionic surfactants, oxidising or where there is a serious risk of increased local dam-
and reducing agents, alcohols, glycerol, glycols, macrogols and age, such as with optic atrophy.
Bencilpenicilina; Bensylpenicillin; Bentsyylipenisilliini; Benzil Penisil- other hydroxy compounds, some paraffins and bases, some pre-
iin; Benzylpénicilline; Benzylpenicillinum; Crystalline Penicillin G; servatives such as chlorocresol or thiomersal, carbohydrate solu- Hypersensitivity. The overall incidence of allergic re-
Penicillin; Penicillin G; Penisilin G. (2S,5R,6R)-3,3-Dimethyl-7-oxo- tions in an alkaline pH, fat emulsions, blood and blood products, actions to penicillin has been reported to vary from
6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-car- and viscosity modifiers. Benzylpenicillin is incompatible with a about 1 to 10% although some patients may have been
boxylic acid; (6R)-6-(2-Phenylacetamido)penicillanic acid. wide range of acidic and basic drugs (see Stability, below) and
with a number of other antimicrobials, including amphotericin B,
incorrectly labelled ‘allergic to penicillin’. Anaphylac-
Бензилпенициллин tic reactions occur in about 0.05% of patients, usually
some cephalosporins, and vancomycin. Benzylpenicillin and
C 16 H 18N 2 O 4 S = 334.4. after parenteral use, but they have also been reported
aminoglycosides are mutually incompatible and injections
C AS — 61-33-6. should be given at separate sites. after taking oral penicillin.
ATC — J01CE01; S01AA14.
ATC Vet — QJ01CE01; QJ51CE01; QS01AA14. Stability. Benzylpenicillin is hydrolysed in aqueous solutions Hypersensitivity to penicillin gives rise to immediate
by degradation of the beta-lactam ring and hydrolysis is acceler- reactions including anaphylaxis, angioedema, urticar-
ated by increased temperature or alkaline conditions; inactiva-
tion also occurs under acid conditions. Degradation products in-
ia, and some maculopapular rashes. Late reactions may
O clude penillic, penicillenic, and penicilloic acids which lower the include serum sickness-like reactions and haemolytic
H H pH and cause a progressive increase in the rate of deterioration; anaemia. Reactions are considered to be due mainly to
S N-formylpenicillamine and very small amounts of penicillamine breakdown products produced in vitro before use or to
N CH3 have also been detected. Degradation is minimal at about pH 6.8
H metabolites of penicillin, and possibly penicillin itself.
N CH3 and deterioration of benzylpenicillin in solution may be retarded
by using a citrate buffer. Dilute solutions are more stable than These act as haptens which, when combined with pro-
O concentrated ones. teins and other macromolecules, produce potential an-
COOH
References. tigens. As the hypersensitivity is related to the basic
1. Lynn B. The stability and administration of intravenous penicil- penicillin structure, patients who are genuinely allergic
Description. The name benzylpenicillin is commonly used to
describe either benzylpenicillin potassium or benzylpenicillin lins. Br J Intraven Ther 1981; 2 (Mar): 22–39. to benzylpenicillin must be assumed to be allergic to all
sodium as these are the forms in which benzylpenicillin is used. 2. Bird AE, et al. N-Formylpenicillamine and penicillamine as deg- penicillins; sensitised patients may also react to the ce-
radation products of penicillins in solution. J Pharm Pharmacol
In Martindale, benzylpenicillin means either the potassium or 1986; 38: 913–17. phalosporins and other beta-lactam antibiotics.
sodium salt.
Tests for hypersensitivity may be used to determine
Benzylpenicillin Potassium (BANM, rINNM) Units those patients most likely to develop serious allergic
Bencilpenicilina potásica; Bensylpenicillinkalium; Bentsyylipenisilli-
The second International Standard Preparation (1952) reactions to penicillins. Skin tests are used to evaluate
inikalium; Benzilpenicilino kalio druska; Benzilpenicillin-kálium; of benzylpenicillin sodium contained 1670 units of the current risk of immediate or accelerated IgE-medi-
Benzylopenicylina potasowa; Benzylpenicilin draselná sůl; Ben- penicillin per mg but was withdrawn in 1968 since ated reactions, the most serious being anaphylaxis.
zylpénicilline potassique; Benzylpenicillinum kalicum; Kalii Ben- penicillin can now be characterised completely by Both the major and minor determinants of penicillin
zylpenicillinum; Penicillin G Potassium; Penisilin G Potasyum. chemical tests. Despite this, doses of benzylpenicillin hypersensitivity should be used; the major determinant
Калия Бензилпенициллин are still expressed in units in some countries. is available as penicilloyl-polylysine (p.2364) and a
C 16 H 17KN 2 O 4 S = 372.5. Benzylpenicillin potassium 600 mg or benzylpenicil- minor-determinant mixture consisting of benzylpeni-
C AS — 113-98-4. cillin and its derivatives, including penicilloic acid and
ATC — J01CE01; S01AA14. lin sodium 600 mg have generally been considered to
ATC Vet — QJ01CE01; QS01AA14. be equivalent to about 1 million units (1 mega unit). benzylpenicilloylamine, can be used, although if this is
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
not available a solution of benzylpenicillin may be sub-
Viet. Adverse Effects stituted. Adrenaline should be available in case an an-
Ph. Eur. 6.2 (Benzylpenicillin Potassium). The potassium salt of a The most common adverse effects of benzylpenicillin aphylactic reaction develops. The results of skin tests
substance produced by growing certain strains of Penicillium no- are hypersensitivity reactions, especially skin rashes; are unreliable if a significant time has elapsed before
tatum or related organisms or obtained by any other means. A beginning therapy. A number of in-vitro tests including
white or almost white crystalline powder. Very soluble in water;
anaphylaxis occasionally occurs and has sometimes
practically insoluble in fatty oils and in liquid paraffin. A 10% been fatal. the radioallergosorbent test (RAST) have been devel-
solution in water has a pH of 5.5 to 7.5. Store in airtight contain- Gastrointestinal effects such as diarrhoea and nausea oped.
ers. are the most common adverse effects after oral use of Desensitisation may be attempted in patients allergic to
USP 31 (Penicillin G Potassium). Colourless or white crystals, or penicillin when treatment with penicillin is considered
white crystalline powder. It is odourless or practically so, and is benzylpenicillin; a sore mouth or tongue or a black
moderately hygroscopic. Very soluble in water, in sodium chlo- hairy tongue have occasionally been reported. Pseu- essential. It involves very small doses of penicillin giv-
ride 0.9%, and in glucose solutions; sparingly soluble in alcohol. domembranous colitis has been associated with the use en at relatively short intervals of 15 minutes or more,
Its solutions retain substantially full potency for several days at of most antibiotics; ampicillin or amoxicillin are the and gradually increased to therapeutic concentrations.
temperatures below 15°, but are rapidly inactivated by acids, by most frequently implicated penicillins (see Antibiotic- However, desensitisation may be hazardous and
alkali hydroxides, by glycerol, and by oxidising agents. pH of a should only be carried out if the patient can be moni-
6% solution in water is between 5.0 and 7.5. Store in airtight con- associated Colitis, p.171).
tainers. tored continuously and adrenaline and resuscitation
Other adverse effects have generally been associated
equipment are immediately available. Desensitisation
Incompatibility and stability. As for Benzylpenicillin Sodi- with large intravenous doses of benzylpenicillin; pa-
um, below. should be regarded as temporary, and allergic reactions
tients with renal impairment are also at increased risk.
may recur during the next exposure to penicillin.
These adverse effects include haemolytic anaemia and
Benzylpenicillin Sodium (BANM, rINNM) neutropenia, both of which might have some immuno- Neutropenia. Neutropenia has been widely reported in
Bencilpenicilina sódica; Bensylpenicillinnatrium; Bentsyylipenisilli- logical basis; prolongation of bleeding time and defec- patients given high doses of beta lactams and an inci-
ininatrium; Benzilpenicilino natrio druska; Benzilpenicillin-nátrium; tive platelet function; convulsions and other signs of dence of from 5 to more than 15% has been reported in
Benzylopenicylina sodowa; Benzylpenicilin sodná sůl; Benzylpén- patients treated for 10 days or more. Warning signs in-
CNS toxicity (encephalopathy has followed intrathecal
icilline sodique; Benzylpenicillinum natricum; Natrii Benzylpenicil- clude fever, rash, and eosinophilia. Monitoring of the
linum; Penicillin G Sodium; Sodyum Penisilin G.
dosage and can be fatal); and electrolyte disturbances
because of the large amounts of potassium or sodium leucocyte count is recommended during long-term
Натрий Бензилпенициллин treatment with high doses. Some have proposed a di-
C 16 H 17N 2 NaO 4 S = 356.4. given when benzylpenicillin potassium or sodium, re-
spectively, are used. rect toxic effect whereas others have postulated an im-
C AS — 69-57-8.
ATC — J01CE01; S01AA14. mune mechanism.
Hepatitis and cholestatic jaundice have been reported
ATC Vet — QJ01CE01; QS01AA14. Effects on the blood. References to neutropenia associated
rarely with some penicillins, notably penicillinase-re-
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet. with penicillins.
sistant penicillins such as flucloxacillin and oxacillin,
Ph. Eur. 6.2 (Benzylpenicillin Sodium). The sodium salt of a sub- 1. Anonymous. Antibiotic-induced neutropenia. Lancet 1985; ii:
stance produced by growing certain strains of Penicillium no- and also combinations of amoxicillin or ticarcillin with 814.
tatum or related organisms or obtained by any other means. A clavulanic acid. 2. Neftel KA, et al. Inhibition of granulopoiesis in vivo and in vitro
white or almost white crystalline powder. Very soluble in water; by β-lactam antibiotics. J Infect Dis 1985; 152: 90–8.
Nephropathy and interstitial nephritis, which may have 3. Olaison L, Alestig K. A prospective study of neutropenia in-
practically insoluble in fatty oils and in liquid paraffin. A 10% duced by high doses of β-lactam antibiotics. J Antimicrob Chem-
solution in water has a pH of 5.5 to 7.5. Store in airtight contain- some immunological basis, have been especially asso-
other 1990; 25: 449–53.
ers. ciated with meticillin, but may be produced by other 4. Scheetz MH, et al. Systematic review of piperacillin-induced
USP 31 (Penicillin G Sodium). Colourless or white crystals, or penicillins. neutropenia. Drug Safety 2007; 30: 295–306.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
214 Antibacterials
Effects on the nervous system. References to CNS effects cell-wall synthesis, although the mechanisms involved teins may also result in resistance in Gram-positive and
associated with penicillins. are still not precisely understood. Bacterial cell walls Gram-negative bacteria.
1. Schliamser SE, et al. Neurotoxicity of β-lactam antibiotics: pre-
disposing factors and pathogenesis. J Antimicrob Chemother are held rigid and protected against osmotic rupture by Most strains of Staphylococcus aureus are now resist-
1991; 27: 405–25. peptidoglycan. Benzylpenicillin inhibits the final ant to benzylpenicillin. Streptococcus pneumoniae
Hypersensitivity. References to hypersensitivity reactions as- cross-linking stage of peptidoglycan production by with reduced susceptibility or complete resistance to
sociated with penicillins. binding to and inactivating transpeptidases, penicillin- benzylpenicillin have increasingly been reported.
1. Sullivan TJ, et al. Skin testing to detect penicillin allergy. J Al- binding proteins on the inner surface of the bacterial
lergy Clin Immunol 1981; 68: 171–80. Strains of Neisseria meningitidis with reduced sensi-
2. Beeley L. Allergy to penicillin. BMJ 1984; 288: 511–12. cell membrane. However, it is now realised that other tivity to benzylpenicillin have been identified. Penicil-
3. Holgate ST. Penicillin allergy: how to diagnose and when to earlier stages in cell-wall synthesis can also be inhibit- linase-producing Neisseria gonorrhoeae are wide-
treat. BMJ 1988; 296: 1213–14. ed. Other mechanisms involved include bacterial lysis
4. Anonymous. Penicillin allergy in childhood. Lancet 1989; i: spread; reduced sensitivity of gonococci to
420. by the inactivation of endogenous inhibitors of bacteri- benzylpenicillin may also result from alterations in
5. Surtees SJ, et al. Allergy to penicillin: fable or fact? BMJ 1991; al autolysins.
302: 1051–2. Correspondence. ibid.: 1462–3. penicillin-binding proteins. Most strains of Haemo-
6. Anonymous. Penicillin allergy. Drug Ther Bull 1996; 34: 87–8. Its action is inhibited by penicillinase and other beta- philus influenzae and Moraxella catarrhalis (Branha-
7. Salkind AR, et al. Is this patient allergic to penicillin? An evi- lactamases that are produced during the growth of cer- mella catarrhalis) are now resistant.
dence-based analysis of the likelihood of penicillin allergy.
JAMA 2001; 285: 2498–2505. tain micro-organisms. Some organisms, usually Gram-positive cocci such as
Many Gram-negative organisms are intrinsically re- staphylococci or streptococci, may develop tolerance
Precautions sistant by virtue of the inability of benzylpenicillin to and are inhibited but not killed by benzylpenicillin; in
Patients known to be hypersensitive to penicillins penetrate their outer membranes. Intrinsic resistance such cases the minimum bactericidal concentration is
should be given an antibacterial of another class. How- can also be due to structural differences in the target much greater than the minimum inhibitory concentra-
ever, sensitised patients may also react to the cepha- penicillin-binding proteins. See under Resistance, be- tion.
losporins and other beta lactams. Desensitisation may low, for reference to acquired resistance.
be attempted if treatment with a penicillin is considered Pharmacokinetics
essential (see Adverse Effects, above). Penicillins Spectrum of activity. The following pathogenic organ-
isms are usually sensitive to benzylpenicillin: Benzylpenicillin rapidly appears in the blood after in-
should be given with caution to patients with a history tramuscular injection of water-soluble salts, and maxi-
of allergy, especially to drugs. • Gram-positive aerobes and anaerobes including Ba- mum concentrations are usually reached in 15 to 30
Care is necessary if very high doses of penicillins are cillus anthracis, Clostridium perfringens, Cl. tetani, minutes; peak plasma concentrations of about
given, especially if renal function is poor, because of Corynebacterium diphtheriae, Erysipelothrix rhusi- 12 micrograms/mL have been reported after single
the risk of neurotoxicity. The intrathecal route should opathiae, Listeria monocytogenes, Peptostreptococ- doses of 600 mg.
be avoided. Renal, hepatic, and haematological status cus spp., non-beta-lactamase-producing staphyloco-
cci, and streptococci including Streptococcus When given orally, benzylpenicillin is inactivated fair-
should be monitored during prolonged and high-dose ly rapidly by gastric acid and only up to about 30% is
therapy. Because of the Jarisch-Herxheimer reaction, agalactiae (group B), Str. pneumoniae (pneumococ-
ci), Str. pyogenes (group A), and some viridans strep- absorbed, mainly from the duodenum; maximum plas-
care is also necessary when treating patients with spi- ma-penicillin concentrations usually occur in about 1
rochaete infections, particularly syphilis. tococci; enterococci are relatively insensitive.
hour. In order to attain plasma-penicillin concentra-
Skin contact with penicillins should be avoided since • Gram-negative cocci including Neisseria meningi- tions after oral use similar to those after intramuscular
sensitisation may occur. tidis (meningococci) and Neisseria gonorrhoeae injection, up to 5 times as much benzylpenicillin may
Penicillin therapy changes the normal bacterial flora (gonococci), although beta-lactamase-producing be necessary. Absorption varies greatly in different in-
and can lead to superinfection with penicillin-resistant strains are common. dividuals and is better in patients with reduced gastric
organisms including Clostridium difficile or Candida, • Gram-negative bacilli including Pasteurella multoc- acid production, including neonates and the elderly.
particularly with prolonged use. ida, Streptobacillus moniliformis, and Spirillum mi- Food decreases the absorption of benzylpenicillin and
Penicillins may interfere with some diagnostic tests nus (or minor); most Gram-negative bacilli, includ- oral doses are best given at least half an hour before or
such as those for urinary glucose using copper sulfate, ing Pseudomonas spp. and Enterobacteriaceae, are 2 to 3 hours after a meal.
direct antiglobulin (Coombs’) tests, and some tests for insensitive although some strains of Proteus mirabi- Benzylpenicillin is widely distributed at varying con-
urinary or serum proteins. Penicillins may interfere lis and Escherichia coli may be inhibited by high centrations in body tissues and fluids. It appears in
with tests that use bacteria, for example the Guthrie test concentrations of benzylpenicillin. pleural, pericardial, peritoneal, and synovial fluids, but
for phenylketonuria using Bacillus subtilis organisms. • Gram-negative anaerobes including Prevotella in the absence of inflammation diffuses only to a small
Potassium and sodium content. Each g of benzylpenicillin (non-fragilis Bacteroides) and Fusobacterium spp. extent into abscess cavities, avascular areas, the eye,
potassium contains about 2.7 mmol of potassium and each g of • Other organisms including Actinomyces and the spi- the middle ear, and the CSF. Inflamed tissue is, howev-
benzylpenicillin sodium contains about 2.8 mmol of sodium. er, more readily penetrated and, for example, in menin-
Care is necessary if large doses of the potassium or sodium salts
rochaetes, Borrelia, Leptospira, and Treponema spp.
are given to patients with renal impairment or heart failure. High • Mycobacteria, fungi, mycoplasmas, and rickettsias gitis higher concentrations of benzylpenicillin are
doses of benzylpenicillin potassium should also be used with are not sensitive. achieved in the CSF. Active transport out of the CSF is
caution in patients receiving potassium-containing drugs or reduced by probenecid. In patients with uraemia, other
potassium-sparing diuretics. Activity with other antimicrobials. Benzylpenicillin organic acids may accumulate in the CSF and compete
may exhibit synergy with other antimicrobials, partic- with benzylpenicillin for active transport; toxic con-
Interactions ularly the aminoglycosides, and such combinations centrations of benzylpenicillin sufficient to cause con-
Probenecid prolongs the half-life of benzylpenicillin have been used against enterococci and other relatively vulsions can result.
by competing with it for renal tubular secretion and insensitive bacteria. Its activity may be enhanced by
may be used therapeutically for this purpose. Ben- clavulanic acid and other beta-lactamase inhibitors, Benzylpenicillin diffuses across the placenta into the
zylpenicillin may also interact with bacteriostatic anti- and both enhancement and antagonism have been fetal circulation, and small amounts appear in breast
bacterials such as chloramphenicol and tetracyclines demonstrated for beta-lactam combinations. Antago- milk.
(see Antimicrobial Action, below), and may be incom- nism has been reported to occur with some bacterio- The plasma half-life is about 30 minutes, although it
patible in vitro with other drugs, including some other static drugs, such as chloramphenicol or tetracyclines, may be longer in neonates and the elderly because of
antibacterials (see above). that interfere with active bacterial growth necessary for reduced renal function. In renal impairment the half-
The possibility of a prolonged bleeding time after oral benzylpenicillin to achieve its effect. life may be increased to about 10 hours. Approximate-
treatment with a broad-spectrum drug like ampicillin ly 60% is reported to be bound to plasma protein.
Resistance. Susceptible Gram-positive bacteria ac-
should be borne in mind in patients receiving anticoag- quire resistance to beta lactams mainly through the in- Benzylpenicillin is metabolised to a limited extent and
ulants. duction of beta-lactamases, including penicillinases. the penicilloic acid derivative has been recovered in the
Hormonal contraceptives. For the effect of penicillins on These enzymes are liberated extracellularly and hydro- urine. Benzylpenicillin is rapidly excreted in the urine,
oral contraceptives, see p.2068. lyse the beta-lactam ring. This resistance is usually principally by tubular secretion and about 20% of a
Methotrexate. For the effect of penicillins on methotrexate, plasmid-mediated and can be transferred from one bac- dose given by mouth appears unchanged in the urine;
see p.748. terium to another. Gram-negative bacteria produce about 60 to 90% of a dose of aqueous benzylpenicillin
beta-lactamases within their cell membranes which given intramuscularly appears in the urine, mainly
Antimicrobial Action may be chromosomally or plasmid-mediated; all within the first hour. Significant concentrations are
Benzylpenicillin is a beta-lactam antibiotic and has a Gram-negative species probably contain small achieved in bile, but in patients with normal renal func-
bactericidal action against Gram-positive bacteria, amounts of beta-lactamases. Resistance in Gram-neg- tion only small amounts are excreted via the bile. Ben-
Gram-negative cocci, some other Gram-negative bac- ative species may also be due to changes in their outer zylpenicillin is removed by haemodialysis.
teria, spirochaetes, and actinomycetes. membrane resulting in the failure of beta lactams to Renal tubular secretion is inhibited by probenecid
Mechanism of action. It exerts its killing action on reach their target penicillin-binding proteins. Changes (p.558), which is sometimes given to increase plasma-
growing and dividing bacteria by inhibiting bacterial in the binding characteristics of penicillin-binding pro- penicillin concentrations.
 Benzylpenicillin/Capreomycin Sulfate 215
Uses and Administration Other routes. Benzylpenicillin eye drops and eye oint- Brodimoprim (rINN)
Benzylpenicillin is used in the treatment of infections ment are used in the treatment of susceptible eye infec- Brodimoprima; Brodimoprime; Brodimoprimum. 2,4-Diamino-
due to susceptible organisms (see Antimicrobial Ac- tions. For subconjunctival injection, 300 or 600 mg of 5-(4-bromo-3,5-dimethoxybenzyl)pyrimidine.
tion, above). They include abscess, actinomycosis, an- benzylpenicillin has been dissolved in 0.5 to 1.0 mL of Бродимоприм
thrax, bites and stings, diphtheria, endocarditis, gas water, or another suitable solvent such as lidocaine 2% C 13 H 15 BrN 4O 2 = 339.2.
gangrene, leptospirosis, Lyme disease, meningitis, with or without adrenaline 1 in 200 000 or similar. C AS — 56518-41-3.
meningococcal infections, necrotising enterocolitis, ATC — J01EA02.
Benzylpenicillin has also been given orally on an emp- ATC Vet — QJ01EA02.
necrotising fasciitis, neonatal conjunctivitis (if gono- ty stomach in adult doses of 125 to 312 mg every 4 to
cocci are sensitive), perinatal streptococcal infections 6 hours.
(intrapartum prophylaxis against group B streptococ- Intrathecal injections are no longer recommended. OCH3
ci), pharyngitis (or tonsillitis), pneumonia, skin infec- Br N NH2
tions, syphilis (neurosyphilis and congenital syphilis), Preparations
tetanus, toxic shock syndrome, and Whipple’s disease. BP 2008: Benzylpenicillin Injection;
USP 31: Penicillin G Potassium Capsules; Penicillin G Potassium for Injec- N
It is also used for surgical infection prophylaxis in first tion; Penicillin G Potassium for Oral Solution; Penicillin G Potassium Injec- H3CO
trimester abortion in women at high risk of pelvic in- tion; Penicillin G Potassium Tablets; Penicillin G Sodium for Injection.
Proprietary Preparations (details are given in Part 3) NH2
fection. For details of these infections and their treat-
Arg.: Penilfedrin P; Austral.: Benpen; Braz.: Aricilina; Benzecilin; Cristalpen;
ment, see under Choice of Antibacterial, p.162. Megapen†; Pencil P; Canad.: Crystapen; Fin.: Geepenil; India: Pencip;
Pentids; Irl.: Crystapen; Mex.: Farmabep; Pendiben L-A; Pengesod; Penisol;
Profile
Administration and dosage. Benzylpenicillin is usually Procasol; Prosodina; Sodipen; Unicil 3/1; Unicil 6:3:3; Unicil Mega; Xozacil†; Brodimoprim is closely related structurally to trimethoprim
NZ: Benpen; Philipp.: Pencarv; S.Afr.: Benzatec; Bio-Pen; Novopen†; (p.355) and has been used in the treatment of infections of the
given intramuscularly or intravenously. For some indi- Spain: Coliriocilina†; Penibiot; Penilevel; Peniroger†; Sodiopen; Unicilina; respiratory tract and ear.
cations benzathine benzylpenicillin (p.212) or procaine Turk.: Benzapen 6.3.3; Deposilin 6.3.3; Devapen; Iecilline; Kristapen; Kristas-
benzylpenicillin (p.319), which provide a prolonged il; Penadur 6.3.3; Pencrist; Penkain-K; Pensilina; Procillin; UK: Crystapen; ◊ References.
USA: Pfizerpen; Venez.: Pebencil†; Pronapen; Silcopen†. 1. Braunsteiner AR, Finsinger F. Brodimoprim: therapeutic effica-
effect, are preferred; they are given intramuscularly. Multi-ingredient: Austria: Fortepen; Ophcillin N; Retarpen composi- cy and safety in the treatment of bacterial infections. J Chemoth-
Benzylpenicillin is sometimes given orally for infec- tum; Braz.: Benapen; Benzapen G; Despacilina; Drenovac†; Expectovac†; er 1993; 5: 507–11.
Ginurovac†; Linfocilin†; Odontovac†; Ortocilin†; Pencil 400; Penkaron; Wy-
tions of moderate severity, but one of the acid-resistant cillin; Chile: Karbasalin†; Prevepen Forte; Fr.: Biclinocilline; Ger.: Bipensaar; Preparations
penicillins such as phenoxymethylpenicillin (p.314) is Jenacillin A†; Retacillin compositum; Hong Kong: Penicillin G Procaine For- Proprietary Preparations (details are given in Part 3)
tified; Hung.: Promptcillin Forte; India: Bistrepen; Ital.: Tri-Wycillina†;
preferable. Mex.: Aguipental; Anapenil; Bencelin Combinado; Benzanil Compuesto;
Mex.: Novatrim†.
Benzetacil Combinado; Hidrocilina; Lugaxil; Megapenil Forte; Pecivax; Pend-
Benzylpenicillin is available as the potassium or sodi- iben Compuesto; Penicil; Penipot; Penisodina; Penprocilina; Procilin; Roben-
um salt. The dose of benzylpenicillin should be suffi- caxil; Suipen; Neth.: Penidural D/F†; Port.: Atralcilina; Atralmicina; Lento-
cilin; Penadur 6.3.3†; Prevecilina; Rus.: Bicillin-3 (Бициллин-3); S.Afr.: Broxyquinoline (rINN)
cient to achieve an optimum bactericidal concentration Penilente Forte†; Ultracillin; Spain: Aqucilina D A; Benzetacil Compuesta; Broksikinoliini; Broxichinolinum; Broxikinolin; Broxiquinolina;
in the blood as rapidly as possible; concentrations may Cepacilina 633; Neopenyl; Penilevel Retard; Venez.: Benzetacil 3-3; Ben-
zetacil 6-3-3. Broxyquinolinum. 5,7-Dibromoquinolin-8-ol.
be increased by giving it with probenecid (p.559). In Броксихинолин
some countries, doses are still expressed in units. Ben- C 9 H 5 Br 2 NO = 303.0.
zylpenicillin potassium 600 mg or benzylpenicillin so- Betamipron (rINN) C AS — 521-74-4.
dium 600 mg have generally been considered to be N-Benzoyl-β-alanine; Bétamipron; Betamipronum; CS-443. 3-
ATC — A07AX01; G01AC06; P01AA01.
equivalent to about 1 million units (1 mega unit). ATC Vet — QA07AX01; QG01AC06.
Benzamidopropionic acid.
For some infections, adult doses of 0.6 to 4.8 g of ben- Бетамипрон
C 10 H 11 NO 3 = 193.2. OH
zylpenicillin daily in 2 to 4 divided doses by intramus-
C AS — 3440-28-6.
cular or slow intravenous injection or intravenous infu- Br N
sion may be adequate, but higher doses given
intravenously, often by infusion, are more usual for se- H
vere infections. For example, in endocarditis, ben- O N O
zylpenicillin 7.2 g daily (1.2 g every 4 hours) intrave- Br
nously, usually with an aminoglycoside, is OH
recommended; doses of up to 18 g daily are not unusu- Profile
al for less sensitive streptococci and enterococci. In Broxyquinoline is a halogenated hydroxyquinoline used topical-
meningococcal and pneumococcal meningitis, ben- ly in vaginal infections. It was formerly given by mouth, with
broxaldine, in the treatment of intestinal protozoal infections, in-
zylpenicillin 14.4 g daily (2.4 g every 4 hours) intrave- cluding amoebiasis, but less toxic drugs are preferred.
Profile
nously is recommended; up to 18 g daily has been rec- Betamipron is a renal protectant used with the carbapenem anti- Preparations
ommended for meningococcal meningitis. High doses bacterial panipenem to reduce its adverse renal effects. Proprietary Preparations (details are given in Part 3)
should be given slowly to avoid irritation of the CNS Preparations Fin.: Starogyn.
and electrolyte imbalance, and a rate of not more than Proprietary Preparations (details are given in Part 3) Multi-ingredient: Fin.: Senikolp†.
300 mg/minute is recommended for intravenous doses Multi-ingredient: Jpn: Carbenin.
above 1.2 g. High doses may need to be reduced in pa-
tients with renal impairment. Capreomycin Sulfate (USAN, rINNM)
Infants and children from 1 month to 12 years may be Biapenem (USAN, rINN) 34977; Capreomycin Sulphate (BANM); Capréomycine, Sulfate
Biapénem; Biapenemum; CL-186815; L-627; LJC-10627. 6- de; Capreomycini Sulfas; Capromycin Sulphate; Sulfato de capre-
given 100 mg/kg daily in 4 divided doses; infants aged omicina.
1 to 4 weeks, 75 mg/kg daily in 3 divided doses; and {[(4R,5S,6S)-2-Carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-
oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio}-6,7-dihydro-5H- Капреомицина Сульфат
neonates 50 mg/kg daily in 2 divided doses. C AS — 11003-38-6 (capreomycin); 1405-37-4 (capreo-
pyrazolo[1,2-a]-s-triazol-4-ium hydroxide, inner salt.
As in adults, higher paediatric doses may be necessary Биапенем mycin sulfate).
ATC — J04AB30.
in severe infections. A dose of 180 to 300 mg/kg daily C 15 H 18 N 4 O 4 S = 350.4.
ATC Vet — QJ04AB30.
given intravenously in 4 to 6 divided doses is recom- C AS — 120410-24-4.
mended for meningococcal meningitis in infants and
children from 1 month to 12 years of age; infants aged H CH3 O
R
O NH2
1 to 4 weeks may be given 150 mg/kg daily in 3 divid- HO H H H
H 2N N NH2
ed doses; neonates up to 7 days old may be given H N N N
H H
100 mg/kg daily in 2 divided doses. S N O
H 3C N +N NH HN O
H H
In patients with suspected meningococcal infection, an O N N NH2
- O
intravenous or intramuscular injection of benzylpeni- COO
cillin should be given before transfer to hospital. Doses O H O
NH
are: adults and children aged 10 years or more, 1.2 g; Profile
children aged 1 to 9 years, 600 mg; children under 1 Biapenem is a carbapenem beta-lactam antibacterial similar to N NH
imipenem (p.286), although it is reported to be more stable to H
year, 300 mg. renal dehydropeptidase I than imipenem. Capreomycin IA R = OH
Capreomycin IB R = H
A dose for intrapartum prophylaxis against group B ◊ Reviews.
streptococcal infection is benzylpenicillin 3 g intrave- 1. Perry CM, Ibbotson T. Biapenem. Drugs 2002; 62: 2221–34.
(capreomycin)
nously initially, then 1.5 g every 4 hours until delivery.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
216 Antibacterials
Description. Capreomycin I consists of capreomycin IA dose of capreomycin 15 to 30 mg/kg daily, to a maximum dose Pain at the injection site and phlebitis may occur. Electrolyte dis-
(C25H44N14O8 = 668.7) and capreomycin IB (C25H44N14O7 of 1 g daily. turbances, particularly hypokalaemia or hypernatraemia, may
= 652.7), which predominates. Capreomycin II, which makes up follow large doses of carbenicillin sodium.
about 10% of the mixture, consists of capreomycin IIA and Administration in renal impairment. As with aminoglyco-
capreomycin IIB. sides, the dose of capreomycin in patients with renal impairment A dose-dependent coagulation defect has been reported, espe-
must be reduced based on creatinine clearance; the desired cially in patients with renal impairment. Carbenicillin appears to
Pharmacopoeias. In Chin. and US. steady-state serum capreomycin level is 10 micrograms/mL. interfere with platelet function thereby prolonging bleeding time;
USP 31 (Capreomycin Sulfate). The disulfate of capreomycin, a purpura and haemorrhage from mucous membranes and else-
polypeptide mixture produced by the growth of Streptomyces Preparations where may result.
capreolus. It contains not less than 90% of capreomycin I. A USP 31: Capreomycin for Injection.
white to practically white amorphous powder. Freely soluble in Precautions
water; practically insoluble in most organic solvents. pH of a 3% Proprietary Preparations (details are given in Part 3) As for Benzylpenicillin, p.214.
solution in water is between 4.5 and 7.5. Store in airtight contain- Austral.: Capastat; Austria: Capastat; Cz.: Capastat†; Gr.: Capastat; Rus.:
ers. Capastat (Капастат); Lykocin (Лайкоцин); Spain: Capastat; UK: Capastat; Sodium content. Each g of carbenicillin sodium contains
USA: Capastat. about 4.7 mmol of sodium. Carbenicillin sodium should there-
Adverse Effects and Treatment fore be given with caution to patients on a restricted sodium diet.
The effects of capreomycin on the kidney and eighth cranial
nerve are similar to those of aminoglycosides such as gentamicin Interactions
(p.282). Nitrogen retention, renal tubular dysfunction, and pro- Carbadox (BAN, USAN, pINN) As for Benzylpenicillin, p.214.
gressive renal damage may occur. Hypokalaemia and other elec- Carbadoxum; GS-6244. Methyl 3-quinoxalin-2-ylmethylenecar-
trolyte abnormalities have been reported. Vertigo, tinnitus, and Antimicrobial Action
bazate 1,4-dioxide. Carbenicillin has a bactericidal mode of action similar to that of
hearing loss may also occur and are sometimes irreversible. Ab-
normalities in liver function have been reported when capreomy- Карбадокс benzylpenicillin, but with an extended spectrum of activity
cin has been used with other antituberculous drugs. Hypersensi- against Gram-negative bacteria. The most important feature of
C 11 H 10N 4 O 4 = 262.2. carbenicillin is its activity against Pseudomonas aeruginosa, al-
tivity reactions including urticaria, maculopapular rashes, and
sometimes fever have been reported. Leucocytosis and leucope- C AS — 6804-07-5. though high concentrations are generally necessary. Activity
nia have also been observed. Thrombocytopenia has been report- against Ps. aeruginosa and some other organisms can be en-
ed rarely. Eosinophilia commonly occurs with capreomycin. hanced by gentamicin and other aminoglycosides. Carbenicillin
Capreomycin also has a neuromuscular blocking action. There is also active against Proteus, including indole-positive spp. such
CH3 as Pr. vulgaris. It is comparable with ampicillin against other
may be pain, induration, and excessive bleeding at the site of in-
tramuscular injection; sterile abscesses may also form. O O Gram-negative bacteria. Sensitive organisms include some En-
terobacteriaceae, for example Escherichia coli and Enterobacter
Teratogenicity has been seen after high doses in rodents. spp.; Haemophilus influenzae; and Neisseria spp. Klebsiella spp.
NH are usually not susceptible. Its activity against Gram-positive
Treatment of overdose is generally supportive. Patients with nor- O N
mal renal function should be hydrated to maintain adequate urine bacteria is less than that of benzylpenicillin. Anaerobic organ-
output. Capreomycin may be removed by haemodialysis in pa- N isms are generally susceptible to carbenicillin, but high concen-
tients with significant renal impairment. trations are required for Bacteroides fragilis.
Resistance. Carbenicillin is inactivated by penicillinases and
Impurities. The manufacturer of a highly-purified capreomy- N some other beta-lactamases, although it is more stable to the
cin product (Capacin; Cheiljedang, Kor.) has claimed that such chromosomally mediated beta-lactamases produced by some
purification reduces the toxicity and alters the pharmacokinetics O Gram-negative organisms, including Ps. aeruginosa and some
in animal studies, suggesting that some of the toxicity of capreo- Proteus spp. Resistance to carbenicillin may develop in Ps. aer-
mycin is due to such impurities.1 uginosa during treatment with carbenicillin or other beta
Profile
1. Lee SH, et al. The impurities of capreomycin make a difference Carbadox is an antibacterial that has been used in veterinary lactams. This resistance may be intrinsic where there are changes
in the safety and pharmacokinetic profiles. Int J Antimicrob practice for treating swine dysentery and enteritis and for pro- in cell wall permeability or penicillin-binding proteins, or it may
Agents 2003; 22: 81–3. be due to plasmid-mediated beta-lactamase production that may
moting growth. However, its use has been prohibited in the EU
and some other countries after reports of carcinogenicity. be transferred to and from certain strains of Enterobacteriaceae.
Precautions
Capreomycin should be given with care and in reduced dosage to There may be cross-resistance between carbenicillin and other
patients with renal impairment. Care is also essential in patients antipseudomonal penicillins.
with signs of eighth cranial nerve damage. It is advisable to mon-
Carbenicillin Sodium (BANM, rINNM) Outbreaks of pseudomonal resistance to carbenicillin have been
itor renal and auditory function and serum-potassium concentra-
associated with extensive use in, for example, hospital burns
tions in patients before and during therapy. Periodic assessment
BRL-2064; Carbenicilina sódica; Carbenicillin Disodium (USAN); units.
of hepatic function is also recommended.
Carbénicilline sodique; Carbenicillinum natricum; α-Carboxyben-
Interactions zylpenicillin Sodium; CP-15-639-2; GS-3159 (carbenicillin potas- Pharmacokinetics
Care should be taken when capreomycin is used with other drugs sium); Karbenicillin-nátrium; Karbenicylina sodowa; Natrii Carbe- Carbenicillin is not absorbed from the gastrointestinal tract and
that have neuromuscular blocking activity. It should not be given nicillinum; NSC-111071. The disodium salt of (6R)-6-(2-carboxy- has therefore been given either intramuscularly or intravenously.
with other drugs that are ototoxic or nephrotoxic. 2-phenylacetamido)penicillanic acid . The half-life of carbenicillin is reported to be about 1 to 1.5
hours; it is increased in patients with renal impairment, especial-
Antimicrobial Action Натрий Карбенициллин
ly if there is also hepatic impairment, and also in neonates. Half-
Capreomycin has activity against various mycobacteria. Resist- C 17 H 16N 2 Na 2 O 6 S = 422.4. lives of 10 to 18 hours have been reported in renal impairment.
ance develops readily if capreomycin is used alone. It shows C AS — 4697-36-3 (carbenicillin); 4800-94-6 (carbenicillin Clearance is enhanced in patients with cystic fibrosis. Carbeni-
cross-resistance with kanamycin and neomycin. disodium); 17230-86-3 (carbenicillin potassium). cillin is about 50% bound to plasma proteins. Distribution of
carbenicillin in the body is similar to that of other penicillins.
◊ References. ATC — J01C A03.
Small amounts have been detected in breast milk. There is little
1. Ho YII, et al. In-vitro activities of aminoglycoside-aminocyclit-
ATC Vet — QJ01C A03. diffusion into the CSF except when the meninges are inflamed.
ols against mycobacteria. J Antimicrob Chemother 1997; 40:
27–32. Relatively high concentrations have been reported in bile, but
2. Maus CE, et al. Molecular analysis of cross-resistance to capre-
carbenicillin is excreted principally by renal tubular secretion
omycin, kanamycin, amikacin, and viomycin in Mycobacterium
O and glomerular filtration.
tuberculosis. Antimicrob Agents Chemother 2005; 49: 3192–7. H H
S Probenecid increases and prolongs plasma concentrations of
N CH3 carbenicillin.
Pharmacokinetics H
Capreomycin is poorly absorbed from the gastrointestinal tract. COOH N CH3 Carbenicillin is removed by haemodialysis and, to some extent,
An intramuscular dose of 1 g has been reported to give a peak O by peritoneal dialysis.
serum concentration of about 30 micrograms/mL after 1 or 2 COOH
hours. About 50% of a dose is excreted unchanged in the urine Uses and Administration
by glomerular filtration within 12 hours. Capreomycin is re- (carbenicillin) Carbenicillin is a carboxypenicillin that has been given by injec-
moved by haemodialysis. tion as the disodium salt, often with gentamicin, in the treatment
of infections due to Pseudomonas aeruginosa; however, other
Uses and Administration Pharmacopoeias. In Pol. and US. antipseudomonal penicillins such as ticarcillin (p.352) or pipera-
Capreomycin is a second-line antimycobacterial that may be USP 31 (Carbenicillin Disodium). A white to off-white crystal- cillin (p.315) are now preferred. It has also been given to treat
used in the treatment of tuberculosis (p.196) as part of a multid- line powder. Freely soluble in water; soluble in alcohol; practi- serious infections due to non-penicillinase-producing strains of
rug regimen when resistance to primary drugs has developed. cally insoluble in chloroform and in ether. pH of a solution in wa- Proteus spp.
ter containing the equivalent of carbenicillin 1% is between 6.5
Capreomycin is given as the sulfate by deep intramuscular injec- Esters of carbenicillin, such as carfecillin (p.217) and carindacil-
and 8.0. Store in airtight containers.
tion or by intravenous infusion. The usual dose is the equivalent lin (p.217), have been given orally in the treatment of urinary-
of 1 g of capreomycin base (maximum 20 mg/kg) given daily for Incompatibility. Carbenicillin sodium has been reported to be tract infections.
2 to 4 months, then 2 or 3 times weekly for the remainder of incompatible with aminoglycosides, tetracyclines, and a number
therapy. of other drugs including other antimicrobials and these drugs Preparations
For details of doses in infants, children, and adolescents, see be- should therefore be given separately.
USP 31: Carbenicillin for Injection.
low. Adverse Effects Proprietary Preparations (details are given in Part 3)
Administration in children. For the treatment of drug-resist- As for Benzylpenicillin, p.213.
Mex.: Carbecin†.
ant tuberculosis in infants, children, and adolescents the Ameri- Hypersensitivity reactions have been reported to be less frequent
can Academy of Pediatrics (AAP) suggests an intramuscular and less severe with carbenicillin than with benzylpenicillin.
 Carbadox/Cefaclor 217
Carfecillin Sodium (BANM, pINNM) mia observed with some cephalosporins (see Adverse Effects of
Cefamandole, p.221), but cefaclor does not contain the side-
BRL-3475; Carbenicillin Phenyl Sodium (USAN); Carfecilina sódica;
S O O chain usually implicated in this reaction.
Carfécilline Sodique; Natrii Carfecillinum. Sodium (6R)-6-(2-phe- H CONH2
noxycarbonyl-2-phenylacetamido)penicillanate. H
H2N N
Antimicrobial Action
Натрий Карфециллин N
H Cefaclor is bactericidal and has antimicrobial activity
C 23 H 21N 2 NaO 6 S = 476.5. N N similar to that of cefalexin (p.218) but is reported to be
C AS — 27025-49-6 (carfecillin); 21649-57-0 (carfecillin O O
sodium). SO3H more active against Gram-negative bacteria including
ATC — G01AA08. Escherichia coli, Klebsiella pneumoniae, Neisseria
ATC Vet — QG01AA08. NaOOC gonorrhoeae, and Proteus mirabilis, and especially
against Haemophilus influenzae. It is active against
(carumonam)
some beta-lactamase-producing strains of H. influen-
O Pharmacopoeias. In Jpn. zae. It may be less resistant to staphylococcal penicilli-
H H nase than cefalexin or cefradine and a marked inocu-
S Profile
N CH3 Carumonam is a monobactam antibacterial with a spectrum of lum effect has been reported in vitro.
H antimicrobial action in vitro similar to that of aztreonam (p.209).
C N CH3 It is given by intramuscular or intravenous injection as the sodi- Pharmacokinetics
O O O um salt and doses are expressed in terms of carumonam; 1.09 g Cefaclor is well absorbed from the gastrointestinal
COONa of carumonam sodium is equivalent to about 1 g of carumonam. tract. Oral doses of 250 mg, 500 mg, and 1 g produce
The usual dose is 1 to 2 g daily in two divided doses.
peak plasma concentrations of about 7, 13, and
Sodium content. Each g of carumonam sodium contains 23 micrograms/mL respectively after 0.5 to 1 hour.
about 3.92 mmol of sodium.
The presence of food may delay the absorption of ce-
Preparations faclor, but the total amount absorbed is unchanged. A
Profile Proprietary Preparations (details are given in Part 3)
Carfecillin is the phenyl ester of carbenicillin (p.216) to which it plasma half-life of 0.5 to 1 hour has been reported; it
Jpn: Amasulin.
is hydrolysed after absorption from the gastrointestinal tract. Its may be slightly prolonged in patients with renal im-
use has been restricted to the treatment of urinary-tract infections pairment. About 25% is bound to plasma proteins.
due to Pseudomonas spp. and other sensitive bacteria including
Proteus spp. Cefaclor appears to be widely distributed in the body;
Cefaclor (BAN, USAN, pINN) it crosses the placenta and low concentrations have
Céfaclor; Cefaclorum; Cefaclorum Monohydricum; Cefaklór; been detected in breast milk. It is rapidly excreted by
Cefaklor; Cefaklor monohydrát; Cefakloras; Compound 99638; the kidneys; up to 85% of a dose appears unchanged in
Carindacillin Sodium (BANM, pINNM) Kefakloori; Sefaklor. (7R)-3-Chloro-7-(α-D-phenylglycylamino)-3- the urine within 8 hours, the greater part within 2 hours.
Carbenicillin Indanyl Sodium (USAN); Carindacilina sódica; Carin- cephem-4-carboxylic acid monohydrate.
High concentrations of cefaclor are achieved in the
dacilline Sodique; CP-15464-2; Natrii Carindacillinum. Sodium Цефаклор
(6R)-6-[2-(indan-5-yloxycarbonyl)-2-phenylacetamido]penicilla-
urine within 8 hours of a dose; peak concentrations of
C 15 H 14 ClN 3O 4 S,H 2 O = 385.8.
nate. 600, 900, and 1900 micrograms/mL have been report-
C AS — 53994-73-3 (anhydrous cefaclor); 70356-03-5
Натрий Кариндациллин
ed after doses of 0.25, 0.5, and 1 g respectively.
(cefaclor monohydrate).
C 26 H 25N 2 NaO 6 S = 516.5. ATC — J01DC04.
Probenecid delays excretion. Some cefaclor is re-
C AS — 35531-88-5 (carindacillin); 26605-69-6 (carinda- ATC Vet — QJ01DC04. moved by haemodialysis.
cillin sodium). ◊ References.
ATC — J01C A05. 1. Wise R. The pharmacokinetics of the oral cephalosporins—a re-
ATC Vet — QJ01C A05. view. J Antimicrob Chemother 1990; 26 (suppl E): 13–20.
O 2. Sourgens H, et al. Pharmacokinetic profile of cefaclor. Int J Clin
H H Pharmacol Ther 1997; 35: 374–80.
S
O O N
H Uses and Administration
H H
S
NH2 N Cefaclor is a cephalosporin antibacterial given orally
O N CH3 O Cl similarly to cefalexin in the treatment of susceptible in-
H
N CH3 COOH fections including upper and lower respiratory-tract in-
O fections, skin infections, and urinary-tract infections.
COONa Pharmacopoeias. In Chin., Eur. (see p.vii), and US. Jpn in- Some classify cefaclor as a second-generation cepha-
cludes the anhydrous substance. losporin and its greater activity against Haemophilus
Ph. Eur. 6.2 (Cefaclor). A white or slightly yellow powder.
Pharmacopoeias. In US. Slightly soluble in water; practically insoluble in dichlorometh- influenzae makes it more suitable than cefalexin for the
USP 31 (Carbenicillin Indanyl Sodium). A white to off-white ane and in methyl alcohol. A 2.5% suspension in water has a pH treatment of infections such as otitis media. For details
powder. Soluble in water and in alcohol. pH of a 10% solution in of 3.0 to 4.5. of these infections and their treatment, see under
water is between 5.0 and 8.0. Store in airtight containers. USP 31 (Cefaclor). A white to off-white crystalline powder. Choice of Antibacterial, p.162.
Slightly soluble in water; practically insoluble in chloroform, in
Profile methyl alcohol, and in benzene. pH of a 2.5% suspension in wa- Cefaclor is given as the monohydrate. Doses are ex-
Carindacillin is the indanyl ester of carbenicillin (p.216) to which ter is between 3.0 and 4.5. Store in airtight containers. pressed in terms of the equivalent amount of anhydrous
it is hydrolysed after absorption from the gastrointestinal tract. Its cefaclor; 1.05 g of cefaclor monohydrate is equivalent
use is restricted to the treatment of urinary-tract infections due to
Pseudomonas spp. and other sensitive bacteria including Proteus Adverse Effects and Precautions to about 1 g of anhydrous cefaclor. The usual adult
spp. As for Cefalexin, p.218. dose is 250 to 500 mg every 8 hours; up to 4 g daily has
Carindacillin is given orally as the sodium salt; 535 mg of carin- Hypersensitivity. Serum-sickness-like reactions may be more been given. A suggested dose for children over 1
dacillin sodium is equivalent to about 382 mg of carbenicillin. common with cefaclor than several other oral antibacterials1 es- month of age is 20 mg/kg daily in three divided doses,
Usual doses, expressed in terms of carbenicillin, are 382 to pecially in young children who have received a number of cours- increased if necessary to 40 mg/kg daily, but not ex-
764 mg four times daily. es of cefaclor;2 typical features include skin reactions and arthral- ceeding a total daily dose of 1 g. A common dosage
Sodium content. Each g of carindacillin sodium contains gia. A relatively high incidence of anaphylactic reactions has regimen is: children over 5 years, 250 mg three times
about 1.9 mmol of sodium. been reported from Japan.3
There has been a report of myocarditis that developed as a hyper-
daily; 1 to 5 years, 125 mg three times daily; under 1
Preparations sensitivity reaction to cefaclor in a 12-year-old child.4 year, 62.5 mg three times daily.
USP 31: Carbenicillin Indanyl Sodium Tablets. 1. McCue JD. Delayed detection of serum sickness caused by oral Modified-release formulations of cefaclor are availa-
Proprietary Preparations (details are given in Part 3) antimicrobials. Adv Therapy 1990; 7: 22–7. ble in some countries.
USA: Geocillin†. 2. Vial T, et al. Cefaclor-associated serum sickness-like disease:
eight cases and review of the literature. Ann Pharmacother 1992; Preparations
26: 910–14.
3. Hama R, Mori K. High incidence of anaphylactic reactions to BP 2008: Cefaclor Capsules; Cefaclor Oral Suspension; Prolonged-release
cefaclor. Lancet 1988; i: 1331. Cefaclor Tablets;
Carumonam Sodium (BANM, USAN, rINNM) 4. Beghetti M, et al. Hypersensitivity myocarditis caused by an al- USP 31: Cefaclor Capsules; Cefaclor Chewable Tablets; Cefaclor Extend-
ed-Release Tablets; Cefaclor for Oral Suspension.
AMA-1080 (carumonam); Carumonam sódico; Carumonam lergic reaction to cefaclor. J Pediatr 1998; 132: 172–3.
Sodique; Natrii Carumonamum; Ro-17-2301 (carumonam); Ro- Proprietary Preparations (details are given in Part 3)
Arg.: Cec†; Cefaklon†; Cefral†; Kwicap†; Austral.: Aclor; Ceclor; Cefkor;
17-2301/006 (carumonam sodium). (Z)-(2-Aminothiazol-4- Interactions Karlor; Keflor; Ozcef; Austria: Cec; Ceclor; Cefastad; Cefax; Lanacef†;
yl){[(2S,3S)-2-carbamoyloxymethyl-4-oxo-1-sulphoazetidin-3- As for Cefalexin, p.218. Belg.: Ceclor; Doccefaclo; Braz.: Ceclor†; Cefacloren; Clorcin-Ped;
yl]carbamoyl}methyleneamino-oxyacetic acid, disodium salt. Faclor†; Plecor†; Reflax†; Canad.: Ceclor; Chile: Keflor†; Cz.: Cec†; Ce-
Anticoagulants. UK licensed product information recom- clor; Serviclor; Vercef; Fin.: Kefolor; Fr.: Alfatil; Alphexine†; Haxifal; Ger.:
Натрий Карумонам mends that monitoring of prothrombin time should be consid- Cec; Ceclorbeta; Cef-Diolan; Cefa-Wolff†; Cephalodoc†; Hefaclor†; Infec-
C 12 H 12N 6 Na 2 O 10 S 2 = 510.4. ered in patients receiving cefaclor and warfarin after rare reports toCef; Panoral; Sigacefal†; Gr.: Afecton; Camirox; Ceclor; Cefacloril;
Fredyren; Hetaclox; Makovan; Panclor; Phacotrex; Ufoxillin†; Hong Kong:
C AS — 87638-04-8 (carumonam); 86832-68-0 (caru- of increased prothrombin times. It is not known whether this in- Castal; Ceclor; Cefalor; Medoclor; Qualiceclor; Qualiphor; Soficlor; Vercef;
monam sodium). teraction is related to the vitamin K-related hypoprothrombinae- Hung.: Ceclor; Cecloretta; Vercef; India: Halocef; Keflor; Indon.: Capabi-

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
218 Antibacterials
otic; Ceclor; Cloracef; Especlor; Forifek; Medikoncef; Soclor; Irl.: Cefager; Cefadroxil is widely distributed to body tissues and flu-
Distaclor; Keftid; Pinaclor; Israel: Ceclor†; Cefalor; Ital.: Altaclor; Bacticef;
Bactigram; Cefulton; Citiclor†; Clorad; Clorazer; Dorf; Erreclor†; Euroce- ids. It crosses the placenta and appears in breast milk.
fix†; Fuclode†; Geniclor; Kliacef; Lafarclor; Macovan; Necloral; Omaspir; O
Oralcef; Panacef; Performer; Selanir†; Selviclor; Takecef; Tibifor; Valeclor; More than 90% of a dose of cefadroxil may be excreted H H
Malaysia: Distaclor†; Sifaclor; Soficlor†; Vercef; Mex.: Arcefal; Cec; Ce- unchanged in the urine within 24 hours by glomerular S
clor; Cefalan; Ceflacid; Fasiclor; Fermed; Ranclor; Serviclor; Teraclox; N
Neth.: Ceclor; NZ: Clorotir; Philipp.: Aczebri; Brelox; Ceclobid; Ceclor; filtration and tubular secretion; peak urinary concentra- H
Clorotir; Ephron; Lorcef; Vefarol; Versef; Verzat; Xelent; Xeztron; Pol.: Ce- tions of 1.8 mg/mL have been reported after a dose of
clor; Cek; Kloracef†; Panclor; Serviclor; Vercef; Port.: Ceclor; Rus.: Ceclor NH2 N
(Цеклор); Vercef (Верцеф); S.Afr.: Cec; Ceclor†; CloraCEF†; Vercef; Sin- 500 mg. Cefadroxil is removed by haemodialysis. O CH3
gapore: Cleancef; Distaclor†; Soficlor; Vercef; Spain: Ceclor; Switz.: Ce-
COOH
clor; Thai.: Celco; Clorotir; Distaclor; Kefaclor†; Sifaclor; Tefaclor†; Vercef; ◊ References.
Turk.: Ceclor; Kefsid; Losefar; UAE: Recocef; UK: Bacticlor; Distaclor;
Keftid; USA: Ceclor; Raniclor; Venez.: Ceclor. 1. Tanrisever B, Santella PJ. Cefadroxil: a review of its antibacteri- Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, US, and Viet.
Multi-ingredient: Mex.: Ceclordox. al, pharmacokinetic and therapeutic properties in comparison Ph. Eur. 6.2 (Cefalexin Monohydrate). A white or almost white
with cephalexin and cephradine. Drugs 1986; 32 (suppl 3): 1–16.
crystalline powder. Sparingly soluble in water; practically insol-
2. Wise R. The pharmacokinetics of the oral cephalosporins—a re- uble in alcohol. A 0.5% solution in water has a pH of 4.0 to 5.5.
view. J Antimicrob Chemother 1990; 26 (suppl E): 13–20.
Protect from light.
Cefadroxil (BAN, USAN, pINN) 3. Garrigues TM, et al. Dose-dependent absorption and elimination USP 31 (Cephalexin). A white to off-white crystalline powder.
of cefadroxil in man. Eur J Clin Pharmacol 1991; 41: 179–83. Slightly soluble in water; practically insoluble in alcohol, in chlo-
BL-S578; Cefadroksilis monohidratas; Cefadroksyl jednowodny;
roform, and in ether. pH of a 5% suspension in water is between
Céfadroxil; Cefadroxil monohydrát; Céfadroxil monohydraté;
Cefadroxilmonohydrat; Cefadroxilo; Cefadroxilum; Cefadrox-
Uses and Administration 3.0 and 5.5. Store in airtight containers.
ilum monohydricum; Cephadroxil; Kefadroksiili; Kefadroksiili- Cefadroxil is a first-generation cephalosporin antibac-
monohydraatti; MJF-11567-3; Sefadroksil. (7R)-7-(α-D-4-Hy- terial that is the para-hydroxy derivative of cefalexin Cefalexin Hydrochloride (BANM, pINNM)
droxyphenylglycylamino)-3-methyl-3-cephem-4-carboxylic acid (p.219), and is used similarly in the treatment of mild Céfalexine, Chlorhydrate de; Cefalexini Hydrochloridum; Ce-
monohydrate. to moderate susceptible infections. It is given orally, phalexin Hydrochloride (USAN); Hidrocloruro de cefalexina; LY-
061188.
Цефадроксил and doses are expressed in terms of the anhydrous sub-
Цефалексина Гидрохлорид
C 16 H 17 N 3 O 5 S,H 2 O = 381.4. stance; 1.04 g of cefadroxil monohydrate is equivalent
C 16 H 17N 3 O 4 S,HCl,H 2 O = 401.9.
C AS — 50370-12-2 (anhydrous cefadroxil); 119922-85-9 to about 1 g of anhydrous cefadroxil. The usual adult C AS — 105879-42-3.
(cefadroxil hemihydrate); 66592-87-8 (cefadroxil monohy- dose is 1 to 2 g daily as a single dose or in two divided ATC — J01DB01.
drate). doses. The following doses are used in children weigh- ATC Vet — QJ01DB01.
ATC — J01DB05. ing less than 40 kg: 500 mg twice daily for those over Pharmacopoeias. In US.
ATC Vet — QJ01DB05. USP 31 (Cephalexin Hydrochloride). A white to off-white crys-
6 years of age, 250 mg twice daily for those aged 1 to
talline powder. Soluble 1 in 100 in water, in acetone, in ace-
6 years, and 25 mg/kg daily in divided doses for infants tonitrile, in alcohol, in dimethylformamide, and in methyl alco-
HO under 1 year. For details of reduced doses of cefadroxil hol; practically insoluble in chloroform, in ether, in ethyl acetate,
O in patients with renal impairment, see below. and in isopropyl alcohol. pH of a 1% solution in water is between
H H 1.5 and 3.0. Store in airtight containers.
S Cefadroxil has also been used as the lysine derivative.
N
H Administration in renal impairment. Following an initial Adverse Effects and Precautions
NH2 N As for Cefalotin Sodium, p.219.
CH3 loading dose of 0.5 to 1 g, dosage of cefadroxil should be adjust-
O ed in patients with renal impairment according to creatinine The most common adverse effects of cefalexin and
COOH clearance (CC): other oral cephalosporins are generally gastrointestinal
• CC 26 to 50 mL/minute per 1.73 m2: 0.5 to 1 g every 12 hours disturbances and hypersensitivity reactions. Pseu-
Pharmacopoeias. In Chin., Eur. (see p.vii), and US. Jpn in-
cludes the anhydrous substance. • CC 11 to 25 mL/minute per 1.73 m2: 0.5 to 1 g every 24 hours domembranous colitis has been reported.
Ph. Eur. 6.2 (Cefadroxil Monohydrate). A white or almost white • CC 10 mL/minute per 1.73 m2 or less: 0.5 to 1 g every 36 ◊ References.
powder. Slightly soluble in water; very slightly soluble in alco- hours. 1. Dave J, et al. Cephalexin induced toxic epidermal necrolysis. J
hol. A 5% suspension in water has a pH of 4.0 to 6.0. Protect Antimicrob Chemother 1991; 28: 477–8.
from light. Preparations 2. Baran R, Perrin C. Fixed-drug eruption presenting as an acute
USP 31 (Cefadroxil). A white to off-white crystalline powder. paronychia. Br J Dermatol 1991; 125: 592–5.
Slightly soluble in water; practically insoluble in alcohol, in chlo- BP 2008: Cefadroxil Capsules; Cefadroxil Oral Suspension; 3. Clark RF. Crystalluria following cephalexin overdose. Pediat-
USP 31: Cefadroxil Capsules; Cefadroxil for Oral Suspension; Cefadroxil rics 1992; 89: 672–4.
roform, and in ether. pH of a 5% suspension in water is between 4. Murray KM, Camp MS. Cephalexin-induced Stevens-Johnson
Tablets.
4.0 and 6.0. Store in airtight containers. syndrome. Ann Pharmacother 1992; 26: 1230–3.
Proprietary Preparations (details are given in Part 3) 5. Czechowicz RT, et al. Bullous pemphigoid induced by cephalex-
in. Australas J Dermatol 2001; 42: 132–5.
Adverse Effects and Precautions Arg.: Cefabiot†; Cefacar; Cefacilina; Cefadrox; Cefamar; Cefasin; Cefatenk; 6. Longstreth KL, et al. Cephalexin-induced acute tubular necrosis.
As for Cefalexin, p.218. Droxil; Kandicin; Klonadroxil†; Versatic; Austria: Biodroxil; Duracef; Belg.:
Duracef; Moxacef†; Braz.: Cefadroxon; Cefamox; Celoxin†; Drofaxil†; Pharmacotherapy 2004; 24: 808–11.
Neo Cefadril; Canad.: Duricef; Chile: Adroxef; Biodroxil†; Cefamox; 7. Skoog SM, et al. Cephalexin-induced cholestatic hepatitis. J
Breast feeding. Although higher concentrations of cefadroxil Clin Gastroenterol 2004; 38: 833.
Sedafex; Cz.: Biodroxil; Cedrox†; Cefadrox†; Duracef; Fin.: Duracef; Fr.:
were reported in breast milk compared with cefalexin, cefalotin, Oracefal; Ger.: Cedrox†; Gruncef; Gr.: Cefalom†; Kleotrat†; Moxacef; Ne- 8. Penttilä J, et al. Delirium in an adolescent patient during treat-
cefapirin, and cefotaxime,1 no detectable cefadroxil would be ex- falox†; Hong Kong: Amben; Androxyl; Biodroxil; Duracef; Qualidrox; ment with cephalexin. J Adolesc Health 2006; 39: 782–3.
pected in breast-fed infants and no adverse effects have been Sofidrox†; Hung.: Biodroxil†; Duracef; India: Cefadrox; Cefadur; Lactocef; Porphyria. Cefalexin is considered to be unsafe in patients with
seen in infants whose mothers were receiving cefadroxil. Ac- Lydroxil; Odoxil; Pendrox; Vepan; Vistadrox; Indon.: Alxil; Ancefa; Bidicef;
Biodroxil; Cefat; Dexacef; Doxef; Duricef; Erphadrox; Ethicef; Kelfex; Lapi- porphyria although there is conflicting experimental evidence of
cordingly, the American Academy of Pediatrics considers2 that cef; Librocef; Longcef; Opicef; Osadrox; Pyricef; Q Cef; Qidrox; Renasistin; porphyrinogenicity.
cefadroxil is usually compatible with breast feeding. Roksicap; Sedrofen; Staforin; Tisacef; Widrox; Irl.: Ultracef; Israel: Biodrox-
1. Kafetzis DA, et al. Passage of cephalosporins and amoxicillin il; Duracef†; Ital.: Cefadril; Ceoxil†; Cephos; Foxil; Oradroxil; Malaysia:
into the breast milk. Acta Paediatr Scand 1981; 70: 285–8. Kefloxin; Sofidrox†; Mex.: Cefamox; Cepotec; Duracef; Teroxina; Philipp.: Interactions
2. American Academy of Pediatrics. The transfer of drugs and oth- Drolex; Drozid; Lexipad; Pol.: Biodroxil; Duracef; Port.: Biofaxil†; Cefacile; The renal excretion of cefalexin, and many other ce-
er chemicals into human milk. Pediatrics 2001; 108: 776–89. Ceforal; Cefra†; S.Afr.: Cipadur; Dacef; Duracef; Singapore: Duricef;
Sofidrox; Spain: Duracef; Swed.: Cefamox; Thai.: Cefadril†; Turk.: Cefra- phalosporins, is delayed by probenecid.
Correction. ibid.; 1029. Also available at:
dur; Duricef; UK: Baxan; USA: Duricef†; Venez.: Bidroxyl; Cedroxim; Ce-
http://aappolicy.a ap public ations.org/cgi/c ontent/full/
fadril†; Cefaval; Cefonax; Drocef; Droxifan; Grunicef; Sanodril. Hormonal contraceptives. There have been isolated reports
pediatrics%3b108/3/776 (accessed 25/05/04) of cefalexin decreasing the efficacy of oestrogen-containing oral
Multi-ingredient: Arg.: Cefacar Mucolitico†; Cefacilina Bronquial; Mex.: contraceptives.1 For a discussion of decreased efficacy of oral
Interactions Duracef Expec. contraceptives and the need for additional contraceptive methods
As for Cefalexin, p.218. in patients taking broad-spectrum antibacterials, see under Hor-
monal Contraceptives, p.2068.
1. Friedman M, et al. Cephalexin and Microgynon-30 do not go
Antimicrobial Action well together. J Obstet Gynaecol 1982; 2: 195–6.
As for Cefalexin, p.218. Cefalexin (BAN, pINN)
66873; Cefaleksinas monohidratas; Cefaleksyna; Cefalexin Antimicrobial Action
Pharmacokinetics monohydrát; Cefalexina; Céfalexine; Céfalexine monohydratée; As for Cefalotin Sodium, p.220, although cefalexin is
Cefadroxil is almost completely absorbed from the Cefalexinmonohydrat; Cefalexinum; Cefalexinum monohydri- generally less potent. Some strains of Gram-negative
gastrointestinal tract. After oral doses of 500 mg and cum; Cephalexin (USAN); Kefaleksiini; Kefaleksiinimonohydraatti; bacteria may be inhibited only by the high concentra-
1 g, peak plasma concentrations of about 16 and Sefaleksin. (7R)-3-Methyl-7-(α-D-phenylglycylamino)-3-cephem- tions achievable in the urinary tract. Haemophilus in-
30 micrograms/mL respectively are obtained after 1.5 4-carboxylic acid monohydrate. fluenzae is moderately resistant to cefalexin.
to 2 hours. Although peak concentrations are similar to Цефалексин
those of cefalexin, plasma concentrations are more sus- C 16 H 17N 3 O 4 S,H 2 O = 365.4.
Pharmacokinetics
tained. Dosage with food does not appear to affect the Cefalexin is almost completely absorbed from the gas-
absorption of cefadroxil. About 20% of cefadroxil is C AS — 15686-71-2 (anhydrous cefalexin); 23325-78-2 trointestinal tract and produces a peak plasma concen-
(cefalexin monohydrate).
reported to be bound to plasma proteins. The plasma tration of about 18 micrograms/mL 1 hour after a 500-
half-life of cefadroxil is about 1.5 hours and is pro- ATC — J01DB01. mg oral dose. If cefalexin is taken with food, absorp-
longed in patients with renal impairment. ATC Vet — QJ01DB01; QJ51DA01. tion may be delayed, but the total amount absorbed is
 Cefadroxil/Cefalotin Sodium 219
not appreciably altered. Up to 15% of a dose is bound Keflex; Pondnacef; Sefasin; Sialexin; Sporicef; Sporidex; Toflex; Ulflex; Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US.
Zeplex; Turk.: Maksipor; Sef; UAE: Cefrin; UK: Ceporex; Keflex; USA: Ph. Eur. 6.2 (Cefalotin Sodium). A white or almost white pow-
to plasma proteins. The plasma half-life is about 1 Biocef†; Cefanex; Keflex; Keftab†; Venez.: Bidocef; Cefaloga†; Keforal;
der. Freely soluble in water; slightly soluble in dehydrated alco-
hour; it increases with reduced renal function. Stricef.
hol. A 10% solution in water has a pH of 4.5 to 7.0. Protect from
Multi-ingredient: India: Caceff; Cephadex LB; Mex.: Arlexen B; Cefab-
Cefalexin is widely distributed in the body but does not roxil; Cepobrom; Mucocef; Rombox. light.
enter the CSF in significant quantities. It crosses the USP 31 (Cephalothin Sodium). A white to off-white, practically
placenta and small quantities are found in breast milk. odourless, crystalline powder. Freely soluble in water, in sodium
chloride 0.9%, and in glucose solutions; insoluble in most organ-
Cefalexin is not metabolised. About 80% or more of a Cefalonium (BAN, pINN) ic solvents. pH of a 25% solution in water is between 4.5 and 7.0.
dose is excreted unchanged in the urine in the first 6 41071; Carbamoylcefaloridine; Cefalonio; Céfalonium; Cephalo- Store in airtight containers.
hours by glomerular filtration and tubular secretion; nium. (7R)-3-(4-Carbamoyl-1-pyridiniomethyl)-7-[2-(2-thienyl)- Incompatibility and stability. Cefalotin sodium has been re-
urinary concentrations greater than 1 mg/mL have acetamido]-3-cephem-4-carboxylate. ported to be incompatible with aminoglycosides and with many
been achieved after a dose of 500 mg. Probenecid de- Цефалоний other drugs. Precipitation may occur in solutions with a pH of
lays urinary excretion. Therapeutically effective con- C 20 H 18 N 4 O 5 S 2 = 458.5. less than 5.
centrations may be found in the bile and some may be C AS — 5575-21-3.
excreted by this route. ATC Vet — QJ51DA90. Adverse Effects
Cefalexin is removed by haemodialysis and peritoneal The adverse effects associated with cefalotin and other
dialysis. O NH2
cephalosporins are broadly similar to those described
H H for penicillins (see Benzylpenicillin, p.213). The most
◊ References. S
common are hypersensitivity reactions, including skin
1. Wise R. The pharmacokinetics of the oral cephalosporins—a re- S N O
view. J Antimicrob Chemother 1990; 26 (suppl E): 13–20. H rashes, urticaria, eosinophilia, fever, reactions resem-
N N+
O
bling serum sickness, and anaphylaxis.
Uses and Administration COO- There may be a positive response to the Coombs’ test
Cefalexin is a first-generation cephalosporin antibacte- although haemolytic anaemia rarely occurs. Neutrope-
rial. It is given orally for the treatment of susceptible Pharmacopoeias. BP(Vet) includes the dihydrate. nia and thrombocytopenia have occasionally been re-
infections including those of the respiratory and uri- BP(Vet) 2008 (Cefalonium). The dihydrate is a white or almost ported. Agranulocytosis has been associated rarely
nary tracts and of the skin (see under Choice of Anti- white crystalline powder. Very slightly soluble in water and in
methyl alcohol; insoluble in alcohol, in dichloromethane, and in
with some cephalosporins. Bleeding complications re-
bacterial, p.162). For severe infections, treatment with ether; soluble in dimethyl sulfoxide. It dissolves in dilute acids lated to hypoprothrombinaemia and/or platelet dys-
parenteral cephalosporins is to be preferred. and in alkaline solutions. Store at temperature not exceeding 30°. function have occurred especially with cephalosporins
Cefalexin is usually given as the monohydrate al- Protect from light. and cephamycins having an N-methylthiotetrazole
though the hydrochloride is sometimes used. Doses are Profile side-chain, including
expressed in terms of the equivalent amount of anhy- Cefalonium is a cephalosporin antibacterial used in veterinary • cefamandole
drous cefalexin; 1.05 g of cefalexin monohydrate and practice.
• cefbuperazone
1.16 g of cefalexin hydrochloride are each equivalent
• cefmenoxime
to about 1 g of anhydrous cefalexin.
Cefaloridine (BAN, pINN) • cefmetazole
The usual dose for adults is 1 to 2 g daily given in di-
vided doses at 6-, 8-, or 12-hourly intervals; in severe 40602; Cefaloridin; Cefaloridina; Céfaloridine; Cefaloridinum; • cefonicid
or deep-seated infections the dose can be increased to Cephaloridine (USAN); Kefaloridiini. (7R)-3-(1-Pyridiniomethyl)-7- • cefoperazone
[(2-thienyl)acetamido]-3-cephem-4-carboxylate. • ceforanide
up to 6 g daily but when high doses are required the use
of a parenteral cephalosporin should be considered. Цефалоридин
• cefotetan
C 19 H 17 N 3 O 4 S 2 = 415.5.
Children may be given 25 to 100 mg/kg daily in divid- C AS — 50-59-9. • cefpiramide
ed doses to a maximum of 4 g daily. ATC — J01DB02. • latamoxef.
For the prophylaxis of recurrent urinary-tract infection, ATC Vet — QJ01DB02.
The presence of a methylthiadiazolethiol side-chain, as
cefalexin may be given in a dose of 125 mg at night. in cefazolin, or an N-methylthiotriazine ring, as in
Cefalexin sodium or cefalexin lysine have been used S O ceftriaxone, might also be associated with such bleed-
parenterally. H H
S ing disorders. Hypoprothrombinaemia which is usual-
The dose of cefalexin may need to be reduced in renal N ly reversible with vitamin K, was once thought to be
impairment, see below. H + due to an alteration in intestinal flora but interference
N N
Administration in renal impairment. Doses of cefalexin O with prothrombin synthesis now seems more likely.
may need to be reduced in patients with renal impairment. The − Nephrotoxicity has been reported with cefalotin al-
BNF recommends the following maximum daily doses accord- COO
ing to creatinine clearance (CC):
though it is less toxic than cefaloridine. Acute renal tu-
• CC 40 to 50 mL/minute: maximum 3 g daily Profile bular necrosis has followed excessive dosage and has
Cefaloridine was one of the first cephalosporin antibacterials to also been associated with its use in older patients or
• CC 10 to 40 mL/minute: maximum 1.5 g daily be available clinically. It has properties similar to those of cefal-
• CC less than 10 mL/minute: maximum 750 mg daily those with pre-existing renal impairment, or when used
otin (below), but is more nephrotoxic and is seldom used now.
Preparations with nephrotoxic drugs such as aminoglycosides.
BP 2008: Cefalexin Capsules; Cefalexin Oral Suspension; Cefalexin Tablets;
Acute interstitial nephritis is also a possibility as a
USP 31: Cephalexin Capsules; Cephalexin for Oral Suspension; Cephalex- manifestation of hypersensitivity.
in Tablets; Cephalexin Tablets for Oral Suspension. Cefalotin Sodium (BANM, pINNM) Transient increases in liver enzyme values have been
Proprietary Preparations (details are given in Part 3)
Arg.: Beliam; Cefalexi†; Cefapoten; Cefarinol; Cefasporina; Cefosporen; 38253; Cefalotin sodná sůl; Cefalotina sódica; Céfalotine sodi- reported. Hepatitis and cholestatic jaundice have oc-
Ceporexin; Fabotop; Keforal; Lars; Lexin; Lorbicefax; Novalexin; Pectorina†; que; Cefalotinnatrium; Cefalotin-nátrium; Cefalotino natrio drus- curred rarely with some cephalosporins.
Permvastat; Sanibiotic; Septilisin; Trexina; Triblix; Velexina; Austral.: Cilex;
Ialex; Ibilex; Keflex; Rancef; Sporahexal; Austria: Cepexin; Cephalobene; ka; Cefalotinum natricum; Cefalotyna sodowa; Cephalothin Sodi- Convulsions and other signs of CNS toxicity have been
Keflex; Ospexin; Sanaxin; Belg.: Ceporex†; Keforal; Braz.: Betacef†; Ce- um (USAN); Kefalotiininatrium; Natrii Cefalotinum; Sodium Ce- associated with high doses, especially in patients with
faben; Cefagel; Cefagon†; Cefagran; Cefalexan†; Cefanal; Cefaxon; Cefexi- phalothin. Sodium (7R)-7-[2-(2-thienyl)acetamido]cephalospo-
na; Ceflexin†; Celen; Celexin; Celinax†; Ceporexin†; Falexin†; Kefalexin†;
ranate; Sodium (7R)-3-acetoxymethyl-7-[2-(2-thienyl)acetami-
severe renal impairment.
Keflaxina†; Keflex; Keforal; Kiflexin†; Lexin; Lifalexin†; Neo Ceflex; Neoce-
flex; Primacef; Profalexina; Todexin†; Valflex; Canad.: Apo-Cephalex; do]-3-cephem-4-carboxylate. Gastrointestinal adverse effects such as nausea, vomit-
Novo-Lexin; Nu-Cephalex; Cz.: Cefaclen; Oracef†; Ospexin; Sporidex; Натрий Цефалотин ing, and diarrhoea have been reported rarely. Pro-
Denm.: Keflex; Fin.: Kefalex; Kefexin; Orakef†; Fr.: Cefacet; Ceporexine;
Keforal; Ger.: Cephalex; Ceporexin†; Oracef†; Hong Kong: Anxer; Ce- C 16 H 15 N 2 NaO 6 S 2 = 418.4. longed use may result in overgrowth of non-suscepti-
facin-M; Cefacure; Ceporex; Felexin; Keflex†; Medolexin; Ospexin; Sofilex; C AS — 153-61-7 (cefalotin); 58-71-9 (cefalotin sodium). ble organisms and, as with other broad-spectrum
Solulexin; Hung.: Keflex†; Pyassan; Servispor†; India: Alexin†; Betaspore†;
Cefmix; Cephadex; Cephaxin; Nufex; Phexin; Rofex†; Sepexin; Sporidex; ATC — J01DB03. antibiotics, pseudomembranous colitis may develop
Indon.: Cefabiotic; Madlexin; Ospexin; Pralexin; Tepaxin; Theralexin; Irl.: ATC Vet — QJ01DB03. (see also below).
Ceporex†; Kefexin†; Keflex; Israel: Cefalin†; Ceforal; Cefovit; Keflex†; Ital.:
Ceporex; Keforal; Lafarin; Jpn: Larixin; Malaysia: Cefax†; Celexin; Cepo- There may be pain at the injection site after intramus-
rex†; Felexin; Kefexin†; Medolexin; Ospexin; Refex†; Sofilex†; Sporidex; cular use, and thrombophlebitis has occurred on intra-
Uphalexin; Mex.: Acacin; Arlexen; Cefalver; Ceporex; Facelit; Falexol†; S O
Fleximin; Flextinol; Keflex; Nafacil; Nixelaf-C; Optocef; Paferxin; Quimospo- H H venous infusion of cephalosporins. Cefalotin appears
rina; Servicef; Neth.: Keforal; Norw.: Keflex; NZ: Keflex†; Philipp.: Airex; S to be more likely to cause such local reactions than oth-
Bacilexin; Bandax; Bloflex; Canelin; Cefalin; Cendalex; Ceporex; Civalex; N
Eliphorin; Forexine; Halcepin; Infexin; Keflex; Lewimycin; Lexum; Lonarel; H er cephalosporins.
Lyceplix; Madexin; Medilexin; Medoxine; Montralex; Nefadon; Neolecsin; N O CH3
Nerfalex; Oneflex; Respinal; Selzef; Servispor; Sorlex; Sporidex; Xinflex; Antibiotic-associated colitis. Pseudomembranous colitis has
Zepharyl; Zeporin; Zucoflaxin; Pol.: Keflex; Port.: Ceflax†; Ceporex; Ke- O occurred with many antibacterials, including broad-spectrum ce-
flex†; S.Afr.: Fexin†; Keflex; Lenocef; Ranceph; Singapore: Celexin; Ce- COOH O phalosporins.1-3 In 1991 the UK CSM warned4 of the dangers of
phalen; Cephanmycin; Ceporex†; Felexin†; Ospexin; Sofilex; Sporidex; Up- pseudomembranous colitis with the newer, as well as the older,
halexin; Spain: Bioscefal†; Cefalexgobens; Defaxina†; Kefloridina; Lexincef;
Sulquipen; Torlasporin; Swed.: Keflex; Thai.: Anxer†; Cefexin; Cefxin†; (cefalotin) oral cephalosporins. In addition to 33 reports of pseudomembra-
Celex; Celexin; Cephalexyl; Cephin; Ceporex†; Farmalex; Felexin; Ibilex; nous colitis associated with cefalexin, cefradine, cefadroxil, and
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
220 Antibacterials
cefaclor, 6 of which proved fatal, they had received 12 reports of active against Gram-positive cocci, and has moderate continuous infusion. It may be given intramuscularly
probable or confirmed cases with cefuroxime axetil and 15 with activity against some Gram-negative bacilli. but this route is painful. Doses are expressed in terms
cefixime, one of them fatal. In clinical trials of cefuroxime axetil
and cefixime, diarrhoea and pseudomembranous colitis ap- Sensitive Gram-positive cocci include both penicilli- of the equivalent amount of cefalotin; 1.06 g of cefalo-
peared to be dose-related and therefore the CSM recommended nase- and non-penicillinase-producing staphylococci, tin sodium is equivalent to about 1 g of cefalotin. The
that higher doses should be reserved for severe infections. In any although meticillin-resistant staphylococci are resist- usual dose is 0.5 to 1 g of cefalotin every 4 to 6 hours;
event they advised that treatment should be stopped if symptoms up to 12 g daily has been given in severe infections.
suggestive of pseudomembranous colitis arose.
ant; most streptococci are also sensitive, but not peni-
For further discussion of the management of this condition, see
cillin-resistant Streptococcus pneumoniae; enterococci Administration in renal impairment. Reduced doses are
p.171. are usually resistant. Some Gram-positive anaerobes recommended if cefalotin is given to patients with renal impair-
are also susceptible. Cefalotin is usually inactive ment. After an intravenous loading dose of 1 to 2 g patients may
1. de Lalla F, et al. Third generation cephalosporins as a risk factor
be given the following maximum doses according to their creat-
for Clostridium difficile-associated disease: a four-year survey against Listeria monocytogenes. inine clearance (CC):
in a general hospital. J Antimicrob Chemother 1989; 23: 623–31.
2. Golledge CL, et al. Extended spectrum cephalosporins and Among Gram-negative bacteria cefalotin has activity • CC 50 to 80 mL/minute: 2 g every 6 hours
Clostridium difficile. J Antimicrob Chemother 1989; 23: against some Enterobacteriaceae including strains of • CC 25 to 50 mL/minute: 1.5 g every 6 hours
929–31.
3. Freiman JP, et al. Pseudomembranous colitis associated with sin- Escherichia coli, Klebsiella pneumoniae, Proteus mi- • CC 10 to 25 mL/minute: 1 g every 6 hours
gle-dose cephalosporin prophylaxis. JAMA 1989; 262: 902. rabilis, Salmonella, and Shigella spp., but not against • CC 2 to 10 mL/minute: 500 mg every 6 hours
4. Committee on Safety of Medicines. Pseudomembranous (antibi- Enterobacter, indole-positive Proteus, or Serratia spp. • CC less than 2 mL/minute: 500 mg every 8 hours
otic-associated) colitis and diarrhoea with cephalosporins. Cur-
re n t P ro b l e m s 3 2 1 9 9 1 . A l s o a v a i l a b l e a t : h t t p : / / It is also active against Moraxella catarrhalis (Branha- Preparations
www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& mella catarrhalis) and Neisseria spp., though Haemo-
dDocName=CON2024450&RevisionSelectionMethod= USP 31: Cephalothin for Injection; Cephalothin Injection.
LatestReleased (accessed 04/08/08) philus influenzae is moderately resistant. Bacteroides Proprietary Preparations (details are given in Part 3)
Effects on the blood. References. fragilis and Pseudomonas aeruginosa are not sensitive Arg.: Arecamin; Cefade†; Dasuglor; Keflin; Rupecef†; Austral.: Keflin Neu-
and neither are mycobacteria, mycoplasma, and fungi. tral; Braz.: Cefalin; Cefalot†; Cefalotil; Cefariston; Kefalotin†; Keflin; Ca-
1. Lipsky JJ. Antibiotic-associated hypoprothrombinaemia. J Anti- nad.: Ceporacin†; Denm.: Keflin†; Fin.: Keflin†; Indon.: Cephation;
microb Chemother 1988; 21: 281–300. Resistance of bacteria to cefalotin may be due to sever- Moraxine; Israel: Keflin†; Ital.: Keflin†; Mex.: Cefelen; Ceftina; Falot; Keflin;
2. Shearer MJ, et al. Mechanism of cephalosporin-induced hypo- Liroken I; Loriken†; Lotin; Neth.: Keflin; Norw.: Keflin; Philipp.: Fezef;
prothrombinemia: relation to cephalosporin side chain, vitamin al mechanisms: the drug may be prevented from reach- S.Afr.: Keflin†; Singapore: Cefadin; Thai.: Cefadin†; Keflin†; Venez.: Ce-
K metabolism, and vitamin K status. J Clin Pharmacol 1988; 28: ing its site of action, for example in some Gram-nega- faciclina†; Ceflen; Keflin†.
88–95.
3. Welage LS, et al. Comparative evaluation of the pharmacokinet- tive organisms the cell wall may be a potential barrier;
ics of N-methylthiotetrazole following administration of cefop- the target penicillin-binding proteins may be altered so
erazone, cefotetan, and cefmetazole. Antimicrob Agents Chem-
other 1990; 34: 2369–74.
that cefalotin cannot bind with these proteins; or, most Cefamandole (BAN, USAN, rINN)
importantly, the organism may produce beta-lactama-
Effects on the kidneys. References. 83405; Cefamandol; Céfamandole; Cefamandolum; Cephaman-
ses (cephalosporinases). Cefalotin is relatively resist- dole; Compound 83405; Kefamandoli. (7R)-7-D-Mandelamido-
1. Zhanel GG. Cephalosporin-induced nephrotoxicity: does it ex-
ist? DICP Ann Pharmacother 1990; 24: 262–5. ant to hydrolysis by staphylococcal beta-lactamase, but 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxyl-
2. Tune BM. Nephrotoxicity of beta-lactam antibiotics: mecha- is inactivated by a variety of beta-lactamases produced ic acid; {6R-[6α,7β(R*)]}-7-[(hydroxyphenylacetyl)amino]-3-{[(1-
nisms and strategies for prevention. Pediatr Nephrol 1997; 11:
768–72. by Gram-negative organisms; resistance of Gram-neg- methyl-1H-tetrazol-5-yl)thio]methyl}-8-oxo-5-thia-1-azabicyc-
ative organisms often depends on more than one factor. lo[4.2.0]oct-2-ene-2-carboxylic acid.
Precautions Resistance can be chromosomally or plasmid-mediat- Цефамандол
Cefalotin should not be given to patients who are hy- ed and may sometimes be inducible by cephalosporins. C 18 H 18N 6 O 5 S 2 = 462.5.
persensitive to it or to other cephalosporins. Immuno- Certain strains of bacteria may be inhibited but not C AS — 34444-01-4.
logical studies have suggested that up to 20% of peni- ATC — J01DC03.
killed by cephalosporins or penicillins and in such cas-
cillin-sensitive patients may also be allergic to ATC Vet — QJ01DC03.
es the minimum bactericidal concentration is much
cephalosporins although clinical studies indicate a greater than the minimum inhibitory concentration;
lower frequency and the true incidence is uncertain; this is known as tolerance.
great care should be taken if cefalotin is to be given to O
As well as with other cephalosporins, some cross-re- H H
such patients. Care is also necessary in patients with a sistance may occur between cefalotin and the penicilli- S
history of allergy. N CH3
nase-resistant penicillins. H
Cefalotin should be given with caution to patients with OH N S N
O N
renal impairment; dosage reduction may be necessary. Pharmacokinetics
Renal and haematological status should be monitored Cefalotin is poorly absorbed from the gastrointestinal COOH N N
especially during prolonged and high-dose therapy. tract. After intramuscular injection peak plasma con-
Cefalotin and some other cephalosporins and ce- centrations of about 10 and 20 micrograms/mL are Cefamandole Nafate (BAN, USAN, rINNM)
phamycins (ceforanide, cefotetan, cefoxitin, and cef- achieved within 30 minutes of doses of 0.5 and 1 g, re- 106223; Cefamandole Formate Sodium; Céfamandole, nafate
pirome) may interfere with the Jaffé method of meas- spectively. A concentration of 30 micrograms/mL has de; Cefamandoli nafas; Cefamandoli Nafatum; Cefamandolio na-
uring creatinine concentrations and may produce been reported 15 minutes after the intravenous injec- fatas; Cefamandolnafat; Cefamandol-nafát; Cefamandolu nafan;
falsely high values; this should be borne in mind when tion of a 1-g dose; a range of 14 to 20 micrograms/mL Cefmandoli Nafas; Cephamandole Nafate; Kefamandolinafaatti;
measuring renal function. Positive results to the direct has been achieved by the continuous intravenous infu- Nafato de cefamandol. Sodium (7R)-7-[(2R)-2-formyloxy-2-phe-
Coombs’ test have been found during treatment with sion of 500 mg/hour. nylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-ce-
cefalotin and these can interfere with blood cross- phem-4-carboxylate.
Cefalotin is widely distributed in body tissues and flu-
matching. The urine of patients being treated with ce- Цефамандола Нафат
ids except the brain and CSF where the concentrations C 19 H 17N 6 NaO 6 S 2 = 512.5.
falotin may give false-positive reactions for glucose achieved are low and unpredictable. It crosses the pla-
using copper-reduction reactions. C AS — 42540-40-9.
centa and low concentrations have been detected in ATC — J01DC03.
Porphyria. Cephalosporins are considered to be unsafe in pa- breast milk. The plasma half-life varies from about 30 ATC Vet — QJ01DC03.
tients with porphyria although there is conflicting experimental to 50 minutes, but may be longer in patients with renal Pharmacopoeias. In Eur. (see p.vii) and US.
evidence of porphyrinogenicity. Ph. Eur. 6.2 (Cefamandole Nafate). A white, or almost white
impairment, especially that of the metabolite. About
Sodium content. Each g of cefalotin sodium contains about 70% of cefalotin is bound to plasma proteins. powder. Freely soluble in water; sparingly soluble in methyl al-
2.39 mmol of sodium. cohol. A 10% solution in water has a pH, measured after 30 min-
About 20 to 30% of cefalotin is rapidly deacetylated in utes, of 6.0 to 8.0. Store in airtight containers. Protect from light.
Interactions the liver and about 60 to 70% of a dose is excreted in USP 31 (Cefamandole Nafate). A white, odourless, crystalline
the urine by the renal tubules within 6 hours as cefalo- solid. Soluble in water and in methyl alcohol; practically insolu-
The use of nephrotoxic drugs such as the aminoglyco- ble in chloroform, in cyclohexane, in ether, and in benzene. pH
sides gentamicin and tobramycin may increase the risk tin and the less active metabolite, desacetylcefalotin. of a 10% solution in water is between 3.5 and 7.0. Store in air-
of kidney damage with cefalotin. There is also some High urine concentrations of 0.8 and 2.5 mg/mL have tight containers.
evidence for enhanced nephrotoxicity with the loop di- been observed after intramuscular doses of 0.5 and 1 g,
Incompatibility and stability. Cefamandole nafate has been
uretic furosemide, but this is less certain than for furo- respectively. Probenecid blocks the renal excretion of reported to be incompatible with aminoglycosides and with met-
semide with cefaloridine. As with penicillins, the renal cefalotin. A very small amount is excreted in bile. ronidazole. Formulations of cefamandole nafate available for in-
excretion of cefalotin and many other cephalosporins jection contain sodium carbonate and are incompatible with so-
Uses and Administration lutions containing calcium or magnesium salts. When
is inhibited by probenecid. There may be antagonism reconstituted with water the sodium carbonate rapidly hydrolys-
between cefalotin and bacteriostatic antibacterials. Cefalotin is a first-generation cephalosporin antibacte- es about 30% of the ester to cefamandole sodium; during storage
rial that has been used in the treatment of infections due of the reconstituted solution at room temperature carbon dioxide
Antimicrobial Action to susceptible bacteria, particularly staphylococci, but is produced.
Cefalotin is a beta-lactam antibacterial. It is bactericid- has generally been replaced by newer cephalosporins. References.
al and acts similarly to benzylpenicillin (p.214) by in- Cefalotin is given as the sodium salt by slow intrave- 1. Frable RA, et al. Stability of cefamandole nafate injection with
parenteral solutions and additives. Am J Hosp Pharm 1982; 39:
hibiting synthesis of the bacterial cell wall. It is most nous injection over 3 to 5 minutes or by intermittent or 622–7. Correction. ibid.; 1479.
 Cefamandole/Cefatrizine 221
Cefamandole Sodium (BANM, rINNM) hours and high urinary concentrations are achieved. Pharmacopoeias. In Eur. (see p.vii), Jpn, and US.
Cefamandol sódico; Céfamandole Sodique; Cephamandole So- Probenecid competes for renal tubular secretion with US also includes Cephapirin Benzathine for veterinary use.
Ph. Eur. 6.2 (Cefapirin Sodium). A white or pale yellow powder.
dium; Natrii Cefamandolum. cefamandole resulting in higher and prolonged plasma Soluble in water; practically insoluble in dichloromethane. A 1%
Натрий Цефамандол concentrations of cefamandole. Therapeutic concen- solution in water has a pH of 6.5 to 8.5. Protect from light.
C 18 H 17N 6 NaO 5 S 2 = 484.5. trations of cefamandole are achieved in bile. USP 31 (Cephapirin Sodium). A white to off-white crystalline
C AS — 30034-03-8. powder, odourless or having a slight odour. Very soluble in wa-
ATC — J01DC03.
Cefamandole is removed by haemodialysis to some
ter; insoluble in most organic solvents. pH of a solution in water
ATC Vet — QJ01DC03. extent. containing the equivalent of cefapirin 1% is between 6.5 and 8.5.
Store in airtight containers.
Adverse Effects and Precautions Uses and Administration
Cefamandole is a second-generation cephalosporin an- Profile
As for Cefalotin Sodium, p.219. Cefapirin is a first-generation cephalosporin antibacterial with
As mentioned under Cefalotin, cephalosporins with an tibacterial used in the treatment of infections due to actions and uses very similar to those of cefalotin (p.219). It is
N-methylthiotetrazole side-chain such as cefamandole susceptible bacteria and for surgical infection prophy- used as the sodium salt but doses are expressed in terms of cefa-
(and possibly those with methylthiadiazolethiol or N- laxis. pirin base; 1.05 g of cefapirin sodium is equivalent to about 1 g
of cefapirin. The usual dose is the equivalent of 0.5 to 1 g of ce-
methylthiotriazine side-chains as well) may produce It is given principally as cefamandole nafate (the sodi- fapirin every 4 to 6 hours by intramuscular injection or intrave-
bleeding disorders associated with hypoprothrombin- um salt of cefamandole formyl ester). Doses are ex- nously. In severe infections up to 12 g daily may be given, pref-
aemia and/or platelet disorders. pressed in terms of the equivalent amount of cefaman- erably intravenously.
Sodium content. 1.05 g of cefamandole sodium and 1.11g of
dole; 1.05 g of cefamandole sodium and 1.11 g of Administration in renal impairment. Reduced doses of ce-
cefamandole nafate each contain about 2.2 mmol of sodium. cefamandole nafate are each equivalent to about 1 g of fapirin sodium may be necessary in patients with renal impair-
cefamandole. It is given by deep intramuscular injec- ment. One regimen, based on creatinine clearance (CC), that has
Interactions tion, by slow intravenous injection over 3 to 5 minutes, been suggested is:
A disulfiram-like interaction with alcohol may occur or by intermittent or continuous infusion in doses of 0.5 • CC 5 to 20 mL/minute: 1 g every 12 hours
and has been attributed to the N-methylthiotetrazole to 2 g every 4 to 8 hours for adults depending on the • CC less than 5 mL/minute: 1 g every 24 hours
side-chain of cefamandole; patients should avoid alco- severity of the infection. Children over 1 month of age Patients undergoing haemodialysis may receive 7.5 to 15 mg/kg
hol during, and for at least several days after, cefaman- may be given 50 to 100 mg/kg daily in equally divided after each dialysis.
dole treatment. Interactions are also possible with prep- doses; 150 mg/kg daily may be given in severe infec- Sodium content. Each g of cefapirin sodium contains about
arations containing significant amounts of alcohol. tions, but this dose should not be exceeded. For details 2.2 mmol of sodium.
Cefamandole, and other cephalosporins with an N- of reduced doses in patients with renal impairment, see Preparations
methylthiotetrazole side-chain, may enhance the hypo- below. If cefamandole is used with an aminoglycoside, USP 31: Cephapirin for Injection.
prothrombinaemic response to anticoagulants as dis- the drugs should be given separately. Proprietary Preparations (details are given in Part 3)
cussed under Warfarin (p.1428). For surgical infection prophylaxis, a dose of 1 or 2 g Cz.: Cefatrexyl†; Fr.: Cefaloject; Gr.: Cefatrex†; Spain: Brisfirina.
Probenecid reduces the renal clearance of cefamandole intravenously or intramuscularly 30 to 60 minutes be-
and many other cephalosporins. fore surgical incision, followed by 1 or 2 g every 6
hours for 24 to 48 hours, is recommended. For patients Cefatrizine (BAN, USAN, pINN)
◊ References.
1. Portier H, et al. Interaction between cephalosporins and alcohol.
undergoing procedures involving implantation of pros- BL-S640; Cefatrizina; Céfatrizine; Cefatrizinum; SKF-60771; S-
Lancet 1980; ii: 263. thetic devices, cefamandole should be continued for up 640P. (7R)-7-(α-D-4-Hydroxyphenylglycylamino)-3-(1H-1,2,3-tri-
2. Drummer S, et al. Antabuse-like effect of β-lactam antibiotics. N to 72 hours. Children over 3 months of age may be azol-4-ylthiomethyl)-3-cephem-4-carboxylic acid.
Engl J Med 1980; 303: 1417–18.
treated similarly to adults and given 50 to 100 mg/kg Цефатризин
Antimicrobial Action daily in equally divided doses. C 18 H 18 N 6 O 5 S 2 = 462.5.
Cefamandole is bactericidal and acts similarly to cefal- Administration in renal impairment. Doses of cefaman- C AS — 51627-14-6.
otin, but has a broader spectrum of activity. It generally dole should be reduced for patients with renal impairment. After ATC — J01DB07.
an initial dose of 1 to 2 g the following maintenance doses have ATC Vet — QJ01DB07.
has similar or less activity against Gram-positive sta- been recommended based on creatinine clearance (CC):
phylococci and streptococci, but is resistant to some • CC 50 to 80 mL/minute: 0.75 to 2 g every 6 hours
beta-lactamases produced by Gram-negative bacteria. • CC 25 to 50 mL/minute: 0.75 to 2 g every 8 hours HO
It is more active than cefalotin against many of the En- O
• CC 10 to 25 mL/minute: 0.5 to 1.25 g every 8 hours H H
terobacteriaceae including some strains of Entero- • CC 2 to 10 mL/minute: 0.5 to 1 g every 12 hours S
N
bacter, Escherichia coli, Klebsiella, Salmonella, and • CC less than 2 mL/minute: 0.25 to 0.75 g every 12 hours H
NH2 N S N
some Proteus spp. However, resistance to cefamandole N
Preparations O
and other beta lactams has emerged in some species, COOH NH
USP 31: Cefamandole Nafate for Injection.
notably Enterobacter, during treatment with cefaman-
Proprietary Preparations (details are given in Part 3)
dole. Cefamandole is very active in vitro against Hae- Austral.: Mandol; Austria: Mandokef; Belg.: Mandol; Cz.: Mandol†; Gr.:
mophilus influenzae although an inoculum effect has Acemycin; Cefadin; Mandokef; Hong Kong: Mandol†; Hung.: Cefam; Cefatrizine Propylene Glycol (BANM, pINNM)
Mandokef†; Indon.: Dardokef; Dofacef; Irl.: Kefadol†; Ital.: Cefam; Cema-
been reported for beta-lactamase-producing strains. do; Lampomandol; Mancef; Mandokef†; Mandolsan†; Septomandolo†; Cefatrizina propilenglicol; Cefatrizinas propilenglikolis; Céfatrizine
Like cefalotin, most strains of Bacteroides fragilis are Neth.: Mandol; NZ: Mandol; Pol.: Tarcefandol; Port.: Mandokef†; Rus.: propylèneglycol; Cefatrizin-propilénglikol; Cefatrizinpropyleng-
Cefat (Цефат); Mandol (Мандол); S.Afr.: Kefdole†; Mandokef; Switz.: lykol; Cefatrizin-propylenglykol; Cefatrizinum propylen glycolum;
resistant to cefamandole, as are Pseudomonas spp. Mandokef; Thai.: Cefadol; Cefmandol; Mandol†.
Cefatrizinum Propylenglycolum; Kefatritsiinipropyleeniglykoli.
◊ References. (7R)-7-(α-D-4-Hydroxyphenylglycylamino)-3-(1H-1,2,3-triazol-
1. Sabath LD. Reappraisal of the antistaphylococcal activities of 4-ylthiomethyl)-3-cephem-4-carboxylate propylene glycol.
first-generation (narrow-spectrum) and second-generation (ex- Cefapirin Sodium (BANM, pINNM)
panded-spectrum) cephalosporins. Antimicrob Agents Chemoth- Цефатризин Пропиленгликол
er 1989; 33: 407–11. BL-P-1322; Cefapirin sodná sůl; Cefapirina sódica; Céfapirine
sodique; Cefapirinnatrium; Cefapirin-nátrium; Cefapirino natrio C 18 H 18 N 6 O 5 S 2 , (C 3 H 8 O 2 ) n .
druska; Cefapirinum natricum; Cephapirin Sodium (USAN); Kefa- C AS — 64217-62-5.
Pharmacokinetics ATC — J01DB07.
Cefamandole is poorly absorbed from the gastrointes- piriininatrium; Natrii Cefapirinum. Sodium (7R)-7-[2-(4-pyri-
dylthio)acetamido]cephalosporanate; Sodium (7R)-3-ace- ATC Vet — QJ01DB07.
tinal tract. It is given intramuscularly or intravenously,
toxymethyl-7-[2-(4-pyridylthio)acetamido]-3-cephem-4-carbox- Pharmacopoeias. In Eur. (see p.vii) and Jpn.
usually as the nafate which is rapidly hydrolysed to re- ylate. Ph. Eur. 6.2 (Cefatrizine Propylene Glycol). A white or almost
lease cefamandole in vivo. Peak plasma concentrations Натрий Цефапирин white powder. Slightly soluble in water; practically insoluble in
for cefamandole of about 13 and 25 micrograms/mL C 17 H 16 N 3 NaO 6 S 2 = 445.4. alcohol and in dichloromethane.
have been achieved 0.5 to 2 hours after intramuscular C AS — 21593-23-7 (cefapirin); 24356-60-3 (cefapirin so- Profile
doses of 0.5 and 1 g respectively; concentrations are dium). Cefatrizine is a cephalosporin antibacterial with actions and uses
very low after 6 hours. About 70% is bound to plasma ATC — J01DB08. similar to those of cefalexin (p.218), although it might be more
ATC Vet — QJ01DB08. active in vitro. It is given orally as the base or, more often, as a
proteins. The plasma half-life varies from about 0.5 to
1.2 hours depending on the route of injection; it is pro- compound with propylene glycol, in usual doses equivalent to
500 mg twice daily of cefatrizine.
longed in patients with renal impairment. O
H H Preparations
Cefamandole is widely distributed in body tissues and S S
fluids including bone, joint fluid, and pleural fluid; it N Proprietary Preparations (details are given in Part 3)
H Belg.: Cefaperos; Fr.: Cefaperos†; Gr.: Anfagladin; Axelorax; Banadroxin†;
diffuses into the CSF when the meninges are inflamed, N N O CH3 Ceftazin; Cetrizin; Clomin†; Fica-F; Gertemycin; Izerin; Kentacef; Klevasin;
but concentrations are unpredictable. Cefamandole has O Liamycin; Liferost; Lingopen; Mekan†; Nibocin; Northiron; Phacobiotic†;
COOH O Relyovix; Specicef-N; Trixilan; Ital.: Biotrixina†; Cefatrix†; Cetrazil†; Cetri-
also been detected in breast milk. It is rapidly excreted nox†; Faretrizin; Ipatrizina†; Ketrizin; Miracef†; Novacef†; Tamyl†; Tricef†;
unchanged by glomerular filtration and renal tubular (cefapirin)
Trizina; Port.: Macropen; Supracefa.
secretion; about 80% of a dose is excreted within 6
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
222 Antibacterials
Cefazolin (BAN, pINN) Effects on the nervous system. References.
1. Manzella JP, et al. CNS toxicity associated with intraventricular
In some countries a modified-release intramuscular
injection of cefazolin: report of three cases. J Neurosurg 1988;
formulation of cefazolin sodium with the less soluble
Cefazolina; Céfazoline; Cefazolinum; Cephazolin; Kefatsoliini; Se-
fazolin. 3-[(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-7-(tetra- 68: 970–1. dibenzylamine salt of cefazolin, in the ratio of 1:4, has
zol-1-ylacetamido)-3-cephem-4-carboxylic acid.
2. Martin ES, et al. Seizures after intraventricular cefazolin admin- been used.
istration. Clin Pharm 1992; 11: 104–5.
Цефазолин Sodium content. Each g of cefazolin sodium contains about Administration in renal impairment. Dosage of cefazolin
C 14 H 14 N 8 O 4 S 3 = 454.5. should be reduced in patients with renal impairment and various
2.1 mmol of sodium.
modifications have been recommended. After a loading dose the
C AS — 25953-19-9. licensed product information suggests the following doses based
ATC — J01DB04. Interactions on creatinine clearance (CC):
ATC Vet — QJ01DB04; QJ51DA04. Cefazolin contains a methylthiadiazolethiol side- Adults
chain; like cephalosporins containing the related N- • CC 55 mL or more per minute: usual doses
methylthiotetrazole side-chain (see Cefamandole, • CC 35 to 54 mL/minute: usual doses but at intervals of at least
H 3C p.221), it may have the potential to cause a disulfiram- 8 hours
N N O N like reaction with alcohol, and enhance the effects of • CC 11 to 34 mL/minute: half the usual dose every 12 hours
H H warfarin. • CC 10 mL or less per minute: half the usual dose every 18 to
N N S S N
24 hours
N The renal excretion of cefazolin and many other cepha-
H Children
N S losporins is delayed by probenecid.
• CC 40 to 70 mL/minute: 60% of the normal daily dose in 2
O divided doses
Antimicrobial Action • CC 20 to 40 mL/minute: 25% of the normal daily dose in 2
COOH
As for Cefalotin Sodium, p.220, although cefazolin is divided doses
Pharmacopoeias. In US.
more sensitive to staphylococcal beta-lactamase. • CC 5 to 20 mL/minute: 10% of the normal daily dose every 24
USP 31 (Cefazolin). A white to slightly off-white, odourless hours.
crystalline powder. Slightly soluble in water, in alcohol, and in Pharmacokinetics One report1 indicated that, for patients on long-term haemodial-
methyl alcohol; sparingly soluble in acetone; practically insolu- Cefazolin is poorly absorbed from the gastrointestinal ysis, a dose of 20 mg/kg given 3 times weekly after dialysis
ble in chloroform, in dichloromethane, in ether, and in benzene; tract and is given by the intramuscular or intravenous maintained therapeutic cefazolin concentrations.
soluble in dimethylformamide and in pyridine; very slightly sol- 1. Ahern JW, et al. Cefazolin dosing protocol for patients receiving
routes. After a 500-mg dose given intramuscularly, long-term hemodialysis. Am J Health-Syst Pharm 2003; 60:
uble in ethyl acetate, in isopropyl alcohol, and in methyl isobutyl
ketone. Store in airtight containers. peak plasma concentrations of 30 micrograms or more 178–81.
per mL are obtained after 1 hour. About 85% of cefazo- Preparations
Cefazolin Sodium (BANM, USAN, pINNM) lin is bound to plasma proteins. The plasma half-life of BP 2008: Cefazolin Injection;
cefazolin is about 1.8 hours, and is increased in patients USP 31: Cefazolin for Injection; Cefazolin Injection; Cefazolin Ophthalmic
46083; Cefazolin sodná sůl; Cefazolina sódica; Céfazoline sodi- Solution.
que; Cefazolinnatrium; Cefazolin-nátrium; Cefazolino natrio with renal impairment. Cefazolin diffuses into bone Proprietary Preparations (details are given in Part 3)
druska; Cefazolinum natricum; Cephazolin Sodium; Kefatsoliini- and into ascitic, pleural, and synovial fluid but not ap- Arg.: Cefalomicina; Cefamezin; Austral.: Kefzol; Austria: Kefzol; Servazo-
preciably into the CSF. It crosses the placenta; only low lin; Zolicef; Belg.: Cefacidal; Kefzol†; Braz.: Ceftrat; Cezolin†; Duocef;
natrium; Natrii Cefazolinum; Sefazolin Sodyum; SKF-41558. Fazolon; Kefazol; Zolin†; Canad.: Kefzol†; Chile: Kefzol†; Cz.: Kefzol†; Ori-
Натрий Цефазолин concentrations are detected in breast milk. zolin†; Vulmizolin; Fr.: Cefacidal†; Ger.: Basocef; Elzogram†; Gr.: Biozolin†;
Vifazolin; Hong Kong: Cefamezin; Hung.: Totacef†; India: Azolin; Reflin;
C 14 H 13 N 8 NaO 4 S 3 = 476.5. Cefazolin is excreted unchanged in the urine, mainly Zolfin†; Indon.: Biozolin; Cefazol; Israel: Cefamezin; Kefazin; Kefzol†; Tota-
C AS — 27164-46-1. by glomerular filtration with some renal tubular secre- cef†; Ital.: Acef; Cefabiozim†; Cefamezin; Cefazil; Cromezin; Nefazol; Re-
ATC — J01DB04. cef; Sicef; Silzolin†; Totacef; Jpn: Cefamezin; Otsuka Cez; Mex.: Cefacidal†;
tion, at least 80% of a dose given intramuscularly being Neth.: Cefacidal; Cefamezin; Kefzol; Servazolin; NZ: Kefzol†; Zepilen;
ATC Vet — QJ01DB04.
excreted within 24 hours. Peak urine concentrations of Philipp.: Cifoxim; Cizo; Cloviz; Fazol; Fonvicol; Ilozef; Lupex; Maxcep; Meg-
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. acef; Oryant; Samarial; Stancef; Zofadep; Zolival; Pol.: Biofazolin; Tarfazolin;
more than 2 and 4 mg/mL have been reported after in- Port.: Cefamezin; Kurgan; Rus.: Cefamezin (Цефамезин); Ifizol (Ифизол);
Jpn also includes the pentahydrate.
Ph. Eur. 6.2 (Cefazolin Sodium). A white or almost white, very tramuscular doses of 0.5 and 1 g respectively. Probene- Intrazoline (Интразолин); Kefzol (Кефзол); Orizolin (Оризолин); Reflin
(Рефлин); S.Afr.: Cefacidal; Izacef; Kefzol; Ranzol; Spain: Areuzolin; Brizoli-
hygroscopic powder. It exhibits polymorphism. Freely soluble in cid delays excretion. Cefazolin is removed to some ex- na; Camil†; Caricef; Cefa Resan†; Cefacene†; Cefadrex; Dacovo†; Fazoplex;
water; very slightly soluble in alcohol. A 10% solution in water tent by haemodialysis. Filoklin†; Gencefal†; Intrazolina; Kefol†; Kurgan; Neofazol†; Tasep; Tecfazoli-
has a pH of 4.0 to 6.0. Store in airtight containers. Protect from na; Zolival; Switz.: Kefzol; Thai.: Cefalin; Cefamezin; Cefazillin; Cefazol; Ce-
High biliary concentrations have been reported, al- fzolin; Fazolin; Zefa; Zepilen†; Zolicef; Zolimed; Turk.: Cefamezin; Cefozin;
light. Equizolin; Iespor; Maksiporin; Sefamax; Sefazol; USA: Ancef†; Zolicef†;
USP 31 (Cefazolin Sodium). A white to off-white, practically
though the amount excreted by this route is small. Venez.: Cefacidal; Cefarizon; Cellozina; Kefzol†.
odourless, crystalline powder, or a white to off-white solid. Free-
ly soluble in water, in sodium chloride 0.9%, and in glucose so- Uses and Administration
lutions; very slightly soluble in alcohol; practically insoluble in Cefazolin is a first-generation cephalosporin antibacte- Cefbuperazone (USAN, rINN)
chloroform and in ether. pH of a solution in water containing the rial used to treat infections due to susceptible organ-
equivalent of cefazolin 10% is between 4.0 and 6.0. Store in air- BMY-25182; Cefbuperazona; Cefbupérazone; Cefbuperazonum;
isms, including biliary-tract infections, endocarditis T-1982. 7-[(2R,3S)-2-(4-ethyl-2,3-dioxopiperazin-1-ylcarboxami-
tight containers.
(staphylococcal), and peritonitis (associated with con- do)-3-hydroxybutyramido]-7-methoxy-3-(1-methyl-1H-tetra-
Incompatibility and stability. Cefazolin sodium has been re- tinuous ambulatory peritoneal dialysis). It is also used zol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
ported to be incompatible with aminoglycosides and many other
drugs. When the pH of a solution exceeds 8.5 there may be hy-
for surgical infection prophylaxis, including prophy- Цефбуперазон
drolysis and when it is below 4.5 insoluble cefazolin may be pre- laxis of endometritis at caesarean section. For details of C 22 H 29N 9 O 9 S 2 = 627.7.
cipitated. these infections and their treatment, see under Choice C AS — 76610-84-9.
References. of Antibacterial, p.162.
1. Nahata MC, Ahalt PA. Stability of cefazolin sodium in peritoneal Administration and dosage. Cefazolin is given as the CH
dialysis solutions. Am J Hosp Pharm 1991; 48: 291–2. HO CH
2. Wu C-C, et al. Stability of cefazolin in heparinized and non-
sodium salt by deep intramuscular injection, by slow O O H
H H S
heparinized peritoneal dialysis solutions. Am J Health-Syst intravenous injection over 3 to 5 minutes, or by intra- N CH
Pharm 2002; 59: 1537–8. N N
venous infusion. Doses are expressed in terms of the H N S N
3. Lin Y-F, et al. Stability of cefazolin sodium in icodextrin-con- H C N O N
taining peritoneal dialysis solution. Am J Health-Syst Pharm equivalent amount of cefazolin; 1.05 g of cefazolin so- O
O
COOH N N
2002; 59: 2362, 2364. dium is equivalent to about 1 g of cefazolin. The usual O
adult dose is the equivalent of 0.5 to 1 g of cefazolin
Adverse Effects and Precautions every 6 to 12 hours. The usual maximum daily dose is
As for Cefalotin Sodium, p.219. Stevens-Johnson syn- 6 g, although up to 12 g has been used in severe life- Cefbuperazone Sodium (rINNM)
drome has occurred. threatening infections. Children over 1 month of age Cefbuperazona de sodio; Cefbupérazone Sodique; Natrii Cefbu-
perazonum.
Like cephalosporins with an N-methylthiotetrazole may be given 25 to 50 mg/kg daily in 3 or 4 divided
Натрий Цефбуперазон
side-chain, cefazolin has been associated with hypo- doses, increased in severe infections to a maximum of
C 22 H 28N 9 NaO 9 S 2 = 649.6.
prothrombinaemia. 100 mg/kg daily.
Pharmacopoeias. In Jpn.
Breast feeding. In a study1 of 20 lactating women receiving For the prophylaxis of infection during surgery, a 1-g
dose is given half to one hour before the operation, fol- Profile
cefazolin, the amount of cefazolin in breast milk was found to be Cefbuperazone is a cephamycin antibiotic similar to cefoxitin
extremely small (equivalent to less than 0.075% of the dose). No lowed by 0.5 to 1 g during surgery for lengthy proce- (p.230) but with an N-methylthiotetrazole side-chain like cefa-
adverse effects have been seen in breast-fed infants whose moth- dures. A dose of 0.5 to 1 g is given every 6 to 8 hours mandole (p.220). It is given by injection as the sodium salt. Its
ers were receiving cefazolin, and the American Academy of spectrum of activity includes Enterobacteriaceae, but more espe-
Pediatrics considers2 that it is therefore usually compatible with postoperatively for 24 hours, or up to 5 days in certain
cases. cially anaerobic bacteria such as Bacteroides fragilis. Cefbuper-
breast feeding. azone does not appear to be active against cefoxitin-resistant
1. Yoshioka H, et al. Transfer of cefazolin into human milk. J Pedi- For details of reduced doses of cefazolin in patients strains of B. fragilis.
atr 1979; 94: 151–2.
2. American Academy of Pediatrics. The transfer of drugs and oth-
with renal impairment, see below. Preparations
er chemicals into human milk. Pediatrics 2001; 108: 776–89. Other routes used for cefazolin sodium include intra- Proprietary Preparations (details are given in Part 3)
Correction. ibid.; 1029. Also available at: peritoneal use in peritoneal dialysis solutions, and in- Jpn: Tomiporan.
http://aappolicy.a ap public ations.org/cgi/c ontent/full/
pediatrics%3b108/3/776 (accessed 25/05/04) tra-ocular injection.
 Cefazolin/Cefepime Hydrochloride 223
Cefcapene Pivoxil Hydrochloride (rINNM) Uses and Administration ◊ Reviews.
Cefcapène Pivoxil, Chlorhydrate de; Cefcapeni Pivoxili Hydro- Cefdinir is a third-generation oral cephalosporin antibacterial 1. Wellington K, Curran MP. Cefditoren pivoxil: a review of its use
with actions and uses similar to those of cefixime (p.224). It is in the treatment of bacterial infections. Drugs 2004; 64:
chloridum; Hidrocloruro de cefcapeno pivoxilo. Pivaloyloxyme- 2597–2618.
given orally in a usual adult dose of 600 mg daily as a single dose
thyl (+)-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-pentenami- or in two divided doses. Children may be given 14 mg/kg daily Administration in renal impairment. Doses of cefditoren
do]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- up to a maximum of 600 mg daily. Doses may need to be reduced pivoxil should be reduced in patients with moderate to severe
ene-2-carboxylic acid carbamate monohydrochloride monohy- in patients with renal impairment (see below). renal impairment according to creatinine clearance (CC):
drate. • CC 30 to 49 mL/minute: the dose should not exceed 200 mg
◊ Reviews.
Цефкапена Пивоксила Гидрохлорид twice daily
1. Guay DRP. Cefdinir: an expanded-spectrum oral cephalosporin.
C 23 H 29N 5 O 8 S 2 ,HCl,H 2 O = 622.1. Ann Pharmacother 2000; 34: 1469–77. • CC less than 30 mL/minute: the dose should be 200 mg once
C AS — 135889-00-8 (cefcapene); 105889-45-0 (cefcap- 2. Guay DR, et al. Cefdinir: an advanced-generation, broad-spec- daily.
ene pivoxil); 147816-23-7 (anhydrous cefcapene pivoxil trum oral cephalosporin. Clin Ther 2002; 24: 473–89.
hydrochloride); 147816-24-8 (cefcapene pivoxil hydrochlo- Preparations
3. Perry CM, Scott LJ. Cefdinir: a review of its use in the manage-
ride);. ment of mild-to-moderate bacterial infections. Drugs 2004; 64: Proprietary Preparations (details are given in Part 3)
1433–64. Gr.: Spectracef; India: Cefditran; Indon.: Meiact; Jpn: Meiact; Mex.: Spec-
4. Sader HS, Jones RN. Cefdinir: an oral cephalosporin for the tracef; Port.: Meiact; Spectracef; Spain: Meiact; Spectracef; Telo; Thai.:
Meiact; Turk.: Spektracef; USA: Spectracef.
H 3C treatment of respiratory tract infections and skin and skin struc-
O ture infections. Expert Rev Anti Infect Ther 2007; 5: 29–43. Cor-
H H rection. ibid.; 754. [dose error]
S
N Administration in renal impairment. Doses of cefdinir Cefepime Hydrochloride
H should be reduced to 300 mg once daily in patients with renal
N O NH2 impairment whose creatinine clearance is less than (BANM, USAN, rINNM)
N O 30 mL/minute. BMY-28142 (cefepime); Céfépime, Chlorhydrate de; Céfépime,
S COOH O Preparations dichlorhydrate de; Cefepimi dihydrochloridum; Cefepimi Hydro-
Proprietary Preparations (details are given in Part 3) chloridum; Hidrocloruro de cefepima; Sefepim Hidroklorür. {6R-
NH2
India: Kefnir†; Sefdin; Jpn: Cefzon; Mex.: Omnicef; Thai.: Omnicef; USA: [6α,7β(Z)]}-1-[(7-{[(2-Amino-4-thiazolyl)-(methoxyimi-
Omnicef. no)acetyl]amino}-2-carboxy-8-oxo-5-thia-1-azabicyc-
(cefcapene)
lo[4.2.0]oct-2-en-3-yl)methyl]-1-methylpyrrolidinium chloride
Pharmacopoeias. In Jpn. monohydrochloride monohydrate; 7-{(2-Amino-1,3-thiazol-4-
Cefditoren Pivoxil (rINNM) yl)-2-[(Z)-methoxyimino]acetamido}-3-(1-methylpyrrolidini-
Profile omethyl)-3-cephem-4-carboxylate hydrochloride.
Cefcapene is an oral cephalosporin antibacterial given orally as Cefditorène, Pivoxil de; Cefditoreni Pivoxil; Cefditoreno pivoxilo;
the pivaloyloxymethyl ester, cefcapene pivoxil hydrochloride. ME-1207; ME-1206 (cefditoren). Pivaloyloxymethyl (+)-(6R,7R)- Цефепима Гидрохлорид
For reference to carnitine deficiency occurring with some pival- 7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-3-[(Z)-2-(4-methyl-5- C 19 H 25 ClN 6 O 5 S 2 ,HCl,H 2 O = 571.5.
oyloxymethyl esters, see Pivampicillin, p.317. thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car- C AS — 88040-23-7 (cefepime); 123171-59-5 (cefepime
boxylic acid 72-(Z)-(O-methyloxime). hydrochloride monohydrate).
Preparations
ATC — J01DE01.
Proprietary Preparations (details are given in Part 3) Цефдиторена Пивоксил
Jpn: Flomox. ATC Vet — QJ01DE01.
C 25 H 28 N 6 O 7 S 3 = 620.7.
C AS — 104145-95-1 (cefditoren); 117467-28-4 (cefdi-
toren pivoxil).
S O
Cefdinir (BAN, USAN, rINN) ATC — J01DD16. H H
S
Cefdinirum; CI-983; FK-482; Kefdiniiri. (−)-(6R,7R)-7-[2-(2-Ami- ATC Vet — QJ01DD16. H N N N
H H C HCl H O
no-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyc- N N N
O O
lo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-oxime; 7-{(2-Ami- O N
S CH COOH Cl
no-1,3-thiazol-4-yl)-2-[(Z)-hydroxyimino]acetamido}-3-vinyl- H H
cephem-4-carboxylic acid. S S
H 2N N CH3
N
Цефдинир H Pharmacopoeias. In Eur. (see p.vii), Jpn, and US.
N N Ph. Eur. 6.2 (Cefepime Dihydrochloride Monohydrate). A white
C 14 H 13N 5 O 5 S 2 = 395.4. O
C AS — 91832-40-5. O or almost white, crystalline powder. Freely soluble in water and
ATC — J01DD15. CH3 COOH in methyl alcohol; practically insoluble in dichloromethane. Pro-
ATC Vet — QJ01DD15. tect from light.
(cefditoren) USP 31 (Cefepime Hydrochloride). A white to off-white, non-
hygroscopic, crystalline powder. Freely soluble in water. Store in
S O Pharmacopoeias. In Jpn. airtight containers. Protect from light.
H H
S Adverse Effects and Precautions Incompatibility and stability. References.
H2N N N As for Cefalotin, p.219. 1. Stewart JT, et al. Stability of cefepime hydrochloride injection in
H polypropylene syringes at −20°C, 4°C, and 22-24°C. Am J
N N CH2 The most frequently reported adverse effects of cefditoren are Health-Syst Pharm 1999; 56: 457–9.
OH O gastrointestinal disturbances, especially diarrhoea. 2. Stewart JT, et al. Stability of cefepime hydrochloride in polypro-
For reference to carnitine deficiency with some pivaloyloxyme- pylene syringes. Am J Health-Syst Pharm 1999; 56: 1134.
COOH 3. Williamson JC, et al. Stability of cefepime in peritoneal dialysis
thyl esters, see Pivampicillin, p.317. solution. Ann Pharmacother 1999; 33: 906–9.
Interactions 4. Baririan N, et al. Stability and compatibility study of cefepime
Pharmacopoeias. In Chin. and Jpn. in comparison with ceftazidime for potential administration by
Absorption of cefditoren after oral doses is decreased by antacids continuous infusion under conditions pertinent to ambulatory
Adverse Effects and Precautions or histamine H2-receptor antagonists. Probenecid reduces the re-
As for Cefalotin Sodium, p.219. There have been reports of red- treatment of cystic fibrosis patients and to administration in in-
nal excretion of cefditoren. tensive care units. J Antimicrob Chemother 2003; 51: 651–8.
dish stools in patients given cefdinir with iron supplements (see 5. Trissel LA, Xu QA. Stability of cefepime hydrochloride in Au-
also Interactions, below). Antimicrobial Action toDose infusion system bags. Ann Pharmacother 2003; 37:
Interactions As for Cefixime, p.224. Cefditoren also has activity against Sta- 804–7.
Absorption of cefdinir is decreased by antacids or iron supple- phylococcus aureus.
ments and doses should be separated by an interval of at least 2 Pharmacokinetics Adverse Effects and Precautions
hours. Probenecid reduces the renal excretion of cefdinir. Cefditoren pivoxil is absorbed from the gastrointestinal tract and As for Cefalotin Sodium, p.219.
Iron. A report1 of red stools in an infant given cefdinir whilst is hydrolysed to cefditoren by esterases to release active cefdi- ◊ The safety of cefepime has been reviewed.1-3 A meta-analysis2
being fed with an infant formula containing supplemental iron. It toren in the bloodstream. Peak plasma concentrations average of studies involving cefepime suggested that there might be an
was considered important to be aware of the interaction because 1.8 micrograms/mL in fasting subjects 1.5 to 3 hours after a 200- increased risk of all-cause mortality compared with other beta-
of the risk that it might be mistaken for a sign of gastrointestinal mg dose. Bioavailability is about 14% in fasting subjects and is lactams. The FDA subsequently announced that it would review
bleeding. increased when cefditoren pivoxil is given with a high-fat meal. safety data to further evaluate the risk of death associated with
1. Lancaster J, et al. Nonbloody, red stools from coadministration Plasma protein binding is reported to be 88%. The plasma half- cefepime use.4
of cefdinir and iron-supplemented infant formulas. Pharmaco- life is about 1.6 hours and is prolonged in patients with renal im- 1. Neu HC. Safety of cefepime: a new extended-spectrum parenter-
therapy 2008; 28: 678–81. pairment. al cephalosporin. Am J Med 1996; 100 (suppl 6A): 68S–75S.
Antimicrobial Action Cefditoren is not appreciably metabolised and is excreted mainly 2. Yahav D, et al. Efficacy and safety of cefepime: a systematic
in the urine by glomerular filtration and tubular secretion. It is review and meta-analysis. Lancet Infect Dis 2007; 7: 338–48.
As for Cefixime, p.224. However, cefdinir is reported to be much 3. Drago L, De Vecchi E. The safety of cefepime in the treatment
more active in vitro than cefixime against Staphylococcus au- removed by haemodialysis. of infection. Expert Opin Drug Saf 2008; 7: 377–87.
reus, but not meticillin-resistant strains, and it is less active Uses and Administration 4. FDA. Early communication about an ongoing safety review:
against some Enterobacteriaceae. Cefditoren is a cephalosporin antibacterial with a broad spectrum cefepime (marketed as Maxipime) (issued 14th November
2007). Available at: http://www.fda.gov/cder/drug/early_comm/
Pharmacokinetics of activity used in the treatment of susceptible infections, partic- cefepime.htm (accessed 04/08/08)
Cefdinir is absorbed from the gastrointestinal tract after oral dos- ularly of the respiratory tract and skin. It is given orally as the
pivaloyloxymethyl ester, cefditoren pivoxil, but doses are ex- Effects on the nervous system. References to neurotoxicity,
es, peak plasma concentrations occurring 2 to 4 hours after a
pressed in terms of cefditoren; 245 mg of cefditoren pivoxil is sometimes manifesting as nonconvulsive status epilepticus, as-
dose. Oral bioavailability has been estimated to range from 16 to
equivalent to about 200 mg of cefditoren. A usual dose is 200 to sociated with use of cefepime (particularly but not exclusively in
25%. It is widely distributed into tissues and is 60 to 70% bound
400 mg given twice daily. patients with impaired renal function).
to plasma proteins. Cefdinir is not appreciably metabolised and
1. Chow KM, et al. Retrospective review of neurotoxicity induced
is excreted in the urine with an elimination half-life of 1.7 hours. For details of reduced doses to be used in patients with moderate by cefepime and ceftazidime. Pharmacotherapy 2003; 23:
Cefdinir is removed by dialysis. to severe renal impairment, see below. 369–73.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
224 Antibacterials
2. Ferrara N, et al. Neurotoxicity induced by cefepime in a very 2 divided doses in severe infections, although up to 6 g Profile
old hemodialysis patient. Clin Nephrol 2003; 59: 388–90. Cefetamet is a third-generation cephalosporin antibacterial simi-
3. Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopa- daily in 3 divided doses has been given for febrile neu-
lar to cefixime (below). It has been given orally as the hydrochlo-
thy. Int J Infect Dis 2004; 8: 59–61. tropenia. Children aged over 2 months and weighing ride of the pivaloyloxymethyl ester, cefetamet pivoxil hydro-
4. Alpay H, et al. Cefepime-induced non-convulsive status epilep-
ticus in a peritoneal dialysis patient. Pediatr Nephrol 2004; 19: up to 40 kg may be given 50 mg/kg twice daily; this chloride, which is hydrolysed to cefetamet in vivo. The usual
445–7. dose may be given 3 times daily for febrile neutrope- dose is 500 mg twice daily.
5. Abanades S, et al. Reversible coma secondary to cefepime neu-
rotoxicity. Ann Pharmacother 2004; 38: 606–8. nia. For reference to carnitine deficiency occurring with some pival-
6. Capparelli FJ, et al. Cefepime- and cefixime-induced encepha- For details of reduced doses to be used in renal impair- oyloxymethyl esters, see Pivampicillin, p.317.
lopathy in a patient with normal renal function. Neurology 2005;
ment, see below. ◊ Reviews.
65: 1840.
7. Maganti R, et al. Nonconvulsive status epilepticus due to 1. Bryson HM, Brogden RN. Cefetamet pivoxil: a review of its an-
cefepime in a patient with normal renal function. Epilepsy Be- ◊ Reviews. tibacterial activity, pharmacokinetic properties and therapeutic
hav 2006; 8: 312–4. 1. Various. Cefepime: a β-lactamase-stable extended-spectrum ce- use. Drugs 1993; 45: 589–621.
8. Lam S, Gomolin IH. Cefepime neurotoxicity: case report, phar- phalosporin. J Antimicrob Chemother 1993; 32 (suppl B): 2. Blouin RA, Stoeckel K. Cefetamet pivoxil clinical pharmacoki-
macokinetic considerations, and literature review. Pharmaco- 1–214. netics. Clin Pharmacokinet 1993; 25: 172–88.
therapy 2006; 26: 1169–74. 2. Barradell LB, Bryson HM. Cefepime: a review of its antibacte- Preparations
9. Sonck J, et al. The neurotoxicity and safety of treatment with rial activity, pharmacokinetic properties and therapeutic use.
cefepime in patients with renal failure. Nephrol Dial Transplant Drugs 1994; 47: 471–505. Proprietary Preparations (details are given in Part 3)
2008; 23: 966–70. 3. Okamoto MP, et al. Cefepime: a new fourth-generation cepha- Braz.: Globocef†; Ger.: Globocef†; Hong Kong: Globocef†; Ital.: Glob-
10. Garces EO, et al. Renal failure is a risk factor for cefepime- losporin. Am J Hosp Pharm 1994; 51: 463–77. ocef†; Pol.: Tarcevis†; Port.: Cefec†; Globocef†; Switz.: Globocef†.
induced encephalopathy. J Nephrol 2008; 21: 526–34. 4. Wynd MA, Paladino JA. Cefepime: a fourth-generation
parenteral cephalosporin. Ann Pharmacother 1996; 30:
Antimicrobial Action 1414–24.
Cefepime is a fourth-generation cephalosporin and is
5. Wong-Beringer A. Treating serious infections: focus on
cefepime. Pharmacotherapy 2004; 24: 216S–23S.
Cefixime (BAN, USAN, rINN)
active against a wide range of Gram-positive and 6. Roberts JA, et al. Cefepime versus ceftazidime: considerations Cefiksimas; Cefixim; Cefixim trihydrát; Cefixima; Céfixime; Cefix-
for empirical use in critically ill patients. Int J Antimicrob Agents imum; Cefiximum Trihydricum; CL-284635; FK-027; FR-17027;
Gram-negative aerobic organisms. Against Gram-pos- 2007; 29: 117–28.
itive cocci, its activity is similar to that of cefotaxime Kefiksiimi; Sefiksim. (Z)-7-[2-(2-Aminothiazol-4-yl)-2-(car-
Administration in renal impairment. Dosage of cefepime boxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic
(p.228) and includes staphylococci (but not meticillin- should be modified in renal impairment. After a normal first dose acid trihydrate.
resistant Staphylococcus aureus) and streptococci. the maintenance dosage should be adjusted according to the pa-
Цефиксим
Against Enterobacteriaceae, it has a broader spectrum tient’s creatinine clearance (CC) and the severity of the infection:
C 16 H 15N 5 O 7 S 2 ,3H 2 O = 507.5.
of activity than other cephalosporins, including activity • CC 30 to 60 mL/minute: 0.5 to 2 g every 24 hours (2 g every
12 hours for febrile neutropenia) C AS — 79350-37-1.
against organisms producing chromosomally mediated ATC — J01DD08.
• CC 11 to 29 mL/minute: 0.5 to 1 g every 24 hours (2 g every
beta-lactamases such as Enterobacter spp. and Proteus 24 hours for febrile neutropenia) ATC Vet — QJ01DD08.
vulgaris. Against Pseudomonas aeruginosa, it has • CC 10 mL/minute or less: 250 to 500 mg every 24 hours (1 g
similar or slightly less activity than ceftazidime every 24 hours for febrile neutropenia)
S O
(p.234), although it may be active against some strains Patients undergoing haemodialysis should be given a dose of 1 g
on the first day of treatment, followed by 500 mg daily; the dose H 2N H H
resistant to ceftazidime. S
should be given after haemodialysis on those days. A dose of 1 g N N
daily should be used for febrile neutropenia. Patients undergoing H
Pharmacokinetics continuous ambulatory peritoneal dialysis should receive normal N N CH2
Cefepime is given by injection as the hydrochloride. It recommended doses at intervals of 48 hours. A dose of 2 g every O O
is rapidly and almost completely absorbed on intra- 48 hours is used for febrile neutropenia.
COOH
muscular injection and mean peak plasma concentra- Preparations COOH
tions of about 14 and 30 micrograms/mL have been re- USP 31: Cefepime for Injection.
ported about 1.5 hours after doses of 500 mg and 1 g Proprietary Preparations (details are given in Part 3) Pharmacopoeias. In Eur. (see p.vii) and US. Jpn includes the
respectively. Within 30 minutes of similar intravenous Arg.: Cefimen-K; Maxcef; Rivepime; Austral.: Maxipime; Austria: Maxip- anhydrous substance.
ime; Belg.: Maxipime; Braz.: Cefepen†; Cemax†; Clocef; Maxcef; Maxil†; Ph. Eur. 6.2 (Cefixime). A white or almost white, slightly hy-
doses, peak plasma concentrations of about 40 and Canad.: Maxipime; Chile: Maxipime; Cz.: Maxipime; Denm.: Maxipime†; groscopic, powder. Slightly soluble in water; sparingly soluble in
80 micrograms/mL are achieved. The plasma half-life Fin.: Maxipime; Fr.: Axepim; Ger.: Maxipime; Gr.: Anticepim; Gencef; dehydrated alcohol; practically insoluble in ethyl acetate; freely
Maxinject; Maxipime; Verapime; Zefipime; Hong Kong: Maxipime; Hung.:
of cefepime is about 2 hours and is prolonged in pa- Maxipime; India: Biopime; Ceficad; Forpar; Indon.: Exepime; Maxicef; soluble in methyl alcohol. A 5% suspension in water has a pH of
tients with renal impairment. About 20% of cefepime Maxipime; Procepim; Sandocef; Irl.: Maxipime†; Israel: Maxcef†; Ital.: Ce- 2.6 to 4.1. Store in airtight containers. Protect from light.
pim; Cepimex; Maxipime; Malaysia: Maxipime; Mex.: Maxipime; NZ: USP 31 (Cefixime). A white to light yellow crystalline powder.
is bound to plasma proteins. Maxipime; Philipp.: Cepimax; Pol.: Maxipime; Port.: Maxipime; Rus.:
Maxipime (Максипим); S.Afr.: Maxipime; Singapore: Maxipime; Spain:
Practically insoluble in water, in ether, in ethyl acetate, and in
Cefepime is widely distributed in body tissues and flu- Maxipime; Swed.: Maxipime; Switz.: Maxipime; Thai.: Maxipime; Turk.: hexane; slightly soluble in alcohol, in acetone, and in glycerol;
ids. High concentrations are achieved in bile. Low con- Maxipime; USA: Maxipime; Venez.: Maxipime. soluble in methyl alcohol and in propylene glycol; very slightly
centrations have been detected in breast milk. soluble in 70% sorbitol and in octanol. pH of a solution in water
containing the equivalent of cefixime 0.07% is between 2.6 and
Cefepime is eliminated principally by the kidneys and 4.1. Store in airtight containers.
about 85% of a dose is recovered unchanged in the Cefetamet (USAN, rINN)
urine. Cefepime is substantially removed by haemodi- Céfétamet; Cefetametum; LY-097964; Ro-15-8074. (Z)-7-[2-(2- Adverse Effects and Precautions
alysis. Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methyl-3-ce-
phem-4-carboxylic acid.
As for Cefalotin Sodium, p.219.
◊ References. Цефетамет The most frequently reported adverse effects of cefixi-
1. Okamoto MP, et al. Cefepime clinical pharmacokinetics. Clin me are gastrointestinal disturbances, especially diar-
Pharmacokinet 1993; 25: 88–102. C 14 H 15N 5 O 5 S 2 = 397.4.
2. Rybak M. The pharmacokinetic profile of a new generation of C AS — 65052-63-3 (cefetamet). rhoea. Cefixime should be stopped if diarrhoea is se-
parenteral cephalosporin. Am J Med 1996; 100 (suppl 6A): ATC — J01DD10. vere.
39S–44S. ATC Vet — QJ01DD10.
3. Reed MD, et al. Pharmacokinetics of intravenously and intra- Although cefixime does not have the N-methylthi-
muscularly administered cefepime in infants and children. Anti- otetrazole side-chain usually associated with hypopro-
microb Agents Chemother 1997; 41: 1783–7. H 3C
4. Allaouchiche B, et al. Pharmacokinetics of cefepime during con-
thrombinaemia increases in prothrombin times have
O O
tinuous venovenous hemodiafiltration. Antimicrob Agents H H occurred in a few patients.
Chemother 1997; 41: 2424–7. N S
5. Blumer JL, et al. Review of the pharmacokinetics of cefepime in Antibiotic-associated colitis. For reports of diarrhoea and
N pseudomembranous colitis associated with cefixime, see Cefalo-
children. Pediatr Infect Dis J 2001; 20: 337–42. H
6. Capparelli E, et al. Population pharmacokinetics of cefepime in N tin, p.219.
the neonate. Antimicrob Agents Chemother 2005; 49: 2760–6. N CH3
O
Interactions
Uses and Administration S COOH
Care should be exercised in patients receiving antico-
Cefepime is a fourth-generation cephalosporin anti- NH2 agulants and cefixime due to the possibility that cefix-
bacterial used in the treatment of infections due to sus- ime may increase prothrombin times (see above).
ceptible organisms. They include infections of the uri-
Cefetamet Pivoxil Hydrochloride (rINNM)
nary tract, respiratory tract, and skin. For details of Antimicrobial Action
Céfétamet Pivoxil, Chlorhydrate de; Cefetameti Pivoxili Hydro-
these infections and their treatment, see under Choice Cefixime is bactericidal and is stable to hydrolysis by
chloridum; Cefetametpivoxilhydroklorid; Cefetametum Pivoxili
of Antibacterial, p.162. Hydrochloridum; Hidrocloruro de cefetamet pivoxilo; Kefeta- many beta-lactamases. It has a mode of action and
Cefepime is given as the hydrochloride by deep intra- meettipivoksiilihydrokloridi; Ro-15-8075 (cefetamet pivoxil). spectrum of activity similar to those of the third-gener-
muscular injection, or intravenously by infusion over Cefetamet pivaloyloxymethyl hydrochloride. ation cephalosporin cefotaxime (p.228), but some En-
at least 30 minutes. Doses are expressed in terms of the Цефетамета Пивоксила Гидрохлорид terobacteriaceae are less susceptible to cefixime. Hae-
equivalent amount of cefepime; 1.19 g of cefepime hy- C 20 H 25N 5 O 7 S 2 ,HCl = 548.0. mophilus influenzae, Moraxella catarrhalis
drochloride is equivalent to about 1 g of cefepime. The C AS — 65243-33-6 (cefetamet pivoxil); 111696-23-2 (Branhamella catarrhalis), and Neisseria gonorrhoeae
(cefetamet pivoxil hydrochloride).
usual adult dose is 1 to 2 g daily in 2 divided doses for ATC — J01DD10. are sensitive, including penicillinase-producing
mild to moderate infections, increased to 4 g daily in ATC Vet — QJ01DD10. strains. Of the Gram-positive bacteria, streptococci are
 Cefetamet/Cefmetazole 225
sensitive to cefixime but most strains of staphylococci, ra; Cephoral; InfectoOpticef; Suprax; Uro-Cephoral; Gr.: Ceftoral; Cov- Cefmetazole Sodium (USAN, rINNM)
ocef-N; Hung.: Suprax; India: Biotax-O; Cefix; Cefocef-LB; Fixx; Si-Fixim†;
enterococci, and Listeria spp. are not. Xim; Ziprax; Indon.: Cefspan; Ceptik; Comsporin; Ethifix; Fixacep; Fixef; Cefmetazol sódico; Cefmétazole Sodique; Cefmetazolnatrium;
Fixiphar; Lanfix; Maxpro; Opixime; Simcef; Sofix; Spancef; Spaxim; Sporetik;
Enterobacter spp., Pseudomonas aeruginosa, and Starcef; Tocef; Irl.: Suprax; Israel: Supran; Ital.: Cefixoral; Suprax; Unixime; Cefmetazolum Natricum; CS-1170; Kefmetatsolinatrium; Natrii
Bacteroides spp. are resistant to cefixime. Jpn: Cefspan; Malaysia: Minixime; Mex.: Denvar; Novacef†; Neth.: Fix- Cefmetazolum; SKF-83088; U-72791A.
im; Philipp.: Tergecef; Ultraxime; Zefral; Port.: Bonocef†; Cefimix; Cefiton;
Cefizel; Neocef; Tricef; Rus.: Suprax (Супракс); S.Afr.: Fixime; Spain: Натрий Цефметазол
Pharmacokinetics Denvar; Necopen; Swed.: Tricef†; Switz.: Cephoral; Thai.: Cefspan;
C 15 H 16 N 7 NaO 5 S 3 = 493.5.
Turk.: Suprax; Zimaks; UK: Suprax; USA: Suprax; Venez.: Longacef.
Only 40 to 50% of an oral dose of cefixime is absorbed C AS — 56796-39-5.
Multi-ingredient: India: Cefix LB.
from the gastrointestinal tract, whether taken before or ATC — J01DC09.
after meals, although the rate of absorption may be de- ATC Vet — QJ01DC09.
creased in the presence of food. Cefixime is better ab-
Cefmenoxime Hydrochloride (USAN, rINNM) Pharmacopoeias. In Jpn and US.
sorbed from oral suspension than from tablets. Absorp-
Abbott-50192; Cefménoxime, Chlorhydrate de; Cefmenoxime USP 31 (Cefmetazole Sodium). A white solid. Very soluble in
tion is fairly slow; peak plasma concentrations of 2 to water and in methyl alcohol; soluble in acetone; practically insol-
Hemihydrochloride; Cefmenoximi Hydrochloridum; Hidro-
3 micrograms/mL and 3.7 to 4.6 micrograms/mL have uble in chloroform. pH of a 10% solution in water is between 4.2
cloruro de cefmenoxima; SCE-1365 (cefmenoxime). (Z)-(7R)-7-
been reported between 2 and 6 hours after single doses [2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(1-me-
and 6.2. Store in airtight containers.
of 200 and 400 mg, respectively. The plasma half-life thyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid Adverse Effects and Precautions
is usually about 3 to 4 hours and may be prolonged hydrochloride. As for Cefalotin Sodium, p.219.
when there is renal impairment. About 65% of cefixi- Цефменоксима Гидрохлорид Cefmetazole contains an N-methylthiotetrazole side-chain and
me is bound to plasma proteins. (C 16 H 17 N 9 O 5 S 3 ) 2 ,HCl = 1059.6. has the potential to cause hypoprothrombinaemia and bleeding.
Information on the distribution of cefixime in body tis- C AS — 65085-01-0 (cefmenoxime); 75738-58-8 (cef-
menoxime hydrochloride). Effects on the blood. References.
sues and fluids is limited. It crosses the placenta. Rela-
ATC — J01DD05. 1. Breen GA, St Peter WL. Hypoprothrombinemia associated with
tively high concentrations may be achieved in bile and ATC Vet — QJ01DD05. cefmetazole. Ann Pharmacother 1997; 31: 180–4.
urine. About 20% of an oral dose (or 50% of an ab-
Sodium content. Each g of cefmetazole sodium contains
sorbed dose) is excreted unchanged in the urine within about 2 mmol of sodium.
24 hours. Up to 60% may be eliminated by nonrenal H 3C
mechanisms; there is no evidence of metabolism but O O Interactions
H H As for Cefamandole, p.221.
some is probably excreted into the faeces from bile. It N S
N CH3
is not substantially removed by dialysis. H
Antimicrobial Action
N S N Cefmetazole is a cephamycin antibacterial with a similar spec-
◊ References. N trum of antibacterial activity to that of cefoxitin (p.230), includ-
N O
1. Brittain DC, et al. The pharmacokinetic and bactericidal charac- ing the anaerobe Bacteroides fragilis.
teristics of oral cefixime. Clin Pharmacol Ther 1985; 38: 590–4. S COOH N N
2. Guay DRP, et al. Pharmacokinetics of cefixime (CL-284,635; NH2 ◊ References.
FK027) in healthy subjects and patients with renal insufficiency.
Antimicrob Agents Chemother 1986; 30: 485–90. 1. Cornick NA, et al. Activity of cefmetazole against anaerobic
3. Faulkner RD, et al. Pharmacokinetics of cefixime in the young
(cefmenoxime) bacteria. Antimicrob Agents Chemother 1987; 31: 2010–12.
and elderly. J Antimicrob Chemother 1988; 21: 787–94. Pharmacokinetics
4. Stone JW, et al. Cefixime, in-vitro activity, pharmacokinetics Pharmacopoeias. In Jpn and US. After cefmetazole sodium 2 g intravenously every 6 hours, peak
and tissue penetration. J Antimicrob Chemother 1989; 23: USP 31 (Cefmenoxime Hydrochloride). White to light orange-
221–8. and trough plasma concentrations of 138 and 6 micrograms/mL
yellow crystals or crystalline powder. Very slightly soluble in have been achieved. Cefmetazole is 65 to 85% bound to plasma
5. Westphal JF, et al. Biliary excretion of cefixime: assessment in water; practically insoluble in dehydrated alcohol and in ether;
patients provided with T-tube drainage. Antimicrob Agents proteins, depending on the plasma concentration. A plasma half-
Chemother 1993; 37: 1488–91. freely soluble in formamide; slightly soluble in methyl alcohol. life of about 1.1 to 1.5 hours has been reported; it is prolonged in
6. Somekh E, et al. Penetration and bactericidal activity of cefixime Store in airtight containers. patients with renal impairment. Small amounts have been detect-
in synovial fluid. Antimicrob Agents Chemother 1996; 40: Profile ed in breast milk. Relatively high concentrations have been
1198–1200. achieved in bile.
Cefmenoxime is a third-generation cephalosporin antibacterial
with actions and uses similar to those of cefotaxime (p.228). It The majority of a dose is excreted unchanged in the urine result-
Uses and Administration has been given as the hydrochloride by intramuscular injection, ing in high concentrations; up to 85% of a dose has been recov-
Cefixime is generally classified as a third-generation or intravenously by injection or infusion in the treatment of sus- ered within 12 hours. Cefmetazole is partly excreted by renal tu-
cephalosporin antibacterial and is given orally in the ceptible infections. bular secretion and probenecid prolongs elimination.
treatment of susceptible infections including gonor- Like cefamandole (p.220), cefmenoxime has an N-methylthi- Cefmetazole is removed to some extent by haemodialysis.
rhoea, otitis media, pharyngitis, lower respiratory-tract otetrazole side-chain and coagulopathy and a disulfiram-like in-
teraction with alcohol have been reported rarely. Uses and Administration
infections such as bronchitis, and urinary-tract infec- Cefmetazole is a cephamycin antibacterial generally classified
Cefmenoxime hydrochloride is also given as eye drops for the
tions. For details of these infections and their treat- treatment of eye infections. with the second-generation cephalosporins and used similarly to
ment, see under Choice of Antibacterial, p.162. cefoxitin (p.230) in the treatment and prophylaxis of anaerobic
◊ Reviews. and mixed bacterial infections, especially intra-abdominal and
Cefixime is available as the trihydrate and doses are 1. Campoli-Richards DM, Todd PA. Cefmenoxime: a review of its pelvic infections. It may also be used in the treatment of gonor-
expressed in terms of anhydrous cefixime; 1.12 g of antibacterial activity, pharmacokinetic properties and therapeu- rhoea. For details of these infections and their treatment, see un-
tic use. Drugs 1987; 34: 188–221.
cefixime trihydrate is equivalent to about 1 g of anhy- der Choice of Antibacterial, p.162.
drous cefixime. It is given orally in adult doses of 200 Preparations Cefmetazole is given intravenously as the sodium salt by infu-
to 400 mg daily as a single dose or in two divided dos- USP 31: Cefmenoxime for Injection. sion over 10 to 60 minutes or by slow injection over 3 to 5 min-
es. Children over 6 months and under 50 kg may be Proprietary Preparations (details are given in Part 3) utes. Cefmetazole sodium is also used intramuscularly in some
given 8 mg/kg daily as an oral suspension, again as a Gr.: Tacef†; Jpn: Bestcall; Bestron. countries. Doses are expressed in terms of the equivalent amount
of cefmetazole; 1.05 g of cefmetazole sodium is equivalent to
single dose or in two divided doses. For details of re- about 1 g of cefmetazole.
duced dosage of cefixime in patients with moderate to
Cefmetazole (USAN, rINN) The usual dose is 0.5 to 1 g intramuscularly or intravenously eve-
severe renal impairment, see below. ry 12 hours. For severe infections the dose may be increased to 3
Cefmetazol; Cefmétazole; Cefmetazolum; U-72791. (6R,7S)-7- to 4 g daily, given in divided doses every 6 to 8 hours.
For uncomplicated gonorrhoea, a single oral dose of {2-[(Cyanomethyl)thio]acetamido}-7-methoxy-3-{[(1-methyl-
400 mg is given. 1H-tetrazol-5-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo- For details of reduced dosage of cefmetazole in patients with re-
nal impairment, see below.
◊ General references. [4.2.0]oct-2-ene-2-carboxylic acid.
1. Leggett NJ, et al. Cefixime. DICP Ann Pharmacother 1990; 24: Цефметазол ◊ References.
489–95. C 15 H 17 N 7 O 5 S 3 = 471.5. 1. Finch R, et al. eds. Cefmetazole: a clinical appraisal. J Antimi-
2. Adam D, Wallace RJ, eds. Symposium on cefixime. Drugs 1991; C AS — 56796-20-4. crob Chemother 1989; 23 (suppl D): 1–142.
42 (suppl 4): 1–32.
ATC — J01DC09.
3. Markham A, Brogden RN. Cefixime: a review of its therapeutic Administration in renal impairment. Doses of cefmetazole
efficacy in lower respiratory tract infections. Drugs 1995; 49: ATC Vet — QJ01DC09. should be reduced in patients with renal impairment. It has been
1007–22. suggested that the interval between doses should be 12, 16, or 24
Administration in renal impairment. Doses of cefixime hours in patients with mild, moderate, or severe renal impair-
should be reduced in patients with moderate to severe renal im- O ment, respectively; patients with virtually no renal function
H3CO H
pairment. A dose of 200 mg daily should not be exceeded in pa- S S might be given cefmetazole every 48 hours, after haemodialysis.
tients with a creatinine clearance of less than 20 mL/minute. N N CH3
H Preparations
Preparations N S N
N USP 31: Cefmetazole for Injection; Cefmetazole Injection.
O
USP 31: Cefixime for Oral Suspension; Cefixime Tablets. Proprietary Preparations (details are given in Part 3)
COOH N N
Proprietary Preparations (details are given in Part 3) Hong Kong: Cefmetazon†; Ital.: Metacaf†; Metafar; Metasal†; Metax;
Arg.: Cetaxim†; Novacef; Vixcef; Austria: Aerocef; Enzine; Exciol; Tricef; Metazol†; Jpn: Cefmetazon†; USA: Zefazone†.
Xefotil; Xetinol; Braz.: Cefnax†; Neo Cefix; Plenax†; Canad.: Suprax; Pharmacopoeias. In US.
Chile: Cefspan†; Tricef; Urotricef; Cz.: Suprax; Fr.: Oroken; Ger.: Cefixdu- USP 31 (Cefmetazole). Store in airtight containers.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
226 Antibacterials
Cefminox Sodium (pINNM) variable activity against Citrobacter spp., and Pseudomonas aer- Pharmacopoeias. In US.
uginosa and Bacteroides fragilis are generally resistant. USP 31 (Cefonicid Sodium). A white to off-white solid. Freely
Cefminox sódico; Cefminox Sodique; MT-141; Natrii Cefminox-
soluble in water, in sodium chloride 0.9%, and in glucose 5%;
um. Sodium 7-{2-[(S)-2-amino-2-carboxyethyl]thioacetamido}- Pharmacokinetics very slightly soluble in dehydrated alcohol; soluble in methyl al-
7-methoxy-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem- Cefodizime is given by injection as the sodium salt. Intramuscu- cohol. pH of a 5% solution in water is between 3.5 and 6.5. Store
4-carboxylate. lar injection of 1 g cefodizime produces peak plasma concentra- in airtight containers.
tions of about 60 to 75 micrograms/mL at about 1 to 1.5 hours.
Натрий Цефминокс
Immediately after intravenous doses of 1 or 2 g cefodizime mean
C 16 H 20 N 7 NaO 7 S 3 = 541.6. peak plasma concentrations of 215 and 394 micrograms/mL, re- Adverse Effects and Precautions
C AS — 75481-73-1 (cefminox). spectively, have been achieved. Cefodizime is about 80% bound As for Cefalotin Sodium, p.219.
to plasma proteins and is widely distributed into body tissues and
fluids. It crosses the placenta and small amounts have been de- Cefonicid contains a substituted N-methylthiotetrazole side-
tected in breast milk. Plasma elimination is reported to be tripha- chain, a structure associated with hypoprothrombinaemia.
O
H3+N H H3CO H sic with a terminal elimination half-life of about 4 hours. The
S S Effects on the blood. References.
-
OOC N CH3 half-life is prolonged by renal impairment.
H
N S N The majority of a dose is excreted unchanged in the urine; up to 1. Riancho JA, et al. Life-threatening bleeding in a patient treated
O N 80% of a dose has been recovered within 24 hours. Cefodizime with cefonicid. Ann Intern Med 1995; 123: 472–3.
COOH N N is mainly excreted by glomerular filtration with some tubular se-
cretion. Probenecid delays excretion. Cefodizime is removed by Effects on the liver. References.
(cefminox) dialysis.
1. Famularo G, et al. Eosinophilic hepatitis associated with cefoni-
Uses and Administration cid therapy. Ann Pharmacother 2001; 35: 1669–71.
Pharmacopoeias. Jpn includes the heptahydrate. Cefodizime is a third-generation cephalosporin antibacterial
Profile with uses similar to those of cefotaxime (p.229). Sodium content. Each g of cefonicid sodium contains about
Cefminox sodium is a cephamycin antibacterial with properties Cefodizime is given as the disodium salt by intramuscular injec- 3.4 mmol of sodium.
similar to those of cefoxitin (p.230) but with an N-methylthi- tion or intravenously by injection or infusion in the treatment of
otetrazole side-chain like cefamandole (p.220). It is given intra- susceptible infections. Doses are expressed in terms of the equiv- Interactions
venously as the sodium salt but doses are expressed in terms of alent amount of cefodizime; 1.08 g of cefodizime sodium is As for Cefamandole, p.221.
cefminox; 1.04 g of cefminox sodium is equivalent to about 1 g equivalent to about 1 g of cefodizime. Adults are usually given 1
of cefminox. A usual dose is 2 to 4 g daily given in divided doses. to 2 g every 12 or 24 hours for lower respiratory-tract infections Antimicrobial Action
and upper and lower urinary-tract infections. Doses up to 4 g dai-
◊ References. ly may be given in severe infection. In women with uncomplicat-
Cefonicid sodium has an antimicrobial action and pattern of re-
1. Watanabe S, Omoto S. Pharmacology of cefminox, a new bacte-
sistance similar to those of cefamandole (p.221), although it is
ed lower urinary-tract infections a single dose of 1 to 2 g may be generally less active against Gram-positive cocci.
ricidal cephamycin. Drugs Exp Clin Res 1990; 16: 461–7. sufficient. For gonorrhoea a single dose of 0.25 to 0.5 g may be
2. Soriano F, et al. Comparative susceptibility of cefminox and ce- given. Doses may need to be reduced in patients with renal im-
foxitin to β-lactamases of Bacteroides spp. J Antimicrob Chem- Pharmacokinetics
other 1991; 28: 55–60. pairment (see below).
Cefonicid is given parenterally as the sodium salt. Peak plasma
3. Aguilar L, et al. Cefminox: correlation between in-vitro suscep- ◊ References. concentrations ranging from 67 to 126 micrograms/mL have
tibility and pharmacokinetics and serum bactericidal activity in been achieved 1 to 2 hours after a 1-g intramuscular dose. Cefo-
healthy volunteers. J Antimicrob Chemother 1994; 33: 91–101. 1. Finch RG, et al., eds. Cefodizime: a third generation cepha-
losporin with immunomodulating properties. J Antimicrob nicid is more than 90% bound to plasma proteins. It has a plasma
4. Mayama T, et al. Postmarketing surveillance on side-effects of
cefminox sodium (Meicelin). Int J Clin Pharmacol Ther 1995; Chemother 1990; 26 (suppl C): 1–134. half-life of about 4.5 hours, which is prolonged in patients with
33: 149–55. 2. Barradell LB, Brogden RN. Cefodizime: a review of its antibac- renal impairment.
5. Hoellman DB, et al. In vitro activities of cefminox against anaer- terial activity, pharmacokinetic properties and therapeutic use.
obic bacteria compared with those of nine other compounds. An- Drugs 1992; 44: 800–834. Therapeutic concentrations of cefonicid have been reported in a
timicrob Agents Chemother 1998; 42: 495–501. 3. Thalhammer F, et al. Single-dose cefodizime as infection proph- wide range of body tissues and fluids.
6. Torres AJ, et al. Cefminox versus metronidazole plus gentamicin ylaxis in abdominal surgery: a prospective multicenter study. In-
in intra-abdominal infections: a prospective randomized control- fection 1998; 26: 136–8. Up to 99% of a dose of cefonicid is excreted unchanged in the
led clinical trial. Infection 2000; 28: 318–22. 4. Matsumoto T, et al. Single dose of cefodizime completely erad- urine within 24 hours. Probenecid reduces excretion of cefoni-
icated multidrug-resistant strain of Neisseria gonorrhoeae in ure- cid.
Sodium content. Each g of cefminox sodium contains about thritis and uterine cervicitis. J Infect Chemother 2006; 12: 97–9.
1.84 mmol of sodium. 5. Matsumoto T, et al. Multiple doses of cefodizime are necessary
for the treatment of Neisseria gonorrhoeae pharyngeal infection. Uses and Administration
Preparations Cefonicid is a second-generation cephalosporin antibacterial
J Infect Chemother 2006; 12: 145–7.
Proprietary Preparations (details are given in Part 3) used similarly to cefamandole (p.221) in the treatment of suscep-
Jpn: Meicelin; Port.: Tencef; Spain: Tencef; Thai.: Meicelin. Administration in renal impairment. Doses of cefodizime tible infections and for surgical infection prophylaxis.
should be reduced in patients with renal impairment according to
creatinine clearance (CC): It is given as the sodium salt by deep intramuscular injection, or
• CC 10 to 30 mL/minute: 1 to 2 g daily intravenously by slow injection over 3 to 5 minutes or by infu-
Cefodizime Sodium (BANM, rINNM) sion. Doses are expressed in terms of the equivalent amount of
• CC less than 10 mL/minute: 0.5 to 1 g daily cefonicid; 1.08 g of cefonicid sodium is equivalent to about 1 g
Cefodizima sódica; Céfodizime Sodique; HR-221; Natrii Cefodiz-
imum; S-771221B; Sefodizim Disodyum; THR-221; TRH-221. In patients undergoing dialysis, 0.5 to 1 g daily is given after di- of cefonicid. The usual dose is cefonicid 1 g once daily. For un-
(Z)-7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- alysis. complicated urinary-tract infections, a dose of 500 mg once daily
(5-carboxymethyl-4-methylthiazol-2-ylthiomethyl)-3-cephem-4- is recommended; up to 2 g once daily has been given in severe
Preparations infections. More than 1 g should not be injected intramuscularly
carboxylic acid, disodium salt. Proprietary Preparations (details are given in Part 3) into a single site.
Натрий Цефодизим Austria: Timecef; Ital.: Diezime; Modivid; Timecef; Jpn: Kenicef; Mex.:
C 20 H 18 N 6 Na 2 O 7 S 4 = 628.6. Modivid†; NZ: Timecef; Port.: Modivid; Turk.: Modivid. For surgical infection prophylaxis, a single dose of 1 g given 1
C AS — 69739-16-8 (cefodizime); 86329-79-5 (cefodiz- hour before surgical incision is usually sufficient, but may be
ime sodium). given daily for a further 2 days in prosthetic arthroplasty or open-
ATC — J01DD09. heart surgery.
Cefonicid Sodium (BANM, USAN, rINNM)
ATC Vet — QJ01DD09.
Cefonicid sódico; Cefonicide sodique; Céfonicide Sodique; Cefo- ◊ References.
nicidum natricum; Natrii Cefonicidum; SKF-D-75073-Z2; SKF-D-
1. Saltiel E, Brogden RN. Cefonicid: a review of its antibacterial
H3C 75073-Z (cefonicid monosodium). 7-[(R)-Mandelamido]-3-(1- activity, pharmacological properties and therapeutic use. Drugs
O O
H H sulphomethyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carbox- 1986; 32: 222–59.
N S ylic acid, disodium salt.
N
H Натрий Цефоницид Administration in renal impairment. For patients with re-
N S S
N COOH nal impairment a loading dose equivalent to cefonicid 7.5 mg/kg
O C 18 H 16N 6 Na 2 O 8 S 3 = 586.5. is recommended, followed by reduced maintenance doses ac-
S COOH N C AS — 61270-58-4 (cefonicid); 61270-78-8 (cefonicid cording to the creatinine clearance and the severity of the infec-
NH2 CH3 disodium); 71420-79-6 (cefonicid monosodium). tion. A dose supplement is not required after dialysis.
ATC — J01DC06.
(cefodizime) ATC Vet — QJ01DC06. Preparations
Pharmacopoeias. In Jpn. USP 31: Cefonicid for Injection.
Adverse Effects and Precautions O Proprietary Preparations (details are given in Part 3)
As for Cefotaxime, p.228. H H
S HO3S Belg.: Monocid†; Israel: Monocef; Ital.: Abiocef†; Auricid†; Bacid†; Biocil;
Sodium content. Each g of cefodizime sodium contains about N Bioticic; Cefobacter; Cefodie; Cefoger†; Cefok; Cefoplus; Cefosporin†;
3.2 mmol of sodium. H Chefir; Clastidin†; Daycef; Delsacid†; Diespor; Emidoxin; Epicef†; Fonexel†;
OH N S N Fonicef†; Fonicid; Fonisal†; Framecef; Ipacid†; Krucef; Lampocef†; Lisa; Max-
Interactions O N id; Microcid†; Modicef; Modiem; Monobios; Monobiotic; Monocid†; Necid;
Probenecid reduces the renal clearance of cefodizime. Nokid; Pantacid†; Parecid; Praticef; Raikocef; Renbiocid†; Rocid†; Silvercef†;
COOH N N Sintocef; Sofarcid; Unicid†; Valecid; Port.: Monocid; Spain: Monocid; Uni-
Antimicrobial Action die; USA: Monocid†.
Cefodizime has similar antimicrobial activity to that of cefotaxi- (cefonicid)
me (p.228) although cefodizime has no active metabolite. It has
 Cefminox Sodium/Ceforanide 227
Cefoperazone Sodium should be monitored in patients at risk of hypopro- Administration in hepatic and renal impairment. In gen-
eral, the dose of cefoperazone should not exceed 4 g daily in pa-
(BANM, USAN, rINNM)
thrombinaemia and vitamin K used if necessary.
tients with liver disease or biliary obstruction or 1 to 2 g daily in
Sodium content. Each g of cefoperazone sodium contains those with both hepatic and renal impairment; if higher doses are
Cefoperazon sodná sůl; Cefoperazon sodowy; Cefoperazona used plasma concentrations of cefoperazone should be moni-
about 1.5 mmol of sodium.
sódica; Céfopérazone sodique; Cefoperazonnatrium; Cefopera- tored.
zon-nátrium; Cefoperazono natrio druska; Cefoperazonum na-
tricum; CP-52640-2; CP-52640 (anhydrous cefoperazone); CP- Interactions Preparations
52640-3 (cefoperazone dihydrate); Kefoperatsoninatrium; Natrii As for Cefamandole, p.221. USP 31: Cefoperazone for Injection; Cefoperazone Injection.
Cefoperazonum; Sefoperazon Sodyum; T-1551 (cefoperazone
or cefoperazone sodium). Sodium (7R)-7-[(R)-2-(4-ethyl-2,3-di- Unlike many other cephalosporins, probenecid has no Proprietary Preparations (details are given in Part 3)
oxopiperazin-1-ylcarboxamido)-2-(4-hydroxyphenyl)acetami- effect on the renal clearance of cefoperazone. Arg.: Cefobid†; Austria: Cefobid; Braz.: Cefazone†; Neoperazona†;
Chile: Cefobid; Cz.: Cefobid; Hong Kong: Cefobid; Hung.: Cefobid; In-
do]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-car- dia: Cefomycin; Magnamycin; Indon.: Bifotik; Cefobid; Cefophar; Ceropid;
boxylate. Antimicrobial Action Cerozon; Ferzobat; Logafox; Stabixin; Ital.: Bioperazone; Cefoneg†; Cefop-
er; Dardum; Farecef; Ipazone†; Novobiocyl†; Tomabef†; Zoncef†; Jpn: Ce-
Натрий Цефоперазон Cefoperazone has antimicrobial activity similar to that fobid†; Cefoperazin; Malaysia: Cefobid; Medocef; Shinfomycin; Mex.: Ce-
C 25 H 26N 9 NaO 8 S 2 = 667.6. of ceftazidime (p.234), although it is slightly less active fobid; Philipp.: Bactizon; Pol.: Biocefazon; Cefobid; Dardum; Rus.:
Cefobid (Цефобид); Medocef (Медоцеф); Singapore: Cefobid; Cefo-
C AS — 62893-19-0 (cefoperazone); 62893-20-3 (cefop-
against some Enterobacteriaceae. It has good activity zone; Dardum; Spain: Cefobid†; Thai.: Cefobid; Cefozone†; Medocef;
erazone sodium). against Pseudomonas aeruginosa, but is less active Turk.: Cefobid; USA: Cefobid†; Venez.: Cefobid†; Ortosep†.
than ceftazidime. Multi-ingredient: Arg.: Sulperazon†; Chile: Sulperazon; Cz.: Sulpera-
ATC — J01DD12. zon; Hong Kong: Sulperazon; India: Lactagard; Sulbacef; Zosul; Indon.:
ATC Vet — QJ01DD12. Cefoperazone is more susceptible than cefotaxime to Fosular; Stabactam; Sulperazon; Malaysia: Sulperazon; Philipp.: Sulpera-
zone; Pol.: Sulperazon; Rus.: Sulcef (Сульцеф); Sulperason (Сульперазон);
hydrolysis by certain beta-lactamases. Thai.: Cebactam; Cefper; Sulcef; Sulperazon; Turk.: Primasef; Sulperazon;
Venez.: Sulperazon.
Activity, particularly against Enterobacteriaceae and
HO
O Bacteroides spp. has been enhanced in the presence of
H H the beta-lactamase inhibitor sulbactam; resistant Ps.
S
N CH3 aeruginosa are not sensitive to the combination. Ceforanide (BAN, USAN, rINN)
H H
NH N S N BL-S786; Ceforanida; Céforanide; Ceforanidum. 7-[2-(α-Amino-
N ◊ References.
O o-tolyl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-ylthiome-
N O COOH N N 1. Fass RJ, et al. In vitro activities of cefoperazone and sulbactam thyl)-3-cephem-4-carboxylic acid.
singly and in combination against cefoperazone-resistant mem-
N bers of the family Enterobacteriaceae and nonfermenters. Anti- Цефоранид
O microb Agents Chemother 1990; 34: 2256–9.
C 20 H 21 N 7 O 6 S 2 = 519.6.
CH3 O 2. Clark RB, et al. Multicentre study on antibiotic susceptibilities
of anaerobic bacteria to cefoperazone-sulbactam and other anti- C AS — 60925-61-3.
microbial agents. J Antimicrob Chemother 1992; 29: 57–67. ATC — J01DC11.
(cefoperazone)
ATC Vet — QJ01DC11.
Pharmacokinetics
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. Cefoperazone is given parenterally as the sodium salt.
Ph. Eur. 6.2 (Cefoperazone Sodium). A white or slightly yel- With intramuscular doses equivalent to cefoperazone
low, hygroscopic, powder. If crystalline it exhibits polymor- H 2N
phism. Freely soluble in water; slightly soluble in alcohol; solu- 1 or 2 g, peak plasma concentrations of 65 and
ble in methyl alcohol. A 25% solution in water has a pH of 4.5 to 97 micrograms/mL have been reported after 1 to 2
6.5. Store in airtight containers at a temperature of 2° to 8°. Pro- hours. The plasma half-life of cefoperazone is about 2 H H
tect from light. N S
hours, but may be prolonged in neonates and in pa-
USP 31 (Cefoperazone Sodium). A white to pale buff crystal- tients with hepatic or biliary-tract disease. Cefopera-
line powder. Freely soluble in water and in methyl alcohol; O
zone is 82 to 93% bound to plasma proteins, depending N S N
slightly soluble in dehydrated alcohol; insoluble in acetone, in
on the concentration. O N
ether, and in ethyl acetate. pH of a 25% solution in water is be-
tween 4.5 and 6.5. Store in airtight containers. N N
Cefoperazone is widely distributed in body tissues and HO O
Incompatibility. As with most beta lactams, admixture of cef- fluids, although penetration into the CSF is generally
operazone sodium with aminoglycosides is not recommended poor. It crosses the placenta, and low concentrations OH
because of the potential for inactivation of either drug. O
have been detected in breast milk.
There have been reports of incompatibility with other drugs in-
cluding diltiazem,1 doxorubicin,2 pentamidine,3 perphenazine,4 Cefoperazone is excreted mainly in the bile where it Pharmacopoeias. In US.
pethidine,5 promethazine,6 and remifentanil.7 rapidly achieves high concentrations. Urinary excre- USP 31 (Ceforanide). A white to off-white powder. Practically
tion is primarily by glomerular filtration. Up to 30% of insoluble in water, in chloroform, in ether, and in methyl alcohol;
1. Gayed AA, et al. Visual compatibility of diltiazem injection with
various diluents and medications during simulated Y-site injec-
very soluble in 1N sodium hydroxide. pH of a 5% suspension in
a dose is excreted unchanged in the urine within 12 to water is between 2.5 and 4.5. Store in airtight containers.
tion. Am J Health-Syst Pharm 1995; 52: 516–20.
2. Trissel LA, et al. Compatibility of doxorubicin hydrochloride li-
24 hours; this proportion may be increased in patients
posome injection with selected other drugs during simulated Y- with hepatic or biliary disease. Cefoperazone A, a deg- Profile
site administration. Am J Health-Syst Pharm 1997; 54: 2708–13. Ceforanide is a second-generation cephalosporin antibacterial
radation product less active than cefoperazone, has with actions and uses similar to those of cefamandole (p.220),
3. Lewis JD, El-Gendy A. Cephalosporin-pentamidine isethionate been found only rarely in vivo.
incompatibilities. Am J Health-Syst Pharm 1996; 53: 1461–2. although it is reported to be less active in vitro against some bac-
teria, including staphylococci and Haemophilus influenzae. It is
4. Gasca M, et al. Visual compatibility of perphenazine with vari-
ous antimicrobials during simulated Y-site injection. Am J Hosp Uses and Administration used in the treatment of susceptible infections and for surgical
Pharm 1987; 44: 574–5. infection prophylaxis.
Cefoperazone is a third-generation cephalosporin anti-
5. Nieves-Cordero AL, et al. Compatibility of narcotic analgesic
biotic used similarly to ceftazidime (p.235) in the treat- It is given as the lysine salt (C26H35N9O8S2 = 665.7) but doses
solutions with various antibiotics during simulated Y-site injec- are expressed in terms of the equivalent amount of ceforanide;
tion. Am J Hosp Pharm 1985; 42: 1108–9. ment of susceptible infections, especially those due to 1.28 g of ceforanide lysine is equivalent to about 1 g of cefora-
6. Scott SM. Incompatibility of cefoperazone and promethazine. Pseudomonas spp. It is not recommended for the treat- nide. It is given by deep intramuscular injection, or intravenously
Am J Hosp Pharm 1990; 47: 519.
ment of meningitis because of poor penetration into the by slow injection over 3 to 5 minutes or by infusion. The usual
7. Trissel LA, et al. Compatibility of remifentanil hydrochloride adult dose is 1 to 2 g every 12 hours. Children may be given
with selected drugs during simulated Y-site administration. Am J CSF.
Health-Syst Pharm 1997; 54: 2192–6.
20 mg/kg daily in 2 divided doses. For surgical infection proph-
Cefoperazone is given as the sodium salt by deep intra- ylaxis, a dose of 1 to 2 g intravenously 1 hour before surgical
muscular injection or intravenously by intermittent or incision is used in adults.
Adverse Effects and Precautions
continuous infusion. Doses are expressed in terms of Ceforanide contains a substituted N-methylthiotetrazole side-
As for Cefalotin Sodium, p.219. chain, a structure associated with hypoprothrombinaemia and al-
the equivalent amount of cefoperazone; 1.03 g of cef-
Like cefotaxime (p.228), cefoperazone has the poten- cohol intolerance. Probenecid does not affect the renal excretion
operazone sodium is equivalent to about 1 g of cefop- of ceforanide.
tial for colonisation and superinfection with resistant erazone. The usual dose is 2 to 4 g daily in 2 divided
organisms. Changes in bowel flora may be more doses. In severe infections, up to 12 g daily in 2 to 4 ◊ References.
marked than with cefotaxime because of the greater divided doses may be given. 1. Campoli-Richards DM, et al. Ceforanide: a review of its antibac-
biliary excretion of cefoperazone; diarrhoea may occur terial activity, pharmacokinetic properties and clinical efficacy.
For details of dosage in patients with hepatic and renal Drugs 1987; 34: 411–37.
more often.
impairment, see below. Preparations
Cefoperazone contains an N-methylthiotetrazole side-
chain, a structure associated with hypoprothrombinae- If cefoperazone is used with an aminoglycoside, the USP 31: Ceforanide for Injection.

mia. Hypoprothrombinaemia has been reported in pa- drugs should be given separately. Proprietary Preparations (details are given in Part 3)
tients treated with cefoperazone and has rarely been as- Cefoperazone has also been given with the beta-lacta- Belg.: Precef†; Gr.: Radacef.
sociated with bleeding episodes. Prothrombin time mase inhibitor sulbactam.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
228 Antibacterials
Cefoselis Sulfate (rINNM) flora are a predisposing factor and have been more Among Gram-positive bacteria, cefotaxime is active
Céfosélis, Sulfate de; Cefoselis Sulphate; Cefoselisi Sulfas; FK-037; marked with cefoperazone and ceftriaxone, possibly against staphylococci and streptococci. Staphylococ-
Sulfato de cefoselís. (−)-5-Amino-2-({(6R,7R)-7-[2-(2-amino-4- because of their greater biliary excretion. Pseudomem- cus aureus, including penicillinase-producing strains
thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyc- branous colitis, associated with Clostridium difficile but not meticillin-resistant Staph. aureus, is sensitive.
lo[4.2.0]oct-2-en-3-yl}methyl)-1-(2-hydroxyethyl)pyrazolium hy- infection, may occasionally be seen with any of the Staph. epidermidis is also sensitive but penicillinase-
droxide, inner salt, 72-(Z)-(O-methyloxime) sulfate. third-generation cephalosporins. producing strains are resistant. Streptococcus agalacti-
Цефозелиса Сульфат ae (group B streptococci), Str. pneumoniae, and Str. py-
C 19 H 22 N 8 O 6 S 2 , H 2 SO 4 = 620.6. ◊ Reviews on adverse effects associated with third-generation
C AS — 122841-10-5 (cefoselis); 122841-12-7 (cefoselis cephalosporins. ogenes (group A streptococci) are all very sensitive al-
sulfate). 1. Neu HC. Third generation cephalosporins: safety profiles after though truly penicillin-resistant pneumococci are
10 years of clinical use. J Clin Pharmacol 1990; 30: 396–403.
2. Fekety FR. Safety of parenteral third-generation cephalosporins.
apparently not sensitive. Enterococci and Listeria
Am J Med 1990; 88 (suppl 4A): 38S–44S. monocytogenes are resistant.
CH3 CO2-
O
Antibiotic-associated colitis. It has been suggested1 that ce- Cefotaxime is active against some anaerobic bacteria.
O fotaxime is associated with an increased risk of Clostridium dif- Bacteroides fragilis may be moderately sensitive, but
N N N
H ficile diarrhoea in elderly patients; however, the manufacturer2 many strains are resistant; synergy has been demon-
N N N has disputed this, arguing that cefotaxime compares favourably
S with alternative third-generation cephalosporins. strated with desacetylcefotaxime in vitro. Clostridium
H2N H H NH2 perfringens is sensitive, but most Cl. difficile are resist-
O 1. Impallomeni M, et al. Increased risk of diarrhoea caused by
S HO Clostridium difficile in elderly patients receiving cefotaxime. ant.
BMJ 1995; 311: 1345–6.
(cefoselis) 2. Rothschild E, et al. Risk of diarrhoea due to Clostridium difficile Other organisms sensitive to cefotaxime include the
during cefotaxime treatment. BMJ 1996; 312: 778. spirochaete Borrelia burgdorferi and Haemophilus
Profile Breast feeding. Although cefotaxime is excreted in breast milk ducreyi.
Cefoselis sulfate is a cephalosporin antibacterial that has been in small amounts,1 no adverse effects have been observed in
breast-fed infants whose mothers were receiving cefotaxime, Activity with other antimicrobials. In addition to possi-
used in the treatment of susceptible bacterial infections.
and the American Academy of Pediatrics considers2 that it is ble synergy or additive effects with desacetylcefotaxi-
Preparations therefore usually compatible with breast feeding. me, the activity of cefotaxime may be enhanced by
Proprietary Preparations (details are given in Part 3) 1. Kafetzis DA, et al. Passage of cephalosporins and amoxicillin aminoglycosides such as gentamicin; synergy has been
Jpn: Wincef†. into the breast milk. Acta Paediatr Scand 1981; 70: 285–8.
2. American Academy of Pediatrics. The transfer of drugs and oth- demonstrated in vitro against Gram-negative bacteria
er chemicals into human milk. Pediatrics 2001; 108: 776–89. including Pseudomonas aeruginosa. There have also
Correction. ibid.; 1029. Also available at: been reports of enhanced activity in vitro with other an-
Cefotaxime Sodium (BANM, USAN, rINNM) h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l /
pediatrics%3b108/3/776 (accessed 25/05/04) tibacterials including fosfomycin and ciprofloxacin
Cefotaksimo natrio druska; Cefotaksym sodowy; Cefotaxim sod- Sodium content. Each g of cefotaxime sodium contains about and variable results with penicillins.
ná sůl; Cefotaxima sódica; Céfotaxime sodique; Cefotaximnatri- 2.09 mmol of sodium. Resistance may develop during treatment with cefo-
um; Cefotaxim-nátrium; Cefotaximum natricum; CTX; HR-756;
Kefotaksiiminatrium; Natrii Cefotaximum; RU-24756; Sefotaksim
taxime due to derepression of chromosomally mediat-
Interactions ed beta-lactamases, and has been reported particularly
Sodyum. Sodium (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(meth- As for many cephalosporins, probenecid reduces the
oxyimino)acetamido]cephalosporanate; Sodium (7R)-3-ace- in Enterobacter spp., with multiresistant strains emerg-
toxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimi-
renal clearance of cefotaxime, resulting in higher and ing during treatment. This type of resistance has also
no)acetamido]-3-cephem-4-carboxylate. prolonged plasma concentrations of cefotaxime and its developed in other bacteria including Citrobacter, Ser-
Натрий Цефотаксим desacetyl metabolite. ratia, and Pseudomonas spp. Another mechanism of
C 16 H 16 N 5 NaO 7 S 2 = 477.4. Antibacterials. The total body clearance of cefotaxime has cefotaxime resistance is the development of plasma-
C AS — 63527-52-6 (cefotaxime); 64485-93-4 (cefotaxi- been reduced in patients with normal and reduced renal function mediated, extended-spectrum beta-lactamases, and
me sodium). by the ureidopenicillins azlocillin1 or mezlocillin.2 Doses of ce-
fotaxime may need to be reduced if either of these penicillins is
this has occurred in Klebsiella spp. and also other En-
ATC — J01DD01. terobacteriaceae. Resistance in Str. pneumoniae is due
being given. Encephalopathy with focal motor status and gener-
ATC Vet — QJ01DD01. to the production of altered penicillin-binding proteins.
alised convulsions have been reported in a patient with renal fail-
ure given cefotaxime and high doses of azlocillin.3
◊ References to the antimicrobial activity of cefotaxime and oth-
1. Kampf D, et al. Kinetic interactions between azlocillin, cefotax-
O OH ime, and cefotaxime metabolites in normal and impaired renal er third-generation cephalosporins, including the problem of
O function. Clin Pharmacol Ther 1984; 35: 214–20. bacterial resistance.
2. Rodondi LC, et al. Influence of coadministration on the pharma- 1. Neu HC. Pathophysiologic basis for the use of third-generation
O CH3 cokinetics of mezlocillin and cefotaxime in healthy volunteers cephalosporins. Am J Med 1990; 88 (suppl 4A): 3S–11S.
H3C O N O O and in patients with renal failure. Clin Pharmacol Ther 1989; 45: 2. Chow JW, et al. Enterobacter bacteremia: clinical features and
527–34. emergence of antibiotic resistance during therapy. Ann Intern
N 3. Wroe SJ, et al. Focal motor status epilepticus following treat- Med 1991; 115: 585–90.
S N ment with azlocillin and cefotaxime. Med Toxicol 1987; 2: 3. Sanders CC. New β-lactams: new problems for the internist. Ann
H 233–4. Intern Med 1991; 115: 650–1.
4. Thomson KS, et al. High-level resistance to cefotaxime and
N Antimicrobial Action ceftazidime in Klebsiella pneumoniae isolates from Cleveland,
Ohio. Antimicrob Agents Chemother 1991; 35: 1001–3.
S Cefotaxime is a third-generation cephalosporin. It has 5. Piddock LJV, et al. Prevalence and mechanism of resistance to
NH2 a bactericidal action similar to cefamandole, but a ‘third-generation’ cephalosporins in clinically relevant isolates
of Enterobacteriaceae from 43 hospitals in the UK, 1990-1991. J
broader spectrum of activity. It is highly stable to hy- Antimicrob Chemother 1997; 39: 177–87.
(cefotaxime) drolysis by most beta-lactamases and has greater activ- 6. Gums JG, et al. Differences between ceftriaxone and cefotaxime:
ity than first- or second-generation cephalosporins microbiological inconsistencies. Ann Pharmacother 2008; 42:
71–9.
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. against Gram-negative bacteria. Although cefotaxime
Ph. Eur. 6.2 (Cefotaxime Sodium). A white or slightly yellow, is generally considered to have slightly less activity
hygroscopic, powder. Freely soluble in water; sparingly soluble Pharmacokinetics
than first-generation cephalosporins against Gram- Cefotaxime is given by injection as the sodium salt. It
in methyl alcohol. A 10% solution in water has a pH of between
4.5 and 6.5. Store in airtight containers. Protect from light. positive bacteria, many streptococci are very sensitive. is rapidly absorbed after intramuscular injection and
USP 31 (Cefotaxime Sodium). An off-white to pale yellow crys- Desacetylcefotaxime is an active metabolite of cefo- mean peak plasma concentrations of about 12 and
talline powder. Freely soluble in water; practically insoluble in taxime and there may be additive or synergistic effects 20 micrograms/mL have been reported 30 minutes af-
organic solvents. pH of a 10% solution in water is between 4.5 against some species.
and 6.5. Store in airtight containers. ter doses of 0.5 and 1 g of cefotaxime, respectively. Im-
Spectrum of activity. Among Gram-negative bacteria, mediately after intravenous injection of 0.5, 1, or 2 g of
Incompatibility. Cefotaxime sodium has been reported to be
incompatible with alkaline solutions such as sodium bicarbonate. cefotaxime is active in vitro against many Enterobacte- cefotaxime, mean peak plasma concentrations of 38,
Licensed product information recommends that it should be giv- riaceae including Citrobacter and Enterobacter spp., 102, and 215 micrograms/mL, respectively, have been
en separately from aminoglycosides. Escherichia coli, Klebsiella spp., both indole-positive achieved with concentrations ranging from about 1 to
and indole-negative Proteus, Providencia, Salmonella, 3 micrograms/mL after 4 hours. The plasma half-life
Adverse Effects and Precautions Serratia, Shigella, and Yersinia spp. Other susceptible of cefotaxime is about 1 hour and that of the active me-
As for Cefalotin Sodium, p.219. Arrhythmias have Gram-negative bacteria, including penicillin-resistant tabolite desacetylcefotaxime about 1.5 hours; half-
been associated with rapid bolus dosage through a cen- strains, are Haemophilus influenzae, Moraxella ca- lives are increased in neonates and in patients with se-
tral venous catheter in a few cases. tarrhalis (Branhamella catarrhalis), Neisseria gonor- vere renal impairment, especially those of the metabo-
The broad-spectrum third-generation cephalosporins rhoeae, and N. meningitidis. Brucella melitensis is also lite, and a reduction in dosage may be necessary. The
have the potential for colonisation and superinfection reported to be moderately sensitive. Some strains of effects of liver disease on clearance of cefotaxime and
with resistant organisms such as Pseudomonas aerugi- Pseudomonas spp. are moderately susceptible to cefo- its metabolite have been variable, but in general dosage
nosa, Enterobacter spp., Candida, and enterococci, at taxime, but most are resistant. Desacetylcefotaxime is adjustment has not been considered necessary. About
various sites in the body, although the incidence has active against many of these Gram-negative bacteria, 40% of cefotaxime is reported to be bound to plasma
generally been low with cefotaxime. Changes in bowel but not against Pseudomonas spp. proteins.
 Cefoselis Sulfate/Cefotetan 229
Cefotaxime and desacetylcefotaxime are widely dis- ical cord is clamped and two further doses intramuscu- Cefotetan Disodium (BANM, USAN, rINNM)
tributed in body tissues and fluids; therapeutic concen- larly or intravenously 6 and 12 hours later. Cefotetán disódico; Céfotétan Disodique; Cefotetanum Dinatri-
trations are achieved in the CSF particularly when the Cefotaxime may be used with an aminoglycoside as
cum; ICI-156834 (cefotetan or cefotetan disodium); YM-09330
meninges are inflamed. Cefotaxime crosses the placen- (cefotetan or cefotetan disodium). (7S)-7-[(4-Carbamoylcar-
synergy may occur against some Gram-negative or- boxymethylene-1,3-dithietan-2-yl)carboxamido]-7-methoxy-3-
ta and low concentrations have been detected in breast ganisms, but the drugs should be given separately. It
milk. [(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic
has sometimes been used with another beta lactam to acid, disodium salt.
After partial metabolism in the liver to desacetylcefo- broaden the spectrum of activity. Cefotaxime has also Динатрий Цефотетан
taxime and inactive metabolites, elimination is mainly been used with metronidazole in the treatment of C 17 H 15 N 7 Na 2 O 8 S 4 = 619.6.
by the kidneys and about 40 to 60% of a dose has been mixed aerobic-anaerobic infections. C AS — 74356-00-6.
recovered unchanged in the urine within 24 hours; a ATC — J01DC05.
further 20% is excreted as the desacetyl metabolite. ◊ General references to third-generation cephalosporins. ATC Vet — QJ01DC05.
Relatively high concentrations of cefotaxime and des- 1. Neu HC, et al., eds. Third-generation cephalosporins: a decade Pharmacopoeias. In US.
acetylcefotaxime are achieved in bile and about 20% of of progress in the treatment of severe infections. Am J Med 1990; USP 31 (Cefotetan Disodium). pH of a 10% solution in water is
88 (suppl 4A): 1S–45S. between 4.0 and 6.5. Store in airtight containers.
a dose has been recovered in the faeces.
◊ General references to cefotaxime. Incompatibility and stability. There may be incompatibility
Probenecid competes for renal tubular secretion with with aminoglycosides. Precipitation has been reported with pro-
cefotaxime resulting in higher and prolonged plasma 1. Todd PA, Brogden RN. Cefotaxime: an update of its pharmacol-
ogy and therapeutic use. Drugs 1990; 40: 608–51. methazine hydrochloride.
concentrations of cefotaxime and its desacetyl metabo- References.
2. Gentry LO. Cefotaxime and prophylaxis: new approaches with a
lite. Cefotaxime and its metabolites are removed by proven agent. Am J Med 1990; 88 (suppl 4A): 32S–37S. 1. Das Gupta V, et al. Chemical stability of cefotetan disodium in
haemodialysis. 3. Davies A, Speller DCE, eds. Cefotaxime—recent clinical inves-
5% dextrose and 0.9% sodium chloride injections. J Clin Pharm
Ther 1990; 15: 109–14.
When microbiological assays have been used, reported tigations. J Antimicrob Chemother 1990; 26 (suppl A): 1–83.
2. Erickson SH, Ulici D. Incompatibility of cefotetan disodium and
pharmacokinetic values may relate to cefotaxime plus 4. Brogden RN, Spencer CM. Cefotaxime: a reappraisal of its anti- promethazine hydrochloride. Am J Health-Syst Pharm 1995; 52:
bacterial activity and pharmacokinetic properties, and a review 1347.
its active metabolite, desacetylcefotaxime. of its therapeutic efficacy when administered twice daily for the
treatment of mild to moderate infections. Drugs 1997; 53: Adverse Effects and Precautions
Hepatic impairment. References. 483–510. As for Cefalotin Sodium, p.219.
1. Höffken G, et al. Pharmacokinetics of cefotaxime and desacetyl- Cefotetan contains an N-methylthiotetrazole side-chain and has
cefotaxime in cirrhosis of the liver. Chemotherapy 1984; 30: Administration in renal impairment. Doses of cefotaxime the potential to cause hypoprothrombinaemia and bleeding.
7–17. should be reduced in severe renal impairment; after an initial
2. Graninger W, et al. Cefotaxime and desacetyl-cefotaxime blood loading dose of 1 g, halving the dose while maintaining the usual Cefotetan, especially at high doses, may interfere with the Jaffé
levels in hepatic dysfunction. J Antimicrob Chemother 1984; 14 frequency of dosing has been suggested. method of measuring creatinine concentrations to produce false-
(suppl B): 143–6. ly elevated values; this should be borne in mind when measuring
3. Hary L, et al. The pharmacokinetics of ceftriaxone and cefotax- renal function.
ime in cirrhotic patients with ascites. Eur J Clin Pharmacol Preparations
1989; 36: 613–16. Effects on the blood. Reviews1,2 and a case report3 of haemo-
BP 2008: Cefotaxime Injection;
4. Ko RJ, et al. Pharmacokinetics of cefotaxime and desacetylcefo- USP 31: Cefotaxime for Injection; Cefotaxime Injection. lytic anaemia associated with cefotetan.
taxime in patients with liver disease. Antimicrob Agents Chem- 1. Moes GS, MacPherson BR. Cefotetan-induced hemolytic ane-
other 1991; 35: 1376–80. Proprietary Preparations (details are given in Part 3) mia: a case report and review of the literature. Arch Pathol Lab
Arg.: Cefacolin; Terasep; Tizoxim†; Austral.: Claforan†; Austria: Claforan; Med 2000; 124: 1344–6.
Renal impairment. References.
Tirotax; Belg.: Claforan; Braz.: Cefacolin†; Ceforan; Claforan; Clafordil; Fo- 2. Viraraghavan R, et al. Cefotetan-induced haemolytic anaemia: a
1. Matzke GR, et al. Cefotaxime and desacetyl cefotaxime kinetics tax†; Kefoxin†; Taxima; Canad.: Claforan; Chile: Grifotaxima†; Cz.: Cefan- review of 85 cases. Adverse Drug React Toxicol Rev 2002; 21:
in renal impairment. Clin Pharmacol Ther 1985; 38: 31–6. tral†; Ceftax; Claforan†; Sefotak; Taxcef; Denm.: Claforan; Fin.: Claforan; 101–7.
2. Paap CM, et al. Pharmacokinetics of cefotaxime and its active Fr.: Claforan; Ger.: Claforan; Gr.: Ceramil; Ciltiren; Claforan; Flemycin; 3. Robinson HE, et al. Cefotetan-induced life-threatening haemol-
metabolite in children with renal dysfunction. Antimicrob Agents Letynol; Molelant; Naspor; Phacocef; Solubilax; Spirosine; Stoparen; Hong ysis. Med J Aust 2006; 184: 251.
Chemother 1991; 35: 1879–83. Kong: Cetan†; Claforan; Valoran; Hung.: Cefalekol; Cefotax†; Claforan;
3. Paap CM, et al. Cefotaxime and metabolite disposition in two Tirotax; India: Biotax; Claforan; Lyforan; Novatax; Omnatax; Omnicef; Ori- Sodium content. Each g of cefotetan disodium contains about
pediatric continuous ambulatory peritoneal dialysis patients. taxim; Talcef†; Zetaxim; Indon.: Baxima; Biocef; Cefor; Cefovell; Cefoxal; 3.2 mmol of sodium.
Ann Pharmacother 1992; 26: 341–3. Clacef; Claforan; Clatax; Combicef; Efotax; Ethiclaf; Foxim; Goforan; Kalfox-
4. Paap CM, Nahata MC. The relation between type of renal dis- im; Lancef; Lapixime; Procefa; Rycef; Siclaxim; Soclaf; Starclaf; Taxegram; Interactions
ease and renal drug clearance in children. Eur J Clin Pharmacol Taximax; Tirdicef; Irl.: Claforan; Israel: Claforan; Ital.: Aximad; Batixim; As for Cefamandole, p.221.
1993; 44: 195–7. Cefomit; Centiax; Claforan; Lirgosin; Refotax; Salocef; Spectrocef; Tafocex;
Taxime; Xame; Zariviz; Zimanel; Malaysia: Cetaxima†; Claforan; Claraxim; Antimicrobial Action
Mex.: Benaxima; Biosint; Cefoclin†; Cefotex; Cefradil; Ceftomax; Claforan; Cefotetan is a cephamycin antibiotic with a mode of action and
Uses and Administration Defradil; Fot-Amsa; Fotexina; Sefoxiram; Sepsilem; Taporin; Tebruxim; Tiro- spectrum of activity similar to those of cefoxitin (p.230). It is
tax; Viken; Xendin; Neth.: Claforan; Tirotax; Norw.: Claforan; NZ: Cla-
Cefotaxime is a third-generation cephalosporin anti- foran; Philipp.: Cladex; Clafetam; Claforan; Clafoxim; Clavocef; Clinbaxef; generally much more active in vitro than cefoxitin against the
bacterial used in the treatment of infections due to sus- Ofetaxim; Pantaxin; Tafoxam; Zefocent; Pol.: Biotaksym; Rantaksym; Tarce- Gram-negative Enterobacteriaceae, but has similar activity
foksym; Tirotax; Port.: Antadar; Cefobetox; Forticeporina†; Ralopar; Resi- against Bacteroides fragilis and may be less active against some
ceptible organisms, especially serious and life-threat- belacta; Totam; Rus.: Cefosin (Цефосин); Claforan (Клафоран); Intrataxi- other Bacteroides spp.
ening infections. They include brain abscess, me (Интратаксим); Oritaxim (Оритаксим); Talcef (Талцеф); Tarcefoksym
endocarditis, gonorrhoea, intensive care (selective (Тарцефоксим); S.Afr.: Claforan; Kefotax; Klafotaxim; Reftax; Totam†; Sin- Pharmacokinetics
gapore: Clacef; Claforan; Spain: Claforan; Swed.: Claforan; Switz.: Cla- On intramuscular injection of cefotetan, peak plasma concentra-
parenteral and enteral antisepsis regimens), Lyme dis- foran; Thai.: Biotaxime†; Cefomic; Ceforan; Cefotax; Ceftaran†; Ceftaxan;
tions of about 70 micrograms/mL at 1 hour and
Claforan; Claraxim; Fontax; Fortax†; Fotax; Motaxim; Oritaxime†; Valor-
ease, meningitis, peritonitis (primary or spontaneous), an†; Turk.: Betaksim; Claforan; Deforan; Sefagen; Sefoksim; Sefotak; Tax- 90 micrograms/mL at 3 hours have been reported after doses of
pneumonia, septicaemia, and typhoid fever. It is also ocef; UAE: Primocef; UK: Claforan; USA: Claforan; Venez.: Balticina†; Ce- 1 and 2 g, respectively. The plasma half-life of cefotetan is usu-
fam; Cefatox; Cefotas†; Claforan; Novatax; Taxibon†; Tirotax. ally in the range of 3.0 to 4.6 hours and is prolonged in patients
used for surgical infection prophylaxis. For details of
Multi-ingredient: India: Sultax. with renal impairment. About 88% of cefotetan may be bound to
these infections and their treatment, see under Choice plasma proteins, depending on the plasma concentration.
of Antibacterial, p.162. Cefotetan is widely distributed in body tissues and fluids. It
Administration and dosage. Cefotaxime is given as the crosses the placenta and low concentrations have been detected
sodium salt by deep intramuscular injection or intrave- Cefotetan (BAN, USAN, rINN) in breast milk. High concentrations are achieved in bile.
nously by slow injection over 3 to 5 minutes or by in- Cefotetan is excreted in the urine, primarily by glomerular filtra-
Céfotétan; Cefotetán; Cefotetanum; ICI-156834 (cefotetan or tion, as unchanged drug; 50 to 80% of a dose has been recovered
fusion over 20 to 60 minutes. Doses are expressed in cefotetan disodium); YM-09330 (cefotetan or cefotetan diso- in the urine in 24 hours and high concentrations are achieved.
terms of the equivalent amount of cefotaxime; 1.05 g dium). (7S)-7-[(4-Carbamoylcarboxymethylene-1,3-dithietan-2- Small amounts of the tautomeric form of cefotetan have been de-
of cefotaxime sodium is equivalent to about 1 g of ce- yl)carboxamido]-7-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thi- tected in both plasma and urine.
fotaxime. It is usually given in doses of 2 to 6 g daily in omethyl]-3-cephem-4-carboxylic acid. Biliary excretion of cefotetan probably accounts for nonrenal
2 to 4 divided doses to adults. In severe infections up to clearance.
Цефотетан
12 g may be given daily by the intravenous route in up Some cefotetan is removed by dialysis.
C 17 H 17 N 7 O 8 S 4 = 575.6.
to 6 divided doses; pseudomonal infections usually re- ◊ References.
quire more than 6 g daily, but a cephalosporin with C AS — 69712-56-7. 1. Martin C, et al. Clinical pharmacokinetics of cefotetan. Clin
greater antipseudomonal activity, such as ceftazidime, ATC — J01DC05. Pharmacokinet 1994; 26: 248–58.
is preferable. Children may be given 100 to 150 mg/kg ATC Vet — QJ01DC05. Uses and Administration
(50 mg/kg for neonates) daily in 2 to 4 divided doses, Cefotetan is a cephamycin antibacterial generally classified with
the second-generation cephalosporins and used similarly to ce-
increased in severe infections to 200 mg/kg (150 to foxitin (p.230) in the treatment and prophylaxis of anaerobic and
O
200 mg/kg for neonates) daily if necessary. H3CO H mixed bacterial infections, especially intra-abdominal and pelvic
S infections.
For details of reduced doses to be used in patients with S N CH3
severe renal impairment, see below. H It is given as the disodium salt by deep intramuscular injection or
N S N
S
N
intravenously by slow injection over 3 to 5 minutes or by infu-
In the treatment of gonorrhoea, a single dose of 0.5 or HOOC O sion. Doses are expressed in terms of the equivalent amount of
1 g of cefotaxime is given. COOH N N cefotetan; 1.08 g of cefotetan disodium is equivalent to about 1 g
CONH2
of cefotetan. The usual dose is 1 or 2 g every 12 hours. For the
For surgical infection prophylaxis, 1 g is given 30 to 90 treatment of life-threatening infections, 3 g every 12 hours may
minutes before surgery. At caesarean section, 1 g is Pharmacopoeias. In Jpn and US. be given intravenously. Doses of cefotetan should be reduced in
given intravenously to the mother as soon as the umbil- USP 31 (Cefotetan). Store in airtight containers. patients with moderate to severe renal impairment (see below).
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
230 Antibacterials
For infection prophylaxis during surgical procedures, an intrave- Interactions
nous dose of 1 or 2 g is given 30 to 60 minutes before surgery or, Probenecid reduces the renal clearance of cefoxitin.
in caesarean section, as soon as the umbilical cord is clamped. CH3 CO2H
Administration in renal impairment. Dosage of cefotetan O O Antimicrobial Action
should be reduced in patients with moderate to severe renal im- N N O Cefoxitin is a cephamycin antibacterial which, like the
pairment. US licensed product information gives the following H H other beta lactams, is bactericidal and is considered to
dosing guidelines based on creatinine clearance (CC): N N
H 2N S act through the inhibition of bacterial cell wall synthe-
• CC 10 to 30 mL/minute: the usual dose every 24 hours or one- H H sis.
half the usual dose every 12 hours S O
It has a similar spectrum of activity to cefamandole
• CC less than 10 mL/minute: the usual dose every 48 hours or (p.221) but is more active against anaerobic bacteria,
one-quarter the usual dose every 12 hours (cefovecin)
especially Bacteroides fragilis.
In patients undergoing haemodialysis, one-quarter the usual dose
may be given every 24 hours on days between dialysis and one- Profile Cefoxitin can induce the production of beta-lactamases
half the usual dose on the day of dialysis. Cefovecin sodium is a third-generation cephalosporin antibacte- by some bacteria, and use of cefoxitin with other beta
rial used in veterinary medicine. lactams have been shown to be antagonistic in vitro.
Preparations
Cefoxitin itself is considered to be resistant to a wide
USP 31: Cefotetan for Injection; Cefotetan Injection.
range of beta-lactamases, including those produced by
Proprietary Preparations (details are given in Part 3) Cefoxitin Sodium (BANM, USAN, rINNM) Bacteroides spp. However, acquired resistance to ce-
Austral.: Apatef†; Belg.: Apacef†; Canad.: Cefotan†; Fr.: Apacef†; Ital.: foxitin has been reported in B. fragilis (see Anaerobic
Apatef†; Jpn: Yamatetan†; NZ: Apatef†; Port.: Apatef†; USA: Cefotan. Cefoksitino natrio druska; Cefoksytyna sodowa; Cefoxitin sodná
sůl; Cefoxitina sódica; Céfoxitine sodique; Cefoxitinnatrium; Ce-
Bacterial Infections, p.163) and has been attributed to
foxitin-nátrium; Cefoxitinum natricum; Kefoksitiininatrium; L- beta-lactamase as well as to alterations in penicillin-
620388; MK-306; Natrii Cefoxitinum. Sodium 3-carbamoy- binding proteins or to outer membrane proteins; there
Cefotiam Hydrochloride (BANM, USAN, rINNM) loxymethyl-7-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4- may be cross-resistance to other antibacterials.
Abbott-48999; Céfotiam, Chlorhydrate de; Cefotiami Hydro- carboxylate. ◊ References.
chloridum; CGP-14221E (cefotiam or cefotiam hydrochloride); Натрий Цефокситин 1. Cuchural GJ, et al. Transfer of β-lactamase-associated cefoxitin
Hidrocloruro de cefotiam; SCE-963. 7-[2-(2-Amino-1,3-thiazol- C 16 H 16N 3 NaO 7 S 2 = 449.4. resistance in Bacteroides fragilis. Antimicrob Agents Chemother
4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5- 1986; 29: 918–20.
C AS — 35607-66-0 (cefoxitin); 33564-30-6 (cefoxitin so- 2. Piddock LJV, Wise R. Cefoxitin resistance in Bacteroides spe-
ylthiomethyl]-3-cephem-4-carboxylic acid dihydrochloride. dium). cies: evidence indicating two mechanisms causing decreased
susceptibility. J Antimicrob Chemother 1987; 19: 161–70.
Цефотиама Гидрохлорид ATC — J01DC01. 3. Brogan O, et al. Bacteroides fragilis resistant to metronidazole,
C 18 H 23 N 9 O 4 S 3 ,2HCl = 598.6. ATC Vet — QJ01DC01. clindamycin and cefoxitin. J Antimicrob Chemother 1989; 23:
660–2.
C AS — 61622-34-2 (cefotiam); 66309-69-1 (cefotiam 4. Wexler HM, Halebian S. Alterations to the penicillin-binding
hydrochloride). proteins in the Bacteroides fragilis group: a mechanism for non-
ATC — J01DC07. O β-lactamase mediated cefoxitin resistance. J Antimicrob Chem-
H3CO H other 1990; 26: 7–20.
ATC Vet — QJ01DC07. S O NH2 5. Cherubin CE, Appleman MD. Susceptibility of cefoxitin-resist-
N ant isolates of bacteroides to other agents including β-lactamase
H inhibitor/β-lactam combinations. J Antimicrob Chemother 1993;
N O 32: 168–70.
O S
H H O
S CH3 Pharmacokinetics
N N COOH
H Cefoxitin is not absorbed from the gastrointestinal
N S N CH3 (cefoxitin) tract; it is given parenterally as the sodium salt. After
N O N
1 g by intramuscular injection a peak plasma concen-
S COOH N N Pharmacopoeias. In Eur. (see p.vii) and US. tration of up to 30 micrograms/mL at 20 to 30 minutes
NH2 Ph. Eur. 6.2 (Cefoxitin Sodium). A white or almost white, very has been reported whereas concentrations of 125, 72,
hygroscopic, powder. Very soluble in water; sparingly soluble in and 25 micrograms/mL have been achieved after intra-
(cefotiam) alcohol. A 1% solution in water has a pH between 4.2 and 7.0.
Store in airtight containers. venous doses of 1 g over 3, 30, and 120 minutes re-
USP 31 (Cefoxitin Sodium). White to off-white, somewhat hy- spectively. Cefoxitin is about 70% bound to plasma
Pharmacopoeias. In Jpn and US. Jpn also includes cefotiam groscopic, granules or powder, having a slight characteristic proteins. It has a plasma half-life of 45 to 60 minutes
hexetil hydrochloride. odour. Very soluble in water; slightly soluble in acetone; insolu-
USP 31 (Cefotiam Hydrochloride). Store in airtight containers. which is prolonged in renal impairment. Cefoxitin is
ble in chloroform and in ether; sparingly soluble in dimethylfor- widely distributed in the body but there is normally lit-
Profile mamide; soluble in methyl alcohol. pH of a 10% solution in wa-
ter is between 4.2 and 7.0. Store in airtight containers at a tle penetration into the CSF, even when the meninges
Cefotiam is a third-generation cephalosporin antibacterial with
actions and uses similar to those of cefamandole (p.220). It is temperature not exceeding 8°. are inflamed. It crosses the placenta and has been de-
given intravenously or intramuscularly as the hydrochloride but tected in breast milk. Relatively high concentrations
doses are expressed in terms of the base; 1.14 g of cefotiam hy- Adverse Effects and Precautions are achieved in bile.
drochloride is equivalent to about 1 g of cefotiam. The usual dose As for Cefalotin Sodium, p.219. The majority of a dose is excreted unchanged by the
is the equivalent of up to 6 g of cefotiam daily in divided doses,
according to the severity of the infection. Cefoxitin may interfere with the Jaffé method of meas- kidneys, up to about 2% being metabolised to descar-
uring creatinine concentrations to produce falsely high bamylcefoxitin which is virtually inactive. Cefoxitin is
Cefotiam hexetil hydrochloride, a prodrug of cefotiam, is given
orally in doses equivalent to 200 to 400 mg of cefotiam twice values; this should be borne in mind when measuring excreted in the urine by glomerular filtration and tubu-
daily. renal function. lar secretion and about 85% of a dose is recovered
within 6 hours; probenecid slows this excretion. After
◊ References. Breast feeding. Cefoxitin is distributed into breast milk but is
an intramuscular dose of 1 g, peak concentrations in
detectable only in low concentrations. In a study1 in which cefox-
1. Brogard JM, et al. Clinical pharmacokinetics of cefotiam. Clin itin was given prophylactically in doses of 2 to 4 g to 18 women the urine are usually greater than 3 mg/mL.
Pharmacokinet 1989; 17: 163–74.
undergoing caesarean section, only one sample of breast milk Cefoxitin is removed to some extent by haemodialysis.
Preparations contained measurable concentrations of cefoxitin, 19 hours after
the last dose. No adverse effects have been observed in breast-fed
USP 31: Cefotiam for Injection.
infants whose mothers were receiving cefoxitin, and the Ameri- Uses and Administration
Proprietary Preparations (details are given in Part 3) can Academy of Pediatrics considers2 that it is therefore usually Cefoxitin is a cephamycin antibacterial that differs
Austria: Spizef; Fr.: Taketiam; Texodil; Ger.: Spizef; Indon.: Aspil; Cefradol; compatible with breast feeding. structurally from the cephalosporins by the addition of
Ceradolan; Ethidol; Fodiclo; Fotaram; Jpn: Pansporin; Philipp.: Ceradolan; 1. Roex AJM, et al. Secretion of cefoxitin in breast milk following a 7-α-methoxy group to the 7-β-aminocephalosporanic
Singapore: Ceradolan; Thai.: Ceradolan. short-term prophylactic administration in caesarean section. Eur
J Obstet Gynecol Reprod Biol 1987; 25: 299–302.
acid nucleus.
2. American Academy of Pediatrics. The transfer of drugs and oth- It is generally classified with the second-generation ce-
er chemicals into human milk. Pediatrics 2001; 108: 776–89. phalosporins and can be used similarly to cefamandole
Correction. ibid.; 1029. Also available at:
Cefovecin Sodium (USAN, rINNM) h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l / (p.221) for the treatment of susceptible infections.
Cefovecina sódica; Céfovécine Sodique; Natrii Cefovecinum; pediatrics%3b108/3/776 (accessed 25/05/04) However, because of its activity against Bacteroides
UK-287074-02. Sodium (6R,7R)-7-{[(2Z)-(2-aminothiazol-4- Effects on the gastrointestinal tract. Marked changes in fragilis and other anaerobic bacteria, it is used princi-
yl)(methoxyimino)acetyl]amino}-8-oxo-3-[(2S)-tetrahydrofuran- anaerobic, facultative, and aerobic faecal flora have been noted pally in the treatment and prophylaxis of anaerobic and
2-yl]-5-thia-1-azabicyclo[4.4.0]oct-2-ene-2-carboxylate. with cefoxitin.1 mixed bacterial infections, especially intra-abdominal
1. Mulligan ME, et al. Alterations in human fecal flora, including
Натрий Цефовецин ingrowth of Clostridium difficile, related to cefoxitin therapy. and pelvic infections. Indications include endometritis
C 17 H 18 N 5 NaO 6 S 2 = 475.5. Antimicrob Agents Chemother 1984; 26: 343–6. (prophylaxis at caesarean section), pelvic inflammato-
C AS — 234096-34-5 (cefovecin); 141195-77-9 (ce- Sodium content. Each g of cefoxitin sodium contains about ry disease, and surgical infection (prophylaxis). It may
fovecin sodium). 2.2 mmol of sodium. also be used in the treatment of gonorrhoea and
 Cefotiam Hydrochloride/Cefpirome Sulfate 231
urinary-tract infections. For details of these infections Preparations
and their treatment, see under Choice of Antibacterial, USP 31: Cefpiramide for Injection.
H 3C
p.162. O O Proprietary Preparations (details are given in Part 3)
H H Jpn: Sepatren.
Administration and dosage. Cefoxitin is given as the N S N
sodium salt by deep intramuscular injection, by slow N N
intravenous injection over 3 to 5 minutes, or by inter- H Cefpirome Sulfate (USAN, rINNM)
N N+
mittent or continuous intravenous infusion. N N O Cefpirome, sulfate de; Cefpirome Sulphate (BANM); Cefpiromi
Doses are expressed in terms of the equivalent amount sulfas; Cefpiromsulfat; HR-810 (cefpirome or cefpirome sulfate);
S COO-
of cefoxitin; 1.05 g of cefoxitin sodium is equivalent to Kefpiromisulfaatti; Sulfato de cefpiroma. (Z)-7-[2-(2-Aminothia-
NH2 zol-4-yl)-2-methoxyiminoacetamido]-3-(1-pyrindiniomethyl)-3-
about 1 g of cefoxitin. The usual adult dose is 1 or 2 g
cephem-4-carboxylate sulphate.
every 8 hours although it may be given more frequent- (cefozopran) Цефпирома Сульфат
ly (every 4 or 6 hours). In severe infections up to 12 g C 22 H 22 N 6 O 5 S 2 ,H 2 SO 4 = 612.7.
daily has been recommended. Children and neonates Pharmacopoeias. In Jpn. C AS — 84957-29-9 (cefpirome); 98753-19-6 (cefpirome
may be given 20 to 40 mg/kg, every 12 hours for ne- sulfate).
Profile ATC — J01DE02.
onates up to 1 week old, every 8 hours for those aged 1 Cefozopran is a cephalosporin antibacterial used parenterally as
to 4 weeks, and every 6 to 8 hours for older infants and ATC Vet — QJ01DE02.
the hydrochloride.
children; in severe infections, up to 200 mg/kg daily ◊ References.
may be given, to a maximum of 12 g daily. 1. Iwahi T, et al. In vitro and in vivo activities of SCE-2787, a new
H 3C
O O
For the treatment of uncomplicated urinary-tract infec- parenteral cephalosporin with a broad antibacterial spectrum. H H
Antimicrob Agents Chemother 1992; 36: 1358–66. N S
tions, cefoxitin 1 g twice daily has been given intra- 2. Paulfeuerborn W, et al. Comparative pharmacokinetics and se- N
muscularly. rum bactericidal activities of SCE-2787 and ceftazidime. Antimi- H
crob Agents Chemother 1993; 37: 1835–41. N
For details of reduced doses of cefoxitin in patients N+
3. Fujii R, et al. Pharmacokinetics and clinical effects of cefozo- N
with renal impairment, see below. pran in pediatric patients. Jpn J Antibiot 1996; 49: 17–33.
O
S COO-
For the treatment of uncomplicated gonorrhoea, a sin- Preparations
gle dose of 2 g intramuscularly has been given with NH2
Proprietary Preparations (details are given in Part 3)
probenecid 1 g orally. Jpn: Firstcin.
(cefpirome)
For surgical infection prophylaxis, the usual adult dose
is cefoxitin 2 g intramuscularly or intravenously 30 to Pharmacopoeias. In Jpn.
60 minutes before the procedure and then every 6 Cefpiramide (USAN, rINN) Adverse Effects and Precautions
hours, not usually for more than 24 hours. Infants and Cefpiramida; Cefpiramidum; SM-1652; Wy-44635. (7R)-7-[(R)- As for Cefalotin, p.219.
children undergoing surgical procedures can be given 2-(4-Hydroxy-6-methylnicotinamido)-2-(4-hydroxyphe- Cefpirome is reported to interfere with the Jaffé method of meas-
doses of 30 to 40 mg/kg, at the same time intervals as nyl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-ce- uring creatinine concentrations to determine renal function.
adults; neonates may be given 30 to 40 mg/kg, but at phem-4-carboxylic acid. ◊ References.
intervals of 8 to 12 hours. Цефпирамид 1. Rubinstein E, et al. A review of the adverse events profile of
cefpirome. Drug Safety 1993; 9: 340–5.
At caesarean section a single 2-g dose may be given C 25 H 24 N 8 O 7 S 2 = 612.6.
C AS — 70797-11-4. Interactions
intravenously to the mother as soon as the umbilical Probenecid reduces the renal clearance of cefpirome.
ATC — J01DD11.
cord is clamped. If necessary, a 3-dose regimen, with ATC Vet — QJ01DD11. Antimicrobial Action
further 2-g doses 4 and 8 hours after the initial dose, Cefpirome is a fourth-generation cephalosporin that is stable to a
may be used. wide range of beta-lactamases. It has a spectrum of activity sim-
HO ilar to that of the third-generation cephalosporin cefotaxime
◊ Reviews. O (p.228), but it appears to be more active in vitro against staphy-
H H lococci, some enterococci, some Enterobacteriaceae, and Pseu-
1. DiPiro JT, May JR. Use of cephalosporins with enhanced an- S
tianaerobic activity for treatment and prevention of anaerobic H 3C N N CH3 domonas aeruginosa. Cefpirome may be less active than ceftazi-
and mixed infections. Clin Pharm 1988; 7: 285–302. H dime (p.234) against Ps. aeruginosa.
N S N
2. Goodwin CS. Cefoxitin 20 years on: is it still useful? Rev Med NH N
Microbiol 1995; 6: 146–53. O Pharmacokinetics
COOH N N Cefpirome is given by injection as the sulfate. Mean peak serum
Administration in renal impairment. In renal impairment, OH O concentrations of 80 to 90 micrograms/mL are attained after a
dosage of cefoxitin should be reduced according to creatinine single intravenous 1-g dose. The elimination half-life is about 2
clearance (CC). After an initial loading dose of 1 to 2 g, mainte- Pharmacopoeias. In US. hours and is prolonged in patients with renal impairment. Cef-
nance doses are: USP 31 (Cefpiramide). Store in airtight containers. pH of a 0.5% pirome is less than 10% bound to plasma proteins.
• CC 30 to 50 mL/minute: 1 to 2 g every 8 to 12 hours suspension in water is between 3.0 and 5.0. Cefpirome is widely distributed into body tissues and fluids and
• CC 10 to 29 mL/minute: 1 to 2 g every 12 to 24 hours appears in breast milk. It is mainly excreted by the kidneys and
• CC 5 to 9 mL/minute: 0.5 to 1 g every 12 to 24 hours Cefpiramide Sodium (USAN, rINNM) 80 to 90% of a dose is recovered unchanged in the urine. Signif-
icant amounts are removed by haemodialysis.
• CC below 5 mL/minute: 0.5 to 1 g every 24 to 48 hours Cefpiramida sódica; Cefpiramide Sodique; Natrii Cefpiramidum.
Натрий Цефпирамид
Uses and Administration
In patients undergoing haemodialysis, the loading dose should be Cefpirome is a fourth-generation cephalosporin antibacterial
repeated after each dialysis session. C 25 H 23 N 8 NaO 7 S 2 = 634.6. used in the treatment of infections due to susceptible organisms.
Preparations C AS — 74849-93-7. They include infections of the urinary tract, respiratory tract, and
ATC — J01DD11. skin, and also septicaemia and infections in immunocompro-
BP 2008: Cefoxitin Injection; mised patients. For details of these infections and their treatment,
USP 31: Cefoxitin for Injection; Cefoxitin Injection. ATC Vet — QJ01DD11.
see under Choice of Antibacterial, p.162.
Proprietary Preparations (details are given in Part 3) Pharmacopoeias. In Jpn.
Cefpirome is given by intravenous injection over 3 to 5 minutes
Arg.: Mefoxin†; Pluricefo†; Austral.: Mefoxin; Austria: Mefoxitin; Belg.:
Mefoxin†; Braz.: Cefoxan; Cefoxin; Cefton; Foxtil†; Gamacef; Mefoxin; Pro- Profile or infusion over 20 to 30 minutes as the sulfate, but doses are
poten†; Canad.: Mefoxin†; Cz.: Mefoxin†; Fin.: Mefoxin†; Fr.: Mefoxin†; Cefpiramide is a third-generation cephalosporin antibacterial re- expressed in terms of the base; 1.19 g of cefpirome sulfate is
Ger.: Mefoxitin; Gr.: Destrepen†; Mefoxil; Metaptyl; Hong Kong: Mefoxin; lated to cefoperazone (p.227) and with similar activity against equivalent to about 1 g of cefpirome. The usual dose is the equiv-
Ital.: Cefociclin; Mefoxin; Tifox†; Neth.: Mefoxin†; Norw.: Mefoxitin†; NZ: Pseudomonas aeruginosa, but possibly less active against En- alent of 1 or 2 g of cefpirome every 12 hours. For details of re-
Mefoxin; Philipp.: Monowel; Panafox; Zepax; Port.: Atralxitina; Mefoxin†; terobacteriaceae. Cefpiramide is also active against staphylococ- duced doses to be used in renal impairment, see below.
Niacef; S.Afr.: Mefoxin; Spain: Mefoxitin†; Swed.: Mefoxitin†; Switz.: Me-
foxitin†; Thai.: Cefoxin; Cefxitin; Maxotin; Zefin; UK: Mefoxin†; USA: Me- ci and streptococci and marginal activity against enterococci in ◊ References.
foxin; Venez.: Mefoxitin†. vitro has been reported. Like cefamandole (p.220), cefpiramide 1. Brown EM, et al. eds. Cefpirome: a novel extended spectrum
contains an N-methylthiotetrazole side-chain, a structure associ- cephalosporin. J Antimicrob Chemother 1992; 29 (suppl A):
ated with hypoprothrombinaemia, alcohol intolerance, and po- 1–104.
tentiation of anticoagulants. 2. Wiseman LR, Lamb HM. Cefpirome: a review of its antibacterial
Cefozopran Hydrochloride (rINNM) Cefpiramide is given by intravenous injection or infusion as the activity, pharmacokinetic properties and clinical efficacy in the
treatment of severe nosocomial infections and febrile neutrope-
Céfozopran, Chlorhydrate de; Cefozoprani Hydrochloridum; sodium salt in the treatment of susceptible infections but doses nia. Drugs 1997; 54: 117–40.
Hidrocloruro de cefozoprán. (−)-1-{[(6R,7R)-7-[2-(5-Amino- are expressed in terms of cefpiramide; 1.04 g of cefpiramide so-
dium is equivalent to about 1 g of cefpiramide. The usual dose is Administration in renal impairment. Dosage of cefpirome
1,2,4-thiadiazol-3-yl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-
1 to 2 g daily in 2 divided doses. should be modified in renal impairment; after a loading dose of
azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1H-imidazo[1,2-b]pyri- 1 or 2 g depending on the severity of infection, the maintenance
dazin-4-ium hydroxide inner salt, 72-(Z)-(O-methyloxime), hy- ◊ References. dosage should be adjusted according to creatinine clearance
drochloride. (CC) and the severity of infection:
1. Wang H, et al. In-vitro antibacterial activities of cefpiramide and
Цефозопрана Гидрохлорид other broad-spectrum antibiotics against 440 clinical isolates in • CC 20 to 50 mL/minute: 0.5 or 1 g twice daily
China. J Infect Chemother 2000; 6: 81–5. • CC 5 to 20 mL/minute: 0.5 or 1 g once daily
C 19 H 17N 9 O 5 S 2 ,HCl = 552.0.
C AS — 113359-04-9 (cefozopran); 113981-44-5 (cefoz- Sodium content. Each g of cefpiramide sodium contains • CC 5 mL/minute or less (in haemodialysis patients): 0.5 or 1 g
opran hydrochloride). about 1.6 mmol of sodium. once daily plus a half-dose after each dialysis session.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
232 Antibacterials
Preparations proxetil ester, which is hydrolysed on absorption to cef- Breast feeding. A study1 in 9 healthy women found that con-
Proprietary Preparations (details are given in Part 3) podoxime. Doses are expressed in terms of the equiva- centrations of cefprozil in breast milk corresponded to no more
Austral.: Cefrom; Austria: Cedixen; Cefrom; Belg.: Cefrom†; Cz.: Ce- than 0.3% of a dose and concluded that cefprozil could be given
from†; Fr.: Cefrom; Gr.: Cefrom†; India: Bacirom†; Ceforth†; Cefrom; Ta-
lent amount of cefpodoxime; 130 mg of cefpodoxime safely during breast feeding. The American Academy of
from; Indon.: Cefir; Cefnos; Cefrin; Cefrom; Lanpirome; Nufirom; Romicef; proxetil is equivalent to about 100 mg of cefpodoxime. Pediatrics2 states that there have been no reports of any clinical
Sopirom; Xenoprom; Irl.: Cefrom†; Mex.: Cefrom; Neth.: Cefrom; NZ: Absorption may be enhanced if cefpodoxime proxetil
Cefrom†; Port.: Cefrom†; Cipiram; Farmocefe; S.Afr.: Cefrom; Thai.: Ce- effect on the infant associated with the use of cefprozil in breast-
from; UK: Cefrom†. is given with food. The usual dose for adults is 100 to feeding mothers, and that it may be considered to be usually
200 mg every 12 hours for respiratory-tract and uri- compatible with breast feeding.
1. Shyu WC, et al. Excretion of cefprozil into human breast milk.
nary-tract infections. A dose of 200 or 400 mg every Antimicrob Agents Chemother 1992; 36: 938–41.
Cefpodoxime Proxetil 12 hours may be used for skin and soft-tissue infec- 2. American Academy of Pediatrics. The transfer of drugs and oth-
er chemicals into human milk. Pediatrics 2001; 108: 776–89.
tions. In the USA children aged 2 months and older Correction. ibid.; 1029. Also available at:
(BANM, USAN, rINNM)
may be given doses of 5 mg/kg every 12 hours, up to a h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
Cefpodoxima proxetilo; Cefpodoxime proxétil; Cefpodoxime, maximum of 200 mg daily for pharyngitis or tonsillitis pediatrics%3b108/3/776 (accessed 25/05/04)
Proxétil de; Cefpodoximi Proxetilum; Cefpodoximum proxetili; or 400 mg daily for acute otitis media or maxillary si- Hypersensitivity. Serum sickness-like reactions were reported
CS-807; R-3763 (cefpodoxime); U-76252; U-76253 (cefpodox-
nusitis. In the UK cefpodoxime may be given to chil- in 4 patients, 3 of them children, given cefprozil.1 Such reactions
ime). The 1-[(isopropoxycarbonyl)oxy]ethyl ester of (Z)-7-[2- have been associated with cefaclor (p.217), but whether they rep-
(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-3-meth- dren and infants aged 15 days and older, in a dose of resent a class-related hypersensitivity reaction is not clear.
oxymethyl-3-cephem-4-carboxylic acid. 4 mg/kg every 12 hours, up to a maximum of 200 mg 1. Lowery N, et al. Serum sickness-like reactions associated with
Цефподоксима Проксетил daily, for infections of the respiratory tract, urinary cefprozil therapy. J Pediatr 1994; 125: 325–8.

C 21 H 27 N 5 O 9 S 2 = 557.6. tract, and skin and soft tissues.

Interactions
C AS — 80210-62-4 (cefpodoxime); 87239-81-4 (cefpo- The interval between doses of cefpodoxime may need As for Cefalexin, p.218.
doxime proxetil). to be extended in patients with renal impairment (see
ATC — J01DD13. below).
ATC Vet — QJ01DD13. Antimicrobial Action
For uncomplicated gonorrhoea, a single dose of Cefprozil is bactericidal and has a similar but wider
200 mg may be given. range of antimicrobial activity than cefaclor (p.217).
H3C ◊ References.
O O Pharmacokinetics
H H 1. Moore EP, et al., eds. Cefpodoxime proxetil: a third-generation
N S oral cephalosporin. J Antimicrob Chemother 1990; 26 (suppl E): Cefprozil is well absorbed from the gastrointestinal
N 1–101.
H 2. Adam D, et al., eds. Cefpodoxime proxetil: a new third genera-
tract with a reported bioavailability of 90 to 95%. Oral
N OCH3 doses of 0.25, 0.5, and 1 g produce peak plasma con-
tion oral cephalosporin. Drugs 1991; 42 (suppl 3): 1–66.
N O
CH3 O CH3 3. Frampton JE, et al. Cefpodoxime proxetil: a review of its anti- centrations of about 6, 10, and 18 micrograms/mL re-
S bacterial activity, pharmacokinetic properties and therapeutic
potential. Drugs 1992; 44: 889–917. spectively at 1 to 2 hours. The presence of food is re-
NH2 O O O O CH3 4. Chocas EC, et al. Cefpodoxime proxetil: a new, broad-spectrum, ported to have little or no effect on the absorption of
oral cephalosporin. Ann Pharmacother 1993; 27: 1369–77.
5. Fulton B, Perry CM. Cefpodoxime proxetil: a review of its use
cefprozil. A plasma half-life of 1 to 1.4 hours has been
Pharmacopoeias. In Jpn and US. reported; it is increased in patients with renal impair-
in the management of bacterial infections in paediatric patients.
USP 31 (Cefpodoxime Proxetil). A white to light brownish- Paediatr Drugs 2001; 3: 137–58.
white powder, odourless or having a faint odour. Very slightly ment, up to about 6 hours in those with end-stage renal
soluble in water; freely soluble in dehydrated alcohol; soluble in Administration in renal impairment. The interval between failure. About 35 to 45% of cefprozil is bound to plas-
acetonitrile and in methyl alcohol; slightly soluble in ether. Store doses of cefpodoxime should be extended in patients with renal ma proteins.
in airtight containers at a temperature not exceeding 25°. impairment to every 24 hours in those with creatinine clearance
of 10 to 39 mL/minute, and to every 48 hours when the creati- Cefprozil is widely distributed in the body tissues.
nine clearance is less than 10 mL/minute. In patients on haemo- Concentrations of cefprozil in tonsillar and adenoidal
Adverse Effects and Precautions dialysis the dose should be given after each dialysis session. tissue are reported to be about 40 to 50% of those in
As for Cefalotin Sodium, p.219.
Preparations plasma, and less than 0.3% of a 1-g dose has been re-
The most frequently reported adverse effects of cefpo- covered in breast milk in 24 hours. About 60% of a
doxime are gastrointestinal disturbances, especially di- USP 31: Cefpodoxime Proxetil for Oral Suspension; Cefpodoxime Proxetil
Tablets. dose is excreted unchanged in the urine in the first 8
arrhoea. Proprietary Preparations (details are given in Part 3) hours by glomerular filtration and tubular secretion.
Austria: Biocef; Celiol; Cintalux; Otreon; Braz.: Orelox; Chile: Cefirax; High concentrations of cefprozil are achieved in the
Interactions Cz.: Orelox†; Fr.: Orelox; Ger.: Orelox; Podomexef; Hong Kong: Banan;
urine; concentrations of 700, 1000, and
India: Cefoprox; Cepodem; Kefpod; Monocef-O; Monotax-O; Tambac; In-
Absorption of cefpodoxime is decreased by antacids or don.: Banan; Irl.: Cefodox; Ital.: Cefodox; Orelox; Otreon; Jpn: Banan; 2900 micrograms/mL have been reported within 4
histamine H2-receptor antagonists. Probenecid reduces Mex.: Orelox; Neth.: Orelox; Otreon; Philipp.: Banan; Zudem; Port.:
hours of doses of 0.25, 0.5, and 1 g respectively. Some
Orelox; S.Afr.: Cepodem; Orelox; Spain: Garia; Instana; Kelbium; Otreon;
the renal excretion of cefpodoxime. Swed.: Orelox; Switz.: Orelox; Podomexef; Thai.: Banan; UK: Orelox; cefprozil is removed by haemodialysis.
USA: Vantin.
Antimicrobial Action Uses and Administration
As for Cefixime, p.224, but cefpodoxime has greater Cefprozil is a cephalosporin antibacterial consisting of
activity against Staphylococcus aureus. Cefprozil (BAN, USAN, rINN) cis- and trans- isomers in a ratio of about 90:10. It is
◊ References. BMY-28100-03-800; BMY-28100 (cis-isomer); BMY-28167 (trans- used similarly to cefaclor (p.217) in the treatment of
1. Valentini S, et al. In-vitro evaluation of cefpodoxime. J Antimi- susceptible infections, including upper and lower res-
crob Chemother 1994; 33: 495–508. isomer); Cefprozilo; Cefprozilum; Kefprotsiili; Sefprozil. (6R,7R)-
7-[(R)-2-Amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-(1- piratory-tract infections and skin and soft-tissue infec-
Pharmacokinetics propenyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tions, and should probably be classified as a second-
monohydrate; 7-(D-4-Hydroxyphenylglycylamino)-3-[(E)prop-1- generation cephalosporin.
Cefpodoxime proxetil is de-esterified in the intestinal
enyl]cephem-4-carboxylic acid monohydrate.
epithelium after oral doses, to release active cefpodox- Cefprozil is given orally as the monohydrate. Doses
Цефпрозил
ime in the bloodstream. Bioavailability is about 50% in are expressed in terms of the equivalent amount of an-
C 18 H 19N 3 O 5 S,H 2 O = 407.4.
fasting subjects and may be increased in the presence hydrous cefprozil; 523 mg of cefprozil monohydrate is
C AS — 92665-29-7 (anhydrous cefprozil); 121123-17-9
of food. Absorption is decreased in conditions of low equivalent to about 500 mg of anhydrous cefprozil.
(cefprozil monohydrate).
gastric acidity. Peak plasma concentrations of about ATC — J01DC10.
The usual adult dose is 500 mg daily (as a single dose
1.5, 2.5, and 4.0 micrograms/mL have been achieved 2 ATC Vet — QJ01DC10.
or in two divided doses), increased to 500 mg twice
to 3 hours after oral doses of 100, 200, and 400 mg cef- daily if necessary. Children may be given up to
podoxime respectively. About 20 to 30% of cefpodox- 20 mg/kg once or twice daily (to a maximum of
ime is bound to plasma proteins. The plasma half-life HO 500 mg once daily, or twice daily if necessary for otitis
O
is about 2 to 3 hours and is prolonged in patients with H H media).
renal impairment. S For details of reduced dosage of cefprozil in patients
N
Cefpodoxime reaches therapeutic concentrations in the H with renal impairment, see below.
respiratory and genito-urinary tracts and bile. It has NH2 N
◊ Reviews.
been detected in low concentrations in breast milk. O CH3 1. Wiseman LR, Benfield P. Cefprozil: a review of its antibacterial
COOH activity, pharmacokinetic properties, and therapeutic potential.
Cefpodoxime is excreted unchanged in the urine. Drugs 1993; 45: 295–317.
Some is removed by dialysis. Pharmacopoeias. In US. 2. Barriere SL. Review of in vitro activity, pharmacokinetic char-
acteristics, safety, and clinical efficacy of cefprozil, a new oral
USP 31 (Cefprozil). pH of a 0.5% solution in water is between cephalosporin. Ann Pharmacother 1993; 27: 1082–9.
Uses and Administration 3.5 and 6.5. Store in airtight containers.
Administration in renal impairment. Doses of cefprozil
Cefpodoxime is a third-generation cephalosporin anti- should be reduced in patients with renal impairment; half the
biotic used similarly to cefixime (p.225) in the treat- Adverse Effects and Precautions standard dose should be given to patients with a creatinine clear-
ment of susceptible infections. It is given orally as the As for Cefalexin, p.218. ance of less than 30 mL/minute.
 Cefpodoxime Proxetil/Cefsulodin Sodium 233
Preparations radine can be painful and thrombophlebitis has oc- Patients undergoing chronic intermittent haemodialysis may be
USP 31: Cefprozil for Oral Suspension; Cefprozil Tablets. curred on intravenous injection. given a 250-mg dose at the start of the session, repeated after 6 to
12 hours, then again 36 to 48 hours after the initial dose, and
Proprietary Preparations (details are given in Part 3) Porphyria. Cefradine is considered to be unsafe in patients with again at the start of the next haemodialysis if more than 30 hours
Arg.: Ceprof; Austria: Procef†; Braz.: Cefzil; Canad.: Cefzil; Chile: porphyria although there is conflicting experimental evidence of
Procef†; Cz.: Cefzil; Gr.: Cefgram; Cefpro; Gramium; Procef; Zamalin; have elapsed since the previous dose.
Hong Kong: Procef; Hung.: Cefzil; India: Refzil-O; Indon.: Cefzil; Lizor; porphyrinogenicity. Further dosage modification may be required in children with re-
Ital.: Cronocef; Procef; Rozicel; Malaysia: Procef†; Mex.: Procef; nal impairment.
Philipp.: Procef; Pol.: Cefzil; Port.: Procef; Radacefe; S.Afr.: Prozef; Sin- Interactions
gapore: Procef†; Spain: Arzimol; Brisoral; Precef; Switz.: Procef; Thai.: Preparations
Procef; Turk.: Serozil; UK: Cefzil†; USA: Cefzil; Venez.: Procef. As for Cefalexin, p.218.
BP 2008: Cefradine Capsules; Cefradine Oral Suspension;
USP 31: Cephradine Capsules; Cephradine for Injection; Cephradine for
Antimicrobial Action Oral Suspension; Cephradine Tablets.
Cefquinome Sulfate (USAN, rINNM) As for Cefalexin, p.218. Proprietary Preparations (details are given in Part 3)
Belg.: Velosef; Chile: Velosef†; Fr.: Dexef; Kelsef†; Zeefra; Gr.: Tracilarin†;
Cefquinome, Sulfate de; Cefquinome Sulphate (BANM); Cefqui- Vethisel†; Hong Kong: Qualisef; Velosef; Zeefra; Indon.: Dynacef; Lovecef;
nomi Sulfas; HR-111V; Sulfato de cefquinoma. {6R-[6α,7β(Z)]}- Pharmacokinetics Velosef; Irl.: Velosef; Ital.: Cefrabiotic†; Ecosporina; Lisacef; Planocid†; Ma-
laysia: Sephros†; Mex.: Veracef; Neth.: Velosef; NZ: Velosef†; Philipp.:
1-[(7-{[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino}-2- Cefradine is rapidly and almost completely absorbed Cefralon; Gramcep; Racep; Sedinef; Senadex; Solphride; Tolzep; Vamosef;
carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]- from the gastrointestinal tract after oral doses. Doses of Velodyne; Yudinef; Zepdril; Pol.: Tafril; Port.: Biocefra; Cefalmin; Cefradur;
5,6,7,8,-tetrahydroquinolinium sulfate (1:1). Novacefrex†; Velosef†; S.Afr.: Bactocef†; Cefril; Ranfradin†; Spain: Septa-
0.25, 0.5, and 1 g given orally have produced peak cef; Velocef; UAE: Eskacef; Julphacef; UK: Nicef; Velosef; USA: Velosef†;
Цефхинома Сульфат plasma concentrations of about 9, 17, and Venez.: Cefracin†; Veracef.
C 23 H 24N 6 O 5 S 2 ,H 2 SO 4 = 626.7. 24 micrograms/mL respectively at 1 hour and are sim-
C AS — 84957-30-2 (cefquinome); 118443-89-3 (cefqui-
nome sulfate); 123766-80-3 (cefquinome sulfate). ilar to those achieved with cefalexin. Absorption is de-
layed by the presence of food although the total Cefsulodin Sodium (BANM, USAN, rINNM)
amount absorbed is not appreciably altered. Following Abbott-46811; Cefsulodina sódica; Cefsulodine Sodique; Cefsu-
H 3C intramuscular injection peak plasma concentrations of lodinnatrium; Cefsulodinum Natricum; CGP-7174E; Kefsulodiin-
O O inatrium; Natrii Cefsulodinum; SCE-129; Sulcephalosporin Sodi-
H H about 6 and 14 micrograms/mL have been obtained um. Sodium 3-(4-carbamoylpyridiniomethyl)-7-[(2R)-2-phenyl-
N S within 1 to 2 hours of doses of 0.5 and 1 g respectively.
N 2-sulphoacetamido]-3-cephem-4-carboxylate.
H Only about 8 to 12% is reported to be bound to plasma Натрий Цефсулодин
N N+ proteins. A plasma half-life of about 1 hour has been C 22 H 19 N 4 NaO 8 S 2 = 554.5.
N O C AS — 62587-73-9 (cefsulodin); 52152-93-9 (cefsulodin
reported; this is prolonged in patients with renal im-
S COO- sodium).
pairment. Cefradine is widely distributed to body tis- ATC — J01DD03.
NH2 sues and fluids, but does not enter the CSF in signifi- ATC Vet — QJ01DD03.
cant quantities. Therapeutic concentrations may be
(cefquinome) found in the bile. It crosses the placenta into the fetal
circulation and is distributed in small amounts into O
Profile breast milk. O
Cefquinome is a fourth-generation cephalosporin antibacterial S OH
used as the sulfate in veterinary medicine. Cefradine is excreted unchanged in the urine by
glomerular filtration and tubular secretion, over 90% O
of an oral dose or 60 to 80% of an intramuscular dose
HN O
being recovered within 6 hours. Peak urinary concen-
Cefradine (BAN, rINN) trations of about 3 mg/mL have been achieved after a
Cefradin; Cefradina; Cefradinas; Céfradine; Cefradinum; Cefra- 500-mg oral dose. Probenecid delays excretion. N O-
dyna; Cephradine (USAN); Kefradiini; Sefradin; SKF-D-39304; SQ-
Cefradine is removed by haemodialysis and peritoneal S
11436; SQ-22022 (cefradine dihydrate). (7R)-7-(α-D-Cy-
clohexa-1,4-dienylglycylamino)-3-methyl-3-cephem-4-carboxyl-
dialysis. O
ic acid. ◊ References.
Цефрадин 1. Wise R. The pharmacokinetics of the oral cephalosporins—a re-
view. J Antimicrob Chemother 1990; 26 (suppl E): 13–20. N+
C 16 H 19N 3 O 4 S = 349.4. 2. Schwinghammer TL, et al. Pharmacokinetics of cephradine ad-
C AS — 38821-53-3 (anhydrous cefradine); 31828-50-9 ministered intravenously and orally to young and elderly sub-
(non-stoichiometric cefradine hydrate); 58456-86-3 (cefra- jects. J Clin Pharmacol 1990; 30: 893–9.
dine dihydrate). H 2N
ATC — J01DB09. Uses and Administration
ATC Vet — QJ01DB09. Cefradine is a first-generation cephalosporin antibacte- O
rial given orally similarly to cefalexin (p.219) and by (cefsulodin)
the parenteral route similarly to cefazolin (p.222) in the
O treatment of susceptible infections and in the prophy- Pharmacopoeias. In Jpn.
H H laxis of infections during surgical procedures. Adverse Effects and Precautions
S
N Cefradine is given orally in doses of 1 to 2 g daily in 2 As for Cefalotin Sodium, p.219.
H to 4 divided doses to adults; up to 4 g daily may be giv- Sodium content. Each g of cefsulodin sodium contains about
NH2 N 1.8 mmol of sodium.
O CH3 en by this route. In severe infections it should be given
parenterally, by deep intramuscular injection or intra- Antimicrobial Action
COOH Cefsulodin is a bactericidal antibiotic with activity against Pseu-
venously by slow injection over 3 to 5 minutes or by
domonas aeruginosa as great as that of ceftazidime (p.234), but
Pharmacopoeias. In Chin., Eur. (see p.vii), and US (which al-
infusion, in doses of 2 to 4 g daily in 4 divided doses; no significant activity against other Gram-negative bacteria.
lows the anhydrous form, the monohydrate, or the dihydrate). up to 8 g daily may be given parenterally. Gram-positive bacteria and anaerobes are not very susceptible.
Ph. Eur. 6.2 (Cefradine). A white or slightly yellow, hygroscop- In children, the usual daily oral dose is 25 to 50 mg/kg Its activity against Ps. aeruginosa may be enhanced by
ic powder. Sparingly soluble in water; practically insoluble in al- in 2 to 4 divided doses, although 75 to 100 mg/kg daily aminoglycosides.
cohol and in n-hexane. A 1% solution in water has a pH of 3.5 to Cefsulodin is stable to hydrolysis by many beta-lactamases, but
6.0. Store at 2° to 8° in airtight containers. Protect from light.
may be given for otitis media. By injection, 50 to
emergence of resistant Ps. aeruginosa has been reported.
USP 31 (Cephradine). A white to off-white crystalline powder. 100 mg/kg daily may be given in 4 divided doses, in-
Sparingly soluble in water; very slightly soluble in alcohol and in creasing to 300 mg/kg daily in severe infections. Pharmacokinetics
Cefsulodin is given parenterally as the sodium salt. It has a plas-
chloroform; practically insoluble in ether. pH of a 1% solution in For surgical infection prophylaxis, 1 to 2 g may be giv- ma half-life of about 1.6 hours, which is prolonged in renal im-
water is between 3.5 and 6.0. Store in airtight containers.
en pre-operatively by intramuscular or intravenous in- pairment. Up to 30% of cefsulodin in the circulation is bound to
Incompatibility and stability. Commercially available injec- jection; subsequent parenteral or oral doses are given plasma proteins. Therapeutic concentrations have been reported
tions contain sodium carbonate or arginine as neutralisers. Injec- in a wide range of body tissues and fluids. The major route of
tions containing sodium carbonate are incompatible with solu-
as appropriate. excretion of cefsulodin is via the urine, mainly by glomerular fil-
tions such as compound sodium lactate injection that contain For details of reduced doses of cefradine in patients tration. Clearance may be enhanced in cystic fibrosis, although
calcium salts. with severe renal impairment, see below. there have been conflicting reports.
References.
Administration in renal impairment. Doses of cefradine ◊ References.
1. Wang Y-C J, Monkhouse DC. Solution stability of cephradine should be reduced in patients with severe renal impairment. The 1. Granneman GR, et al. Cefsulodin kinetics in healthy subjects af-
neutralized with arginine or sodium bicarbonate. Am J Hosp ter intramuscular and intravenous injection. Clin Pharmacol
Pharm 1983; 40: 432. following oral and parenteral doses are recommended in UK li-
Ther 1982; 31: 95–103.
2. Mehta AC, et al. Chemical stability of cephradine injection so- censed product information according to creatinine clearance 2. Reed MD, et al. Single-dose pharmacokinetics of cefsulodin in
lutions. Intensive Therapy Clin Monit 1988; 9: 195–6. (CC): patients with cystic fibrosis. Antimicrob Agents Chemother
• CC more than 20 mL/minute: 500 mg every 6 hours 1984; 25: 579–81.
Adverse Effects and Precautions 3. Hedman A, et al. Increased renal clearance of cefsulodin due to
• CC 5 to 20 mL/minute: 250 mg every 6 hours higher glomerular filtration rate in cystic fibrosis. Clin Pharma-
As for Cefalexin, p.218. Intramuscular injections of cef- • CC less than 5 mL/minute: 250 mg every 12 hours cokinet 1990; 18: 168–75.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
234 Antibacterials
Uses and Administration Ceftazidime is generally considered to be compatible with met- 2. Jackson GD, Berkovic SF. Ceftazidime encephalopathy: absence
Cefsulodin is a third-generation cephalosporin antibiotic with a ronidazole, but degradation of ceftazidime has been reported.5 status and toxic hallucinations. J Neurol Neurosurg Psychiatry
narrow spectrum of activity that has been used similarly to Precipitation has occurred with vancomycin6 and therefore the 1992; 55: 333–4.
ceftazidime (p.235) for the treatment of infections caused by sus- product information considers it prudent to flush giving sets and 3. Chow KM, et al. Retrospective review of neurotoxicity induced
by cefepime and ceftazidime. Pharmacotherapy 2003; 23:
ceptible strains of Pseudomonas aeruginosa. intravenous lines between giving the two drugs. However, in one 369–73.
It is given as the sodium salt by intravenous injection. Doses are study7 ceftazidime and/or vancomycin were stable in a glucose-
expressed in terms of the equivalent amount of cefsulodin; 1.04 g containing peritoneal dialysis solution when kept for 6 days in a Effects on the skin. References.
of cefsulodin sodium is equivalent to about 1 g of cefsulodin. refrigerator or 48 to 72 hours at room temperature, and in a fur- 1. Vinks SATMM, et al. Photosensitivity due to ambulatory intra-
The usual adult dose is 6 g daily in 4 divided doses; in less severe ther study8 the two drugs were stable when combined in similar venous ceftazidime in cystic fibrosis patient. Lancet 1993; 341:
solutions containing 1.5% or 4.25% glucose for up to 12 hours 1221–2.
infections daily doses of 3 to 4 g may be given. Children may be
given a usual dose of 100 mg/kg daily; 50 mg/kg daily may be when stored at 37° and for 24 hours when stored at 4° and 24°.
given in less severe infections. Ceftazidime and teicoplanin9 were stable in combination in a Interactions
peritoneal dialysis solution at 37° for 8 hours when it had been Unlike many other cephalosporins, probenecid has lit-
◊ References. previously stored at 4°, but not when previously stored at 25°.
1. Smith BR. Cefsulodin and ceftazidime, two antipseudomonal ce-
tle effect on the renal clearance of ceftazidime.
Ceftazidime was not stable when mixed in solution with amino-
phalosporins. Clin Pharm 1984; 3: 373–85. phylline.10 There was some evidence of possible incompatibility ◊ References.
2. Wright DB. Cefsulodin. Drug Intell Clin Pharm 1986; 20: with pentamidine.11
845–9. 1. Verhagen CA, et al. The renal clearance of cefuroxime and
1. Elliott TSJ, et al. Stability of gentamicin in combination with ceftazidime and the effect of probenecid on their tubular excre-
Administration in renal impairment. The dosage of cefsu- selected new β-lactam antibiotics. J Antimicrob Chemother tion. Br J Clin Pharmacol 1994; 37: 193–7.
lodin given intravenously should be adjusted in patients with re- 1984; 14: 668–9.
nal impairment according to creatinine clearance (CC): 2. Elliott TSJ, et al. Stability of tobramycin in combination with
selected new β-lactam antibiotics. J Antimicrob Chemother Antimicrobial Action
• CC 20 to 50 mL/minute: a loading dose of 1.5 g then 1 g every 1986; 17: 680–1. Ceftazidime has a bactericidal action and broad spec-
8 hours 3. Pennell AT, et al. Effect of ceftazidime, cefotaxime, and cefop-
erazone on serum tobramycin concentrations. Am J Hosp Pharm trum of activity similar to that of cefotaxime (p.228),
• CC 5 to 20 mL/minute: a loading dose of 1.5 g then 1 g every 1991; 48: 520–2.
12 hours 4. Mason NA, et al. Stability of ceftazidime and tobramycin sul-
but increased activity against Pseudomonas spp.; it is
• CC less than 5 mL/minute: a loading dose of 1.5 g then 1 g fate in peritoneal dialysis solution. Am J Hosp Pharm 1992; 49: less active against staphylococci and streptococci. Un-
1139–42. like cefotaxime it has no active metabolite.
every 24 hours 5. Messerschmidt W. Pharmazeutische kompatibilität von ceftazi-
In patients undergoing haemodialysis, 1 g is given before and af- dim und metronidazol. Pharm Ztg 1990; 135: 36–8. Ceftazidime is highly stable to hydrolysis by most
ter dialysis. 6. Cairns CJ, Robertson J. Incompatibility of ceftazidime and van-
comycin. Pharm J 1987; 238: 577. beta-lactamases. It is active in vitro against many
Preparations 7. Vaughan LM, Poon CY. Stability of ceftazidime and vancomy- Gram-negative bacteria including Pseudomonas aeru-
cin alone and in combination in heparinized and nonheparinized
Proprietary Preparations (details are given in Part 3) peritoneal dialysis solution. Ann Pharmacother 1994; 28: ginosa, Burkholderia pseudomallei (Pseudomonas
Fr.: Pyocefal; Jpn: Takesulin. 572–6. pseudomallei), and Enterobacteriaceae including Cit-
8. Stamatakis MK, et al. Stability of high-dose vancomycin and
ceftazidime in peritoneal dialysis solutions. Am J Health-Syst robacter and Enterobacter spp., Escherichia coli,
Pharm 1999; 56: 246–8. Klebsiella spp., both indole-positive and indole-nega-
9. Manduru M. et al. Stability of ceftazidime sodium and teico-
Ceftazidime (BAN, USAN, rINN) planin sodium in a peritoneal dialysis solution. Am J Health- tive Proteus, Providencia, Salmonella, Serratia, and
Syst Pharm 1996; 53: 2731–4. Shigella spp. and Yersinia enterocolitica. Other sus-
Ceftazidim; Ceftazidim pentahydrát; Ceftazidima; Ceftazidimas; 10. Pleasants RA, et al. Compatibility of ceftazidime and amino-
Ceftazidimum; Ceftazidimum Pentahydricum; Ceftazydym; GR- phylline admixtures for different methods of intravenous infu- ceptible Gram-negative bacteria include Haemophilus
20263; Keftatsidiimi; LY-139381; Seftazidim. (Z)-(7R)-7-[2-(2- sion. Ann Pharmacother 1992; 26: 1221–6. influenzae, Moraxella catarrhalis (Branhamella ca-
11. Lewis JD. El-Gendy A. Cephalosporin-pentamidine isethionate
Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetami- incompatibilities. Am J Health-Syst Pharm 1996; 53: 1462–3. tarrhalis), and Neisseria spp. Among Gram-positive
do]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate pentahy- Stability. References.
bacteria it is active against some staphylococci and
drate. 1. Richardson BL, et al. The pharmacy of ceftazidime. J Antimi- streptococci, but meticillin-resistant staphylococci, en-
Цефтазидим crob Chemother 1981; 8 (suppl B): 233–6. terococci, and Listeria monocytogenes are generally
2. Brown AF, et al. Freeze thaw stability of ceftazidime. Br J
C 22 H 22 N 6 O 7 S 2 ,5H 2 O = 636.7. Parenter Ther 1985; 6: 43, 45, 50. resistant. Ceftazidime is active against some anaer-
C AS — 72558-82-8 (anhydrous ceftazidime); 78439-06- 3. Walker SE, Dranitsaris G. Ceftazidime stability in normal saline obes, although most strains of Bacteroides fragilis and
2 (ceftazidime pentahydrate). and dextrose in water. Can J Hosp Pharm 1988; 41: 65–6,
69–71. Clostridium difficile are resistant.
ATC — J01DD02. 4. Wade CS, et al. Stability of ceftazidime and amino acids in
parenteral nutrient solutions. Am J Hosp Pharm 1991; 48:
The activity of ceftazidime against Ps. aeruginosa and
ATC Vet — QJ01DD02.
1515–19. some Enterobacteriaceae may be enhanced by
5. Stiles ML, et al. Stability of ceftazidime (with arginine) and of aminoglycosides. Antagonism has been reported in vit-
cefuroxime sodium in infusion-pump reservoirs. Am J Hosp
S O Pharm 1992; 49: 2761–4. ro between ceftazidime and chloramphenicol.
H H 6. Stewart JT, et al. Stability of ceftazidime in plastic syringes and
H 2N S glass vials under various storage conditions. Am J Hosp Pharm Resistance. As with cefotaxime, resistance may devel-
N N 1992; 49: 2765–8. op during treatment due to the derepression of chromo-
H + 7. Nahata MC, et al. Stability of ceftazidime (with arginine) stored
N N N in plastic syringes at three temperatures. Am J Hosp Pharm somally mediated beta-lactamases. It has been noted
O O 1992; 49: 2954–6. particularly in Pseudomonas spp. and in Enterobacte-
− 8. Bednar DA, et al. Stability of ceftazidime (with arginine) in an
COO elastomeric infusion device. Am J Health-Syst Pharm 1995; 52: riaceae including Citrobacter, Enterobacter spp. and
HOOC CH3
CH3 1912–14. Proteus vulgaris. Resistance may also occur due to the
9. van Doorne H, et al. Ceftazidime degradation rates for predict-
ing stability in a portable infusion-pump reservoir. Am J Health- production of plasmid-mediated extended-spectrum
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. Syst Pharm 1996; 53: 1302–5. beta-lactamases, particularly in Klebsiella spp. and E.
Ph. Eur. 6.2 (Ceftazidime). A white or almost white crystalline 10. Stendal TL, et al. Drug stability and pyridine generation in
ceftazidime injection stored in an elastomeric infusion device. coli.
powder. Slightly soluble in water and in methyl alcohol; practi- Am J Health-Syst Pharm 1998; 55: 683–5.
cally insoluble in alcohol and in acetone; it dissolves in acid and 11. Servais H, Tulkens PM. Stability and compatibility of ceftazi-
alkali solutions. A 0.5% solution in water has a pH of 3.0 to 4.0. dime administered by continuous infusion to intensive care pa- Pharmacokinetics
Store in airtight containers. tients. Antimicrob Agents Chemother 2001; 45: 2643–7. Ceftazidime is given by injection as the sodium salt or
USP 31 (Ceftazidime). A white to cream-coloured crystalline in solution with arginine. Mean peak plasma concen-
powder. Slightly soluble in water, in dimethylformamide, and in Adverse Effects and Precautions trations of 17 and 39 micrograms/mL have been re-
methyl alcohol; insoluble in alcohol, in acetone, in chloroform, As for Cefalotin Sodium, p.219. ported about 1 hour after intramuscular doses of 0.5
in dioxan, in ether, in ethyl acetate, and in toluene; soluble in al- Like cefotaxime (p.228), ceftazidime has the potential
kali and in dimethyl sulfoxide. pH of a 0.5% solution in water is and 1 g of ceftazidime, respectively. Five minutes after
between 3.0 and 4.0. Store in airtight containers. for colonisation and superinfection with resistant or- intravenous bolus injections of 0.5, 1, and 2 g of
ganisms. The risk of superinfection with, for example, ceftazidime, mean plasma concentrations of 45, 90,
Formulation. Ceftazidime for injection is available as a dry
powder containing ceftazidime with sodium carbonate. When re-
Staphylococcus aureus may be higher than with cefo- and 170 micrograms/mL, respectively, have been re-
constituted ceftazidime sodium is formed with the evolution of taxime, since ceftazidime is less active against staphy- ported. The plasma half-life of ceftazidime is about 2
carbon dioxide. An alternative formulation, ceftazidime with ar- lococci. hours, but this is prolonged in patients with renal im-
ginine, appears to overcome the problems associated with effer- pairment and in neonates. Clearance may be enhanced
Breast feeding. No adverse effects have been seen in breast-
vescence.1 In some countries a frozen injection containing
ceftazidime sodium is also used.
fed infants whose mothers were receiving ceftazidime, and the in patients with cystic fibrosis. It is about 10% bound
American Academy of Pediatrics considers1 that it is therefore to plasma proteins.
1. Stiles ML, et al. Gas production of three brands of ceftazidime. usually compatible with breast feeding.
Am J Hosp Pharm 1991; 48: 1727–9. Ceftazidime is widely distributed in body tissues and
1. American Academy of Pediatrics. The transfer of drugs and oth-
Incompatibility. It has been reported that ceftazidime does not er chemicals into human milk. Pediatrics 2001; 108: 776–89. fluids; therapeutic concentrations are achieved in the
cause decreased activity when incubated in solution with Correction. ibid.; 1029. Also available at:
h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l / CSF when the meninges are inflamed. It crosses the
gentamicin1 or tobramycin2 at 37°, or when mixed with tobramy-
cin in serum.3 Ceftazidime and tobramycin4 were also stable for
pediatrics%3b108/3/776 (accessed 25/05/04) placenta and is distributed into breast milk.
up to 16 hours at room temperature when combined in a glucose- Effects on the blood. References. Ceftazidime is passively excreted in bile, although
containing dialysis solution, and for a further 8 hours at 37°. 1. Hui CH, Chan LC. Agranulocytosis associated with cepha- only a small proportion is eliminated by this route. It is
However, licensed product information recommends that losporin. BMJ 1993; 307: 484.
ceftazidime, like most other beta lactams, should not be mixed
mainly excreted by the kidneys, almost exclusively by
Effects on the nervous system. References.
with an aminoglycoside in the same giving set or syringe because 1. Al-Zahawi MF, et al. Hallucinations in association with ceftazi-
glomerular filtration; probenecid has little effect on the
of the potential for inactivation of either drug. dime. BMJ 1988; 297: 858. excretion. About 80 to 90% of a dose appears un-
 Ceftazidime/Ceftibuten 235
changed in the urine within 24 hours. It is removed by ill children up to 150 mg/kg daily to a maximum of 6 g
haemodialysis and peritoneal dialysis. daily (9 g in cystic fibrosis with pseudomonal lung in-
fection) may be given in 3 divided doses. Neonates and H2N
Cystic fibrosis. References.
1. Leeder JS, et al. Ceftazidime disposition in acute and stable cyst- infants up to 2 months have been given 25 to 60 mg/kg S
ic fibrosis. Clin Pharmacol Ther 1984; 36: 355–62. daily in 2 divided doses. N
2. Hedman A, et al. Influence of the glomerular filtration rate on CH3
renal clearance of ceftazidime in cystic fibrosis. Clin Pharma- In the elderly the dose should generally not exceed 3 g
cokinet 1988; 15: 57–65. O
daily. H CH3
3. Vinks AATMM, et al. Continuous infusion of ceftazidime in N N H
cystic fibrosis patients during home treatment: clinical outcome, Although not licensed for nebulisation in the UK, the S
microbiology and pharmacokinetics. J Antimicrob Chemother N
1997; 40: 125–33. BNFC suggests a dose of 1 g inhaled twice daily for the O N
management of chronic Burkholderia cepacia (Pseu- N N
The elderly. References. N
domonas cepacia) infection in patients aged 1 month O
1. LeBel M, et al. Pharmacokinetics of ceftazidime in elderly vol-
unteers. Antimicrob Agents Chemother 1985; 28: 713–15. and older with cystic fibrosis.
2. Higbee MD, et al. Pharmacokinetics of ceftazidime in elderly HO O
patients. Clin Pharm 1989; 8: 59–62. For details of reduced doses in patients with renal im-
3. Sirgo MA, Norris S. Ceftazidime in the elderly: appropriateness pairment, see below. (cefteram)
of twice-daily dosing. DICP Ann Pharmacother 1991; 25:
284–8. For surgical infection prophylaxis in patients undergo- Pharmacopoeias. In Jpn.
Hepatic impairment. References. ing prostatic surgery, a dose of 1 g may be given at in-
Profile
1. El Touny M, et al. Pharmacokinetics of ceftazidime in patients duction of anaesthesia and repeated if necessary when Cefteram is a cephalosporin antibacterial used for the treatment
with liver cirrhosis and ascites. J Antimicrob Chemother 1991; the catheter is removed. of susceptible infections. It is given orally as the pivaloyloxyme-
28: 95–100.
thyl ester, cefteram pivoxil, and doses are expressed in terms of
Neonates. References. Ceftazidime can be used with an aminoglycoside, an- cefteram; 186 mg of cefteram pivoxil is equivalent to about
1. van den Anker JN, et al. Ceftazidime pharmacokinetics in pre- other beta lactam such as piperacillin, or vancomycin 150 mg of cefteram. The usual dose is 150 to 300 mg daily in 3
term infants: effects of renal function and gestational age. Clin in patients with severe neutropenia, or, if infection with divided doses after meals. For severe infections, up to 600 mg
Pharmacol Ther 1995; 58: 650–9. Bacteroides fragilis is suspected, with an antimicrobial daily may be given.
2. van den Anker JN, et al. Ceftazidime pharmacokinetics in pre-
term infants: effect of postnatal age and postnatal exposure to such as clindamycin or metronidazole. The drugs For reference to carnitine deficiency occurring after the adminis-
indomethacin. Br J Clin Pharmacol 1995; 40: 439–43. should generally be given separately (see also Incom- tration of some pivaloyloxymethyl esters, see Pivampicillin,
3. van den Anker JN, et al. Once-daily versus twice-daily adminis- p.317.
tration of ceftazidime in the preterm infant. Antimicrob Agents
patibility, above).
Chemother 1995; 39: 2048–50.
Preparations
◊ References. Proprietary Preparations (details are given in Part 3)
Renal impairment. References. Jpn: Tomiron.
1. Rains CP, et al. Ceftazidime: an update of its antibacterial activ-
1. Welage LS, et al. Pharmacokinetics of ceftazidime in patients ity, pharmacokinetic properties and therapeutic efficacy. Drugs
with renal insufficiency. Antimicrob Agents Chemother 1984; 1995; 49: 577–617.
25: 201–4.
2. Leroy A, et al. Pharmacokinetics of ceftazidime in normal and Administration in renal impairment. In patients with renal Ceftezole Sodium (rINNM)
uremic subjects. Antimicrob Agents Chemother 1984; 25: impairment the dosage of ceftazidime may need to be reduced.
638–42. Ceftezol sódico; Ceftézole Sodique; Natrii Ceftezolum. Sodium
After a loading dose of 1 g, maintenance doses are based on the
3. Ackerman BH, et al. Effect of decreased renal function on the (7R)-7-[2-(1H-tetrazol-1-yl)acetamido]-3-(1,3,4-thiadiazol-2-
pharmacokinetics of ceftazidime. Antimicrob Agents Chemother
creatinine clearance (CC):
ylthiomethyl)-3-cephem-4-carboxylate.
1984; 25: 785–6. • CC 31 to 50 mL/minute: 1 g every 12 hours
4. Lin N-S, et al. Single- and multiple-dose pharmacokinetics of Натрий Цефтезол
ceftazidime in infected patients with varying degrees of renal • CC 16 to 30 mL/minute: 1 g every 24 hours C 13 H 11 N 8 NaO 4 S 3 = 462.5.
function. J Clin Pharmacol 1989; 29: 331–7. C AS — 26973-24-0 (ceftezole); 41136-22-5 (ceftezole
5. Kinowski J-M, et al. Multiple-dose pharmacokinetics of ami-
• CC 6 to 15 mL/minute: 500 mg every 24 hours
sodium).
kacin and ceftazidime in critically ill patients with septic multi- • CC less than 5 mL/minute: 500 mg every 48 hours ATC — J01DB12.
ple-organ failure during intermittent hemofiltration. Antimicrob
Agents Chemother 1993; 37: 464–73. In severe infections these doses may need to be increased by ATC Vet — QJ01DB12.
6. Demotes-Mainard F, et al. Pharmacokinetics of intravenous and 50%. In these patients ceftazidime trough serum concentrations Pharmacopoeias. In Chin.
intraperitoneal ceftazidime in chronic ambulatory peritoneal di- should not exceed 40 micrograms/mL. In patients undergoing
alysis. J Clin Pharmacol 1993; 33: 475–9. peritoneal dialysis a loading dose of 1 g may be given followed Profile
by 500 mg every 24 hours; ceftazidime sodium may also be add- Ceftezole is a cephalosporin antibacterial with properties similar
Uses and Administration ed to the dialysis fluid, usually 125 to 250 mg of ceftazidime for to those of cefalotin (p.219). It is given as the sodium salt but
2 litres of dialysis fluid. In patients undergoing haemodialysis a doses are expressed in terms of the base; 1.05 g of ceftezole so-
Ceftazidime is a third-generation cephalosporin anti- dium is equivalent to about 1 g of ceftezole. The usual dose is 2
bacterial with enhanced activity against Pseudomonas loading dose of 1 g is given and then 0.5 to 1 g after each dialysis
period. to 4 g daily by intramuscular injection in 2 or 3 divided doses.
aeruginosa. It is used in the treatment of susceptible
Sodium content. Each g of ceftezole sodium contains about
infections especially those due to Pseudomonas spp. Preparations 2.16 mmol of sodium.
They include biliary-tract infections, bone and joint in- USP 31: Ceftazidime for Injection; Ceftazidime Injection. Preparations
fections, cystic fibrosis (respiratory-tract infections),
Proprietary Preparations (details are given in Part 3) Proprietary Preparations (details are given in Part 3)
endophthalmitis, infections in immunocompromised Ital.: Alomen.
patients (neutropenic patients), melioidosis, meningi- Arg.: Crima; Fortum; Pluseptic; Tinacef; Zidima; Austral.: Fortum; Austria:
Fortum; Kefazim; Belg.: Glazidim; Kefadim†; Braz.: Cefazima†; Cef-
tis, peritonitis, pneumonia, upper respiratory-tract in- tanorth†; Ceftazidon; Ceften; Cetaz; Fortaz; Intracef; Kefadim; Roycefax†;
fections, septicaemia, skin infections (including burns, Canad.: Ceptaz†; Fortaz; Tazidime†; Chile: Fortum; Kefzim†; Cz.: Fortum;
Kefadim†; Denm.: Fortum; Fin.: Glazidim; Fr.: Fortum; Fortumset; Ger.:
ecthyma gangrenosum, and ulceration), and urinary- Fortum; InfectoZidim; Gr.: Cefin; Ceftaridem; Ftazidime; Lemoxol; Malocef; Ceftibuten (BAN, USAN, rINN)
tract infections. It is also used for surgical infection Novocral; Septax; Sipiel; Solvetan; Hong Kong: Fortum; Hung.: Cetazime;
Fortum; India: Cefazid; Ceftaz; Ceftidin; Fortum; Zytaz; Indon.: Caltum; Ceftibutène; Ceftibuteno; Ceftibutenum; Keftibuteeni; 7432-S;
prophylaxis. For details of these infections and their Ceftum; Cetazum; Extimon; Fortum; Lacedim; Pharodime; Sodime; Thidim; Sch-39720. 7-[2-(2-Amino-1,3-thiazol-4-yl)-4-carboxyisocroton-
treatment, see under Choice of Antibacterial, p.162. Zefidim; Zibac; Zidifec; Irl.: Fortum; Israel: Fortum; Ital.: Cedizim; Ceftim; amide]-3-cephem-4-carboxylic acid.
Dizatec; Etazim; Fribat; Glazidim; Liotixil; Panzid; Spectrum; Starcef; Tazidif;
Administration and dosage. Ceftazidime is available as Tottizim; Malaysia: Cef-4; Fortum; Mex.: Fenit; Fortum; Izadima; Lezi- Цефтибутен
dim†; Tagal; Taloken; Taxifur; Zadolina; Zidicef; Neth.: Fortum; Tazalux; C 15 H 14 N 4 O 6 S 2 = 410.4.
the pentahydrate but it is formulated with sodium car- Norw.: Fortum; NZ: Fortum; Philipp.: Baxidyme; Dimzef; Fortum; Forzid;
bonate, to form the sodium salt in solution, or with ar- Tazicef; Tazidan; Tazidem; Uniranz; Zadim; Zeptrigen; Pol.: Biotum; Fortum; C AS — 97519-39-6.
Mirocef; Port.: Cefortam; Ceftazim; Zidimox; Rus.: Bestum (Бестум); For-
ginine. Doses are expressed in terms of anhydrous tum (Фортум); Lorazidime (Лоразидим); S.Afr.: Fortum; Kefzim†; Taziject; ATC — J01DD14.
ceftazidime; ceftazidime pentahydrate 1.16 g is equiv- Singapore: Cefazime; Fortum; Spain: Fortam; Kefamin; Swed.: Fortum; ATC Vet — QJ01DD14.
Switz.: Fortam; Thai.: CEF-4; Cef-Dime; Cefodime; Dimase; Fortadim;
alent to about 1 g of anhydrous ceftazidime. It is given Fortum; Forzid; Fournox†; Zeftam; Turk.: Fortum; Iesetum; UAE: Negacef;
by deep intramuscular injection, slow intravenous in- UK: Fortum; Kefadim; USA: Ceptaz; Fortaz; Tazicef; Tazidime; Venez.:
Betazidim; Biozidima; Cefgram; Fortum; Kesterina†. O
jection over 3 to 5 minutes, or intravenous infusion
over up to 30 minutes. The usual dose for adults ranges S OH
from 1 to 6 g daily in divided doses every 8 or 12 hours.
The higher doses are used in severe infections especial- Cefteram Pivoxil (rINNM) N NH
HO
ly in immunocompromised patients. In adults with Ceftéram, Pivoxil de; Cefteram pivoxilo; Cefterami Pivoxil; T-
cystic fibrosis who have pseudomonal lung infections, 2588. Pivaloyloxymethyl (Z)-7-[2-(2-aminothiazol-4-yl)-2-meth- O
O O
high doses of 90 to 150 mg/kg daily in 3 divided doses oxyiminoacetamido]-3-(5-methyl-2H-tetrazol-2-ylmethyl)-3-ce-
are used; up to 9 g daily has been given to those with phem-4-carboxylic acid. N S
normal renal function. Single doses of more than 1 g Цефтерама Пивоксил
should be given intravenously. C 22 H 27 N 9 O 7 S 2 = 593.6. H 2N
Children are usually given ceftazidime 30 to C AS — 82547-58-8 (cefteram); 82547-81-7 (cefteram
100 mg/kg daily in 2 or 3 divided doses, but in severely pivoxil). Pharmacopoeias. Jpn includes the dihydrate.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
236 Antibacterials
Adverse Effects and Precautions Ceftiofur Hydrochloride (BANM, USAN, rINNM) secretion as well as glomerular filtration and giving it
As for Cefalotin Sodium, p.219. Ceftiofur, Chlorhydrate de; Ceftiofuri Hydrochloridum; Hidro- with probenecid results in higher and more prolonged
The most frequently reported adverse effects of cefti- cloruro de ceftiofur; U-64279A. (6R,7R)-7-[2-(2-Amino-4-thia- plasma concentrations. Some ceftizoxime is removed
zolyl)-glyoxylamido]-3-mercaptomethyl-8-oxo-5-thia-1-azabicy- by haemodialysis.
buten are gastrointestinal disturbances, especially diar- clo[4.2.0]oct-2-ene-2-carboxylate, 72-(Z)-(O-methyloxime), 2-
rhoea, and headache. furoate (ester), monohydrochloride. Neonates. References.
1. Fujii R. Investigation of half-life and clinical effects of ceftizox-
Цефтиофура Гидрохлорид ime in premature and newborn infants. Drug Invest 1990; 2:
Antimicrobial Action C 19 H 17N 5 O 7 S 3 .HCl = 560.0. 143–9.
As for Cefixime, p.224. It is less active in vitro against C AS — 80370-57-6 (ceftiofur); 103980-44-5 (ceftiofur 2. Reed MD, et al. Ceftizoxime disposition in neonates and infants
hydrochloride). during the first six months of life. DICP Ann Pharmacother
Streptococcus pneumoniae. 1991; 25: 344–7.

◊ References. Uses and Administration

S O
1. Shawar R, et al. Comparative in vitro activity of ceftibuten (Sch- Ceftizoxime is a third-generation cephalosporin anti-
39720) against bacterial enteropathogens. Antimicrob Agents H 2N H
Chemother 1989; 33: 781–4. N HN S bacterial used similarly to cefotaxime (p.229) for the
2. Bragman SGL, Casewell MW. The in-vitro activity of ceftibuten N
treatment of susceptible infections.
against 475 clinical isolates of Gram-negative bacilli, compared N S
with cefuroxime and cefadroxil. J Antimicrob Chemother 1990;
O
O
O It is given as the sodium salt by deep intramuscular in-
25: 221–6. CH3 O jection, or intravenously as a slow injection over 3 to 5
3. Wise R, et al. Ceftibuten—in-vitro activity against respiratory HO O minutes or as a continuous or intermittent infusion. If
pathogens, β-lactamase stability and mechanism of action. J An- 2 g of ceftizoxime is injected intramuscularly the dose
timicrob Chemother 1990; 26: 209–13. (ceftiofur)
4. Maioli E, et al. In vitro activity of ceftibuten at sub-inhibitory
should be divided between sites.
concentrations in comparison with other antibiotics against res- Doses are expressed in terms of the equivalent amount
piratory and urinary tract pathogens. J Chemother 2007; 19: Ceftiofur Sodium (BANM, USAN, rINNM) of ceftizoxime; 1.06 g of ceftizoxime sodium is equiv-
152–60.
Ceftiofur sódico; Ceftiofur sodique; Ceftiofurum natricum; CM- alent to about 1 g of ceftizoxime. It is usually given in
31-916; Natrii Ceftiofurum; U-64279E. an adult dose of 1 to 2 g every 8 to 12 hours. In severe
Pharmacokinetics Натрий Цефтиофур
Ceftibuten is rapidly absorbed from the gastrointestinal infections 2 to 4 g may be given intravenously every 8
C 19 H 16N 5 NaO 7 S 3 = 545.5. hours; doses up to 2 g every 4 hours have been given in
tract, although the rate and extent of absorption are C AS — 104010-37-9.
somewhat decreased by the presence of food. Peak life-threatening infections.
Profile Children over 6 months of age may be given 50 mg/kg
plasma concentrations of about 17 micrograms/mL are Ceftiofur is a cephalosporin antibacterial used as the hydrochlo-
attained about 2 hours after a 400-mg dose. The plasma ride and sodium salts in veterinary practice. every 6 to 8 hours.
half-life of ceftibuten is about 2.0 to 2.3 hours and is For the treatment of uncomplicated urinary-tract infec-
prolonged in patients with renal impairment. Ceftib- tions, a dose of 500 mg every 12 hours is used.
uten is 65 to 77% bound to plasma proteins. For details of reduced doses in patients with renal im-
Ceftizoxime Sodium (BANM, USAN, rINNM) pairment, see below.
Ceftibuten distributes into middle-ear fluid and bron- Ceftizoxima sódica; Ceftizoxime Sodique; Ceftizoximnatrium;
chial secretions. About 10% of a dose is converted to A single intramuscular dose of 1 g has been given in
Ceftizoximum Natricum; FK-749; FR-13749; Keftitsoksiiminatri-
the trans-isomer, which has about one-eighth of the ac- um; Natrii Ceftizoximum; Seftizoksim Sodyum; SKF-88373-Z. uncomplicated gonorrhoea.
tivity of the cis-isomer. Ceftibuten is excreted mainly Sodium (Z)-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetami- ◊ References.
in the urine and also in the faeces. Significant amounts do]-3-cephem-4-carboxylate. 1. Richards DM, Heel RC. Ceftizoxime: a review of its antibacteri-
are removed by haemodialysis. al activity, pharmacokinetic properties and therapeutic use.
Натрий Цефтизоксим Drugs 1985; 29: 281–329.
C 13 H 12N 5 NaO 5 S 2 = 405.4.
Administration in renal impairment. Doses of ceftizoxime
Uses and Administration C AS — 68401-81-0 (ceftizoxime); 68401-82-1 (ceftizox- should be modified in renal impairment; after a loading dose of
Ceftibuten is a third-generation cephalosporin antibac- ime sodium). 0.5 to 1 g, the maintenance dosage should be adjusted according
terial used similarly to cefixime (p.225) in the treat- ATC — J01DD07. to creatinine clearance (CC) and the severity of the infection:
ment of urinary-tract and respiratory-tract infections. It ATC Vet — QJ01DD07. • CC 50 to 79 mL/minute: 0.5 to 1.5 g every 8 hours
is given orally as the dihydrate, but doses are expressed Pharmacopoeias. In Jpn and US. • CC 5 to 49 mL/minute: 0.25 to 1 g every 12 hours
in terms of anhydrous ceftibuten; 435 mg of ceftibuten USP 31 (Ceftizoxime Sodium). A white to pale yellow crystal- • CC less than 5 mL/minute: 250 to 500 mg every 24 hours or
line powder. Freely soluble in water. pH of a 10% solution in wa- 0.5 to 1 g every 48 hours, after dialysis.
dihydrate is equivalent to about 400 mg of anhydrous ter is between 6.0 and 8.0. Store in airtight containers.
ceftibuten. The usual adult dose is 400 mg once daily Preparations
Stability. References.
on an empty stomach. Children over 6 months of age 1. Lesko AB, et al. Ceftizoxime stability in iv solutions. DICP Ann
USP 31: Ceftizoxime for Injection; Ceftizoxime Injection.
and weighing 45 kg or less may be given 9 mg/kg daily Pharmacother 1989; 23: 615–18. Proprietary Preparations (details are given in Part 3)
Arg.: Ceftix†; Ceftizon†; Canad.: Cefizox; Cz.: Cefizox†; Fr.: Cefizox†; In-
as a single dose. For reduced doses in patients with dia: Cefizox; Indon.: Cefizox; Tizos; Ital.: Eposerin; Jpn: Epocelin†; Mex.:
moderate to severe renal impairment, see below. Adverse Effects and Precautions Cefizox†; Neth.: Cefizox; Philipp.: Tergecin; Unizox; Port.: Cefizox; Turk.:
Cefizox; USA: Cefizox.
As for Cefotaxime Sodium, p.228.
◊ Reviews.
Sodium content. Each g of ceftizoxime sodium contains
1. Wiseman LR, Balfour JA. Ceftibuten: review of its antibacterial
activity, pharmacokinetic properties and clinical efficacy. Drugs about 2.5 mmol of sodium. Ceftobiprole Medocaril (USAN, rINN)
1994; 47: 784–808.
BAL-5788; BAL-5788-001; BAL-9141 (ceftobiprole); Ceftobi-
2. Nelson JD, McCracken GH (eds). Ceftibuten: a new orally active Interactions prol Medocarilo; Ceftobiprole Médocaril; Ceftobiprolum Medo-
cephalosporin for pediatric infections. Pediatr Infect Dis J 1995; Probenecid reduces the renal clearance of ceftizoxime.
14 (suppl): S76–S133. carilum; Ro-65-5788; Ro-63-9141 (ceftobiprole). (6R,7R)-7-
3. Guay DRP. Ceftibuten: a new expanded-spectrum oral cepha- [(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)aceta-
losporin. Ann Pharmacother 1997; 31: 1022–33. Antimicrobial Action mido]-3-((E){(3′R)-1′-[(5-methyl-2-oxo-1,3-dioxol-4-yl)meth-
4. Owens RC, et al. Ceftibuten: an overview. Pharmacotherapy As for Cefotaxime Sodium, p.228, although ceftizoxi- oxycarbonyl]-2-oxo-(1,3′-bipyrrolidin)-3-ylidene}methyl)-8-oxo-
1997; 17: 707–20. me has no active metabolite. 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Administration in renal impairment. Doses of ceftibuten Цефтобипрол Медокарил
should be reduced in patients with moderate to severe renal im- Pharmacokinetics C 26 H 26N 8 O 11 S 2 = 690.7.
pairment. The following doses based on creatinine clearance After intramuscular injection of 0.5 and 1 g of ceftizox- C AS — 209467-52-7 (ceftobiprole); 376653-43-9 (cefto-
(CC) may be used: biprole medocaril); 252188-71-9 (ceftobiprole medocaril
ime, mean peak plasma concentrations of about 14 and sodium).
• CC 30 to 49 mL/minute: 200 mg once daily 39 micrograms/mL respectively have been reported af-
• CC 5 to 29 mL/minute: 100 mg once daily ter 1 hour. The plasma half-life of ceftizoxime is about
1.7 hours and is prolonged in neonates and in renal im- CO2H O
Patients undergoing haemodialysis 2 or 3 times weekly may be
pairment. Ceftizoxime is 30% bound to plasma pro- OH O
given a dose of 400 mg after each dialysis session. N N NH
teins. H N
N
Preparations Ceftizoxime is widely distributed in body tissues and
N
S
H
S H H
Proprietary Preparations (details are given in Part 3) fluids; therapeutic concentrations are achieved in the N O
Arg.: Cedax†; Sepex†; Austria: Caedax†; Cz.: Cedax†; Ger.: Keimax; Gr.: CSF when the meninges are inflamed. It crosses the H 2N
Caedax†; Hong Kong: Cedax; Hung.: Cedax; India: Procadax; Israel:
Cedax; Ital.: Cedax; Isocef; Jpn: Seftem; Malaysia: Cedax; Mex.: Cedax; placenta and low concentrations have been detected in
Neth.: Cedax; Philipp.: Cedax; Pol.: Cedax; Port.: Caedax; Rus.: Cedax breast milk. (ceftobiprole)
(Цедекс); S.Afr.: Cedax†; Sepexin†; Singapore: Cedax; Spain: Biocef;
Cedax; Cepifran†; Swed.: Cedax; Switz.: Cedax; Thai.: Cedax; USA: Nearly all of a dose is excreted unchanged in the urine Profile
Cedax; Venez.: Cedax; Sepexin†. within 24 hours of dosage, thus achieving high urinary Ceftobiprole is a broad-spectrum cephalosporin that is being
concentrations. Ceftizoxime is excreted by tubular tried in the treatment of susceptible infections, including meticil-
 Ceftiofur Hydrochloride/Ceftriaxone Sodium 237
lin-resistant Staphylococcus aureus. It is given as the medocaril urine. Isolated cases of death in term or premature ne- Effects on the pancreas. References.
derivative. onates have been associated with precipitation of calci- 1. Zimmermann AE, et al. Ceftriaxone-induced acute pancreatitis.
Ann Pharmacother 1993; 27: 36–7.
◊ References. um ceftriaxone in lungs and kidneys, and in some of 2. Maranan MC, et al. Gallstone pancreatitis caused by ceftriaxone.
1. Noel GJ. Clinical profile of ceftobiprole, a novel beta-lactam an- these cases a calcium-containing product has been giv- Pediatr Infect Dis J 1998; 17: 662–3.
tibiotic. Clin Microbiol Infect 2007; 13 (suppl 2): 25–9.
2. Murthy B, Schmitt-Hoffmann A. Pharmacokinetics and pharma- en by a different route or line, or at a different time. US Neonates. References to the displacement of bilirubin by
codynamics of ceftobiprole, an anti-MRSA cephalosporin with licensed product information therefore contra-indi- ceftriaxone in neonates.
broad-spectrum activity. Clin Pharmacokinet 2008; 47: 21–33. 1. Gulian J-M, et al. Bilirubin displacement by ceftriaxone in ne-
3. Zhanel GG, et al. Ceftobiprole: a review of a broad-spectrum and cates the use of ceftriaxone within 48 hours of products onates: evaluation by determination of ‘free’ bilirubin and eryth-
anti-MRSA cephalosporin. Am J Clin Dermatol 2008; 9: or solutions containing calcium, particularly in ne- rocyte-bound bilirubin. J Antimicrob Chemother 1987; 19:
245–54. 823–9.
4. Deresinski SC. The efficacy and safety of ceftobiprole in the
onates. Ceftriaxone is highly protein bound and is able
2. Fink S, et al. Ceftriaxone effect on bilirubin-albumin binding.
treatment of complicated skin and skin structure infections: evi- to displace bilirubin from albumin binding sites, caus- Pediatrics 1987; 80: 873–5.
dence from 2 clinical trials. Diagn Microbiol Infect Dis 2008; ing hyperbilirubinaemia; its use should be avoided in
61: 103–9. Sodium content. Each g of ceftriaxone sodium contains about
5. Anderson SD, Gums JG. Ceftobiprole: an extended-spectrum jaundiced neonates. 3.0 mmol of sodium.
anti-methicillin-resistant Staphylococcus aureus cephalosporin. Neutropenia has been reported with most cepha-
Ann Pharmacother 2008; 42: 806–16.
losporins; a complex mechanism has been attributed to Interactions
that associated with ceftriaxone. There have been rare Ceftriaxone has an N-methylthiotriazine side-chain
reports of fatal haemolysis associated with ceftriaxone. and may have the potential to increase the effects of
Ceftriaxone Sodium (BANM, USAN, rINNM) Although ceftriaxone has an N-methylthiotriazine ring anticoagulants and to cause a disulfiram-like reaction
Ceftriakson sodowy; Ceftriaksono natrio druska; Ceftriaxon sod- rather than an N-methylthiotetrazole side-chain, it with alcohol.
ná sůl trihemihydrát; Ceftriaxona sódica; Ceftriaxone sodique; might still have the potential to cause hypoprothrombi- Unlike many cephalosporins, probenecid does not af-
Ceftriaxonnatrium; Ceftriaxon-nátrium; Ceftriaxonum natricum; fect the renal excretion of ceftriaxone.
Ceftriaxonum Natricum Trihemihydricum; Keftriaksoninatrium;
naemia.
Natrii Ceftriaxonum; Ro-13-9904; Ro-13-9904/000 (ceftriax- Breast feeding. A study of drug distribution and protein bind- Antimicrobial Action
one); Seftriakson Sodyum. (Z)-7-[2-(2-Aminothiazol-4-yl)-2- ing between maternal blood and breast milk post partum in a 26-
year-old woman given ceftriaxone 2 g daily by intravenous infu- As for Cefotaxime Sodium, p.228, although ceftriax-
methoxyiminoacetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-
5-oxo-1,2,4-triazin-3-yl)thiomethyl]-3-cephem-4-carboxylic acid, sion for 10 days found that penetration of ceftriaxone into breast one has no active metabolite.
disodium salt, sesquaterhydrate. milk increased at these doses as protein binding capacity was sat- ◊ References.
urated, although no adverse effects occurred in the infant.1 The 1. Goldstein FW, et al. Resistance to ceftriaxone and other β-
Натрий Цефтриаксон authors advised caution in breast-feeding mothers given acidic lactams in bacteria isolated in the community. Antimicrob Agents
C 18 H 16N 8 Na 2 O 7 S 3 ,3 ⁄ H 2O = 661.6. drugs which also have high protein binding such as ceftriaxone1 Chemother 1995; 39: 2516–19.
C AS — 73384-59-5 (ceftriaxone); 74578-69-1 (anhy- although, on the basis that no adverse effects have been observed
drous ceftriaxone sodium); 104376-79-6 (ceftriaxone so- in breast-fed infants whose mothers were receiving ceftriaxone, Pharmacokinetics
dium sesquaterhydrate). the American Academy of Pediatrics considers2 that it is there-
fore usually compatible with breast feeding.
Ceftriaxone demonstrates nonlinear dose-dependent
ATC — J01DD04.
ATC Vet — QJ01DD04. 1. Bourget P, et al. Ceftriaxone distribution and protein binding be- pharmacokinetics because of its protein binding; about
tween maternal blood and milk postpartum. Ann Pharmacother 85 to 95% is bound to plasma proteins depending on
1993; 27: 294–7. the concentration of ceftriaxone.
2. American Academy of Pediatrics. The transfer of drugs and oth-
S O er chemicals into human milk. Pediatrics 2001; 108: 776–89. Mean peak plasma concentrations of about 40 and
H 2N H H Correction. ibid.; 1029. Also available at:
S CH3 h t tp : // a a pp o l ic y. a a p p u b li c a ti o n s. o rg / c g i /c on t e n t /f ul l /
80 micrograms/mL have been reported 2 hours after
N N
H pediatrics%3b108/3/776 (accessed 25/05/04) intramuscular injection of 0.5 and 1 g of ceftriaxone re-
N N S N spectively. The plasma half-life of ceftriaxone is not
O NH Effects on the biliary tract. Using abdominal ultrasonogra-
OCH3 phy, biliary sludge or pseudolithiasis was found in about 40% of dependent on the dose and varies between 6 and 9
COOH N
O severely ill children being treated with high doses of ceftriaxone1 hours; it may be prolonged in neonates. The half-life
and was later reported in adults.2-4 The sludge has been identified does not change appreciably in patients with moderate
O
as a calcium salt of ceftriaxone.5 Patients are often asymptomatic
and the sludge usually dissolves once ceftriaxone is stopped. renal impairment, but it may be prolonged in severe
(ceftriaxone) impairment especially when there is also hepatic im-
Gallstones with ceftriaxone as a major component have been
identified in a patient given long-term high-dose treatment.6 pairment.
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. Similarly, a bile-duct stone composed of ceftriaxone occurred
Ph. Eur. 6.2 (Ceftriaxone Sodium). A semi-synthetic product
Ceftriaxone is widely distributed in body tissues and
with high-dose ceftriaxone in a child.7 In another report, intrac-
derived from a fermentation product. An almost white to yellow- table hiccups were associated with ceftriaxone-related pseudo- fluids. It crosses both inflamed and non-inflamed me-
ish, slightly hygroscopic, crystalline powder. Freely soluble in lithiasis in a 10-year-old boy.8 ninges, generally achieving therapeutic concentrations
water; very slightly soluble in dehydrated alcohol; sparingly sol- 1. Schaad UB, et al. Reversible ceftriaxone-associated biliary pseu- in the CSF. It crosses the placenta and low concentra-
uble in methyl alcohol. A 12% solution in water has a pH of 6.0 dolithiasis in children. Lancet 1988; ii: 1411–13. tions have been detected in breast milk. High concen-
to 8.0. Store in airtight containers. Protect from light. 2. Pigrau C, et al. Ceftriaxone-associated biliary pseudolithiasis in
USP 31 (Ceftriaxone Sodium). A white to yellowish-orange adults. Lancet 1989; ii: 165. trations are achieved in bile.
crystalline powder. Freely soluble in water; very slightly soluble 3. Heim-Duthoy KL, et al. Apparent biliary pseudolithiasis during About 40 to 65% of a dose of ceftriaxone is excreted
ceftriaxone therapy. Antimicrob Agents Chemother 1990; 34:
in alcohol; sparingly soluble in methyl alcohol. pH of a 10% so- 1146–9. unchanged in the urine, principally by glomerular fil-
lution in water is between 6.0 and 8.0. Store in airtight containers. 4. Bickford CL, Spencer AP. Biliary sludge and hyperbilirubinemia tration; the remainder is excreted in the bile and is ulti-
associated with ceftriaxone in an adult: case report and review of
Incompatibility. UK licensed product information warns of in- the literature. Pharmacotherapy 2005; 25: 1389–95. mately found in the faeces as unchanged drug and
compatibility if ceftriaxone sodium is mixed with calcium-con- 5. Park HZ, et al. Ceftriaxone-associated gallbladder sludge: iden- microbiologically inactive compounds.
taining solutions or with aminoglycosides, amsacrine, flucona- tification of calcium-ceftriaxone salt as a major component of
zole, labetalol, or vancomycin. Published reports of gallbladder precipitate. Gastroenterology 1991; 100: 1665–70. ◊ Reviews.
incompatibility have included that between ceftriaxone and 6. Lopez AJ, et al. Ceftriaxone-induced cholelithiasis. Ann Intern 1. Hayton WL, Stoeckel K. Age-associated changes in ceftriaxone
vancomycin1 or pentamidine.2 Med 1991; 115: 712–14. pharmacokinetics. Clin Pharmacokinet 1986; 11: 76–86.
7. Robertson FM, et al. Ceftriaxone choledocholithiasis. Pediatrics 2. Yuk JH, et al. Clinical pharmacokinetics of ceftriaxone. Clin
1. Pritts D, Hancock D. Incompatibility of ceftriaxone with vanco- Pharmacokinet 1989; 17: 223–35.
mycin. Am J Hosp Pharm 1991; 48: 77. 1996; 98: 133–5.
8. Bonioli E, et al. Pseudolithiasis and intractable hiccups in a boy 3. Perry TR, Schentag JJ. Clinical use of ceftriaxone: a pharmacok-
2. Lewis JD, El-Gendy A. Cephalosporin-pentamidine isethionate inetic-pharmacodynamic perspective on the impact of minimum
incompatibilities. Am J Health-Syst Pharm 1996; 53: 1461–2. receiving ceftriaxone. N Engl J Med 1994; 331: 1532.
inhibitory concentration and serum protein binding. Clin Phar-
Stability. References. Effects on the blood. References. macokinet 2001; 40: 685–94.
1. Nahata MC. Stability of ceftriaxone sodium in peritoneal dialy- 1. Haubenstock A, et al. Hypoprothrombinaemic bleeding associ- Hepatic impairment. References.
sis solutions. DICP Ann Pharmacother 1991; 25: 741–2. ated with ceftriaxone. Lancet 1983; i: 1215–16.
2. Rey D, et al. Ceftriaxone-induced granulopenia related to a pe- 1. Stoeckel K, et al. Single-dose ceftriaxone kinetics in liver insuf-
2. Canton E, Esteban MJ. Stability of ceftriaxone solution. J Anti- ficiency. Clin Pharmacol Ther 1984; 36: 500–9.
microb Chemother 1992; 30: 397–8. culiar mechanism of granulopoiesis inhibition. Am J Med 1989;
87: 591–2. 2. Hary L, et al. The pharmacokinetics of ceftriaxone and cefotax-
3. Bailey LC, et al. Stability of ceftriaxone sodium in injectable ime in cirrhotic patients with ascites. Eur J Clin Pharmacol
solutions stored frozen in syringes. Am J Hosp Pharm 1994; 51: 3. Bernini JC, et al. Fatal hemolysis induced by ceftriaxone in a
child with sickle cell anemia. J Pediatr 1995; 126: 813–15. 1989; 36: 613–16.
2159–61. 3. Toth A, et al. Pharmacokinetics of ceftriaxone in liver-transplant
4. Plumridge RJ, et al. Stability of ceftriaxone sodium in polypro- 4. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. J
Pediatr 1995; 126: 816–17. recipients. J Clin Pharmacol 1991; 31: 722–8.
pylene syringes at −20, 4, and 20°C. Am J Health-Syst Pharm
1996; 53: 2320–3. 5. Scimeca PG, et al. Hemolysis after treatment with ceftriaxone. Pregnancy. References.
J Pediatr 1996; 128: 163.
6. Moallem HJ, et al. Ceftriaxone-related fatal hemolysis in an ad- 1. Bourget P, et al. Pharmacokinetics and protein binding of ceftri-
Adverse Effects and Precautions olescent with perinatally acquired human immunodeficiency vi- axone during pregnancy. Antimicrob Agents Chemother 1993;
rus infection. J Pediatr 1998; 133: 279–81. 37: 54–9.
As for Cefotaxime Sodium, p.228. 7. Meyer O, et al. Fatal immune haemolysis due to a degradation Renal impairment. The pharmacokinetics of ceftriaxone are
Changes in bowel flora may be more marked than with product of ceftriaxone. Br J Haematol 1999; 105: 1084–5.
not markedly altered in mild to moderate renal impairment,1 but
8. Viner Y, et al. Severe hemolysis induced by ceftriaxone in a
cefotaxime because of the greater biliary excretion of child with sickle-cell anemia. Pediatr Infect Dis J 2000; 19: the half-life can be prolonged in severe or end-stage renal dis-
ceftriaxone; diarrhoea may occur more often, especial- 83–5. ease.1-4 Ceftriaxone is generally not removed by peritoneal
ly in children. Biliary sludge or pseudolithiasis due to a 9. Seltsam A, Salama A. Ceftriaxone-induced immune haemoly- dialysis4 or by haemodialysis1-3 although a decrease in half-life
sis: two case reports and a concise review of the literature. In- has been reported during haemodialysis.5 In many patients no al-
precipitate of calcium ceftriaxone has been seen occa- tensive Care Med 2000; 26: 1390–4.
teration in dosage is necessary, but some individuals have re-
sionally in patients given ceftriaxone. Similarly, depo- 10. Citak A, et al. Ceftriaxone-induced haemolytic anaemia in a
child with no immune deficiency or haematological disease. J duced non-renal clearance despite apparently normal hepatic
sition of the calcium salt has occurred rarely in the Paediatr Child Health 2002; 38: 209–10. function.2,3 It is advisable to monitor plasma ceftriaxone in
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
238 Antibacterials
patients with severe renal impairment and unknown non-renal Zeftrix; Irl.: Rocephin; Israel: Keftriaxon; Rocephin; Triax; Ital.: Axobat; chloroform, in ether, and in ethyl acetate; soluble in methyl alco-
clearance. Bixon; Davixon; Daytrix; Deixim; Eftry; Fidato; Frineg; Iliaxone; Kappacef; hol. pH of a 10% solution in water is between 6.0 and 8.5. Store
Kocefan; Monoxar; Nilson; Panatrix; Pantoxon; Ragex; Rocefin; Setriox; Sir-
1. Patel IH, et al. Ceftriaxone pharmacokinetics in patients with tap; Valexime; Jpn: Rocephin; Malaysia: Cefaxone; Ceftrex; Eftriax; Me- in airtight containers.
various degrees of renal impairment. Antimicrob Agents Chem- sporin; Rocephin; Trixone; Mex.: Amcef; Aurofox; Axtar; Benaxona; Ce-
other 1984; 25: 438–42. faxona; Cefraden; Ceftrex; Ceftrilem; Centrifal; Limiprol; Megion; Primotox;
Incompatibility and stability. Cefuroxime sodium may be in-
2. Stoeckel K, et al. Single-dose ceftriaxone kinetics in functional- Rocephin; Tacex; Terbac; Triaken; Triox; Xonatil; Neth.: Elfaxone; Exogran; compatible with aminoglycosides.
ly anephric patients. Clin Pharmacol Ther 1983; 33: 633–41. Lopratin; Rocephin; Norw.: Rocephalin; NZ: Rocephin; Philipp.: Acrexon; References.
3. Cohen D, et al. Pharmacokinetics of ceftriaxone in patients with CEF-3; Cikedrix; Cryaxon; Eurosef; Fenadef; Forgram; Keptrix; Megion;
renal failure and in those undergoing hemodialysis. Antimicrob Monocrin; Noxoram; Pantrixon; Retrokor; Rocephin; Roxon; Samjizon; 1. Barnes AR. Chemical stabilities of cefuroxime sodium and met-
Agents Chemother 1983; 24: 529–32. Sergimax; Trixophin; Xtenda; Pol.: Biotrakson; Lendacin; Rocephin; Tartri- ronidazole in an admixture for intravenous infusion. J Clin
4. Ti T-Y, et al. Kinetic disposition of intravenous ceftriaxone in akson; Port.: Betasporina; Ceriax; Kemudin; Mesporin; Rocephin; Rus.: Pharm Ther 1990; 15: 187–96.
normal subjects and patients with renal failure on hemodialysis Azaran (Азаран); Ceftrifin (Цефтрифин); Ificef (Ифицеф); Lendacin 2. Stiles ML, et al. Stability of ceftazidime (with arginine) and of
or peritoneal dialysis. Antimicrob Agents Chemother 1984; 25: (Лендацин); Loraxone (Лораксон); Medaxone (Медаксон); Novosef cefuroxime sodium in infusion-pump reservoirs. Am J Hosp
83–7. (Новосеф); Oframax (Офрамакс); Stericef (Стерицеф); Tercef (Терцеф); Pharm 1992; 49: 2761–4.
5. Garcia RL, et al. Single-dose pharmacokinetics of ceftriaxone in Torocef (Тороцеф); S.Afr.: Fraxone†; Oframax; Rocephin; Rociject; Singa- 3. Hebron B, Scott H. Shelf life of cefuroxime eye-drops when dis-
patients with end-stage renal disease and hemodialysis. Chemo- pore: Antibacin; Cefaxone; Cefin†; Oframax; Rocephin; Trexofin; Tricefin; pensed in artificial tear preparations. Int J Pharm Pract 1993; 2:
therapy 1988; 34: 261–6. Spain: Rocefalin; Swed.: Rocephalin; Switz.: Rocephine; Thai.: CEF-3; 163–7.
Cef-Zone; Cefine†; Ceftrex; Ceftriphin; Lephin†; Oframax; Rinxofay; Roce-
phin; Sedalin†; Triacef; Tricephin; Trixone; Zefaxone; Turk.: Baktisef; Cefa-
Uses and Administration day; Cephaxon; Desefin; Equiceft; Forsef; Iesef; Nevakson; Novosef; Roce- Adverse Effects and Precautions
Ceftriaxone is a third-generation cephalosporin anti- phin; Unacefin; UAE: Triaxone; UK: Rocephin; USA: Rocephin; Venez.: As for Cefalotin Sodium, p.219.
Bioceftrax; Cefin; Cefix; Ceftrialin; Ciplacef; Eftrival; Feliden†; Megion; Roce-
bacterial used similarly to cefotaxime for the treatment phin; Strixone; Tricefi. Gastrointestinal disturbances, including diarrhoea,
of susceptible infections. They include chancroid, en- Multi-ingredient: India: Axone; Dibact†; Keftragard. nausea, and vomiting, have occurred in some patients
docarditis, gastro-enteritis (invasive salmonellosis; receiving cefuroxime axetil. There have been rare re-
shigellosis), gonorrhoea, Lyme disease, meningitis (in- ports of erythema multiforme, Stevens-Johnson syn-
cluding meningococcal meningitis prophylaxis), pneu- Cefuroxime (BAN, USAN, rINN) drome, and toxic epidermal necrolysis. Mild to moder-
monia, septicaemia, syphilis, typhoid fever, and Whip- ate hearing loss has been reported in some children
640/359; Cefuroxim; Cefuroxima; Céfuroxime; Cefuroximum;
ple’s disease. It is also used for surgical infection Kefuroksiimi; Sefuroksim. (Z)-3-Carbamoyloxymethyl-7-[2-(2-fu- given cefuroxime for the treatment of meningitis.
prophylaxis. For details of these infections and their ryl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid. Antibiotic-associated colitis. For reports of pseudomembra-
treatment, see under Choice of Antibacterial, p.162. Цефуроксим nous colitis associated with cefuroxime axetil, see Cefalotin,
Administration and dosage. Ceftriaxone is given as the C 16 H 16N 4 O 8 S = 424.4. p.219.
sodium salt by slow intravenous injection over at least C AS — 55268-75-2. Hypersensitivity. A report1 of a serum sickness-like reaction to
2 to 4 minutes, by intermittent intravenous infusion ATC — J01DC02. cefuroxime. Similar reactions have occurred with cefaclor
over at least 30 minutes, or by deep intramuscular in- ATC Vet — QJ01DC02; QJ51DA06. (p.217), although it is unclear whether they represent a class ef-
jection. If more than 1 g is to be injected intramuscular- fect.
ly then the dose should be divided between more than 1. Katta R, Anusuri V. Serum sickness-like reaction to cefuroxime:
a case report and review of the literature. J Drugs Dermatol
one site. Doses are expressed in terms of the equivalent O 2007; 6: 747–8.
amount of ceftriaxone; 1.19 g of ceftriaxone sodium is CH3
Porphyria. Cefuroxime is considered to be unsafe in patients
equivalent to about 1 g of ceftriaxone. The usual adult O with porphyria although there is conflicting experimental evi-
dose is 1 to 2 g daily as a single dose or in two divided N H H dence of porphyrinogenicity.
N S
doses; in severe infections up to 4 g daily may be giv- Sodium content. Each g of cefuroxime sodium contains about
en. Doses for infants and children (under 50 kg) are 20 O 2.2 mmol of sodium.
to 50 mg/kg once daily; for severe infections up to N O O
80 mg/kg daily may be given. In neonates, the maxi- O Interactions
mum dose should not exceed 50 mg/kg daily; intrave- NH2 Probenecid reduces the renal clearance of cefuroxime.
nous doses in neonates should be given over 60 min- O OH
utes. Doses above 50 mg/kg should be given by Antimicrobial Action
intravenous infusion only. Cefuroxime Axetil (BANM, USAN, rINNM) Cefuroxime is bactericidal and has a similar spectrum
A single intramuscular dose of 250 mg is recommend- CCI-15641; Cefuroksimas aksetilas; Cefuroksymu aksetyl; Ce-
of antimicrobial action and pattern of resistance to
ed for the treatment of uncomplicated gonorrhoea. furoxima axetilo; Cefuroximaxetil; Cefuroxim-axetil; Céfuroxime those of cefamandole (p.221). It is more resistant to hy-
For surgical infection prophylaxis, a single dose of 1 g axétil; Céfuroxime, Axétil de; Cefuroximi Axetilum; Cefuroxi- drolysis by beta-lactamases than cefamandole, and
may be given 0.5 to 2 hours before surgery; a 2-g dose mum axetili; Cefuroximum Axetilum; Kefuroksiimiaksetiili; Se- therefore may be more active against beta-lactamase-
is suggested before colorectal surgery. furoksim Aksetil. producing strains of, for example, Haemophilus influ-
Цефуроксима Аксетил enzae and Neisseria gonorrhoeae. However, treatment
For the prevention of secondary cases of meningococ- C 20 H 22N 4 O 10S = 510.5. failures have occurred in patients with H. influenzae
cal meningitis, a single intramuscular dose of 250 mg C AS — 64544-07-6.
ATC — J01DC02.
meningitis given cefuroxime and might be associated
may be used for adults and 125 mg for children.
ATC Vet — QJ01DC02. with a relatively high minimum bactericidal concentra-
◊ References. tion when compared with the minimum inhibitory con-
Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US.
1. Brogden RN, Ward A. Ceftriaxone: a reappraisal of its antibac-
terial activity and pharmacokinetic properties, and an update on Ph. Eur. 6.2 (Cefuroxime Axetil). A white or almost white pow- centration or with a significant inoculum effect. Re-
its therapeutic use with particular reference to once-daily admin- der. Slightly soluble in water and in alcohol; soluble in acetone, duced affinity of penicillin-binding proteins for
istration. Drugs 1988; 35: 604–45. in ethyl acetate, and in methyl alcohol. Store in airtight contain- cefuroxime has also been reported to be responsible for
2. Lamb HM, et al. Ceftriaxone: an update of its use in the manage- ers. Protect from light.
ment of community-acquired and nosocomial infections. Drugs USP 31 (Cefuroxime Axetil). A mixture of the diastereoisomers resistance in a beta-lactamase-negative strain of H. in-
2002; 62: 1041–89. fluenzae.
3. Bijie H, et al. In vitro activity, pharmacokinetics, clinical effica- of cefuroxime axetil. A white or almost white powder. The amor-
cy, safety and pharmacoeconomics of ceftriaxone compared with phous form is insoluble in water and in ether; slightly soluble in ◊ References.
third and fourth generation cephalosporins: review. J Chemother dehydrated alcohol; freely soluble in acetone; soluble in chloro- 1. Arditi M, et al. Cefuroxime treatment failure and Haemophilus
2005; 17: 3–24. form, in ethyl acetate, and in methyl alcohol. The crystalline influenzae meningitis: case report and review of literature. Pedi-
Administration in hepatic and renal impairment. A re- form is insoluble in water and in ether; slightly soluble in dehy- atrics 1989; 84: 132–5.
duction in dosage of ceftriaxone may be necessary in patients drated alcohol; freely soluble in acetone; sparingly soluble in 2. Mendelman PM, et al. Cefuroxime treatment failure of nontypa-
with severe renal impairment (creatinine clearance below chloroform, in ethyl acetate, and in methyl alcohol. Store in air- ble Haemophilus influenzae meningitis associated with altera-
tight containers. tion of penicillin-binding proteins. J Infect Dis 1990; 162:
10 mL/minute), in whom the daily dose should not exceed 2 g. 1118–23.
In patients undergoing dialysis, and in those with both renal and 3. Brown NM, et al. Cefuroxime resistance in Haemophilus influ-
hepatic impairment, plasma concentrations of ceftriaxone should Cefuroxime Sodium (BANM, rINNM) enzae. Lancet 1992; 340: 552.
be monitored to determine whether dose adjustment is needed. Cefuroksimo natrio druska; Cefuroksym sodowy; Cefuroxim
Preparations sodná sůl; Cefuroxima sódica; Céfuroxime sodique; Cefuroxim- Pharmacokinetics
BP 2008: Ceftriaxone Injection; natrium; Cefuroxim-nátrium; Cefuroximum natricum; Kefuroksi- Cefuroxime axetil is absorbed from the gastrointestinal
USP 31: Ceftriaxone for Injection; Ceftriaxone Injection. iminatrium; Natrii Cefuroximum; Sefuroksim Sodyum. tract and is rapidly hydrolysed in the intestinal mucosa
Proprietary Preparations (details are given in Part 3) Натрий Цефуроксим and blood to cefuroxime; absorption is enhanced in the
Arg.: Acantex; Bioteral; Cefomax; Ceftriaz†; Exempla; Rivacefin; Soltrimox; C 16 H 15N 4 NaO 8 S = 446.4.
Austral.: Rocephin; Austria: Exogran; Rocephin; Belg.: Rocephine; Braz.: presence of food. Peak plasma concentrations are
Amplospec†; Bioteral†; Ceft†; Ceftriax; Glicocef; Mesporan; Neoceftriona; C AS — 56238-63-2.
Prodoxin; Rocefin; Rofoxin†; Triaxon; Triaxton; Trioxina; Canad.: Rocephin; ATC — J01DC02. reported about 2 to 3 hours after an oral dose. The
Chile: Acantex; Grifotriaxona; Cz.: Cefaxone†; Lendacin; Longaceph†; ATC Vet — QJ01DC02. sodium salt is given by intramuscular or intravenous
Megion; Novosef†; Oframax†; Rocephin†; Samixon; Denm.: Cefotrix; Ro- Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. injection. Peak plasma concentrations of about
cephalin; Fin.: Rocephalin; Fr.: Rocephine; Ger.: Cefotrix; Rocephin; Gr.:
Antibacin; Azatyl; Bresec; Ceftrixon; Farcef; Gladius; Glorixone; Labilex; Ph. Eur. 6.2 (Cefuroxime Sodium). A white or almost white 27 micrograms/mL have been achieved 45 minutes af-
Medaxone; Rocephin; Rolisporin; Travilan; Ugotrex; Veracol; Hong Kong: slightly hygroscopic powder. Freely soluble in water; very slight- ter an intramuscular dose of 750 mg with measurable
Medaxonum; Mesporin; Rocephin; Hung.: Cefotrix; Lendacin; Megion; Ro- ly soluble in alcohol. A 1% solution in water has a pH of 5.5 to
cephin; India: Cefocef; Ciplacef; Lyceft; Monocef; Monotax; Oframax; Pow- 8.5. Store in airtight containers. amounts present 8 hours after a dose. Up to 50% of ce-
ercef; Stericef†; Indon.: Biotriax; Bioxon; Broadced; Brospec; Cefaxon; Ce- furoxime in the circulation is bound to plasma proteins.
friex; Ceftrox; Cefxon; Cephaflox; Criax; Ecotrixon; Elpicef; Erocef; Foricef; USP 31 (Cefuroxime Sodium). A white or faintly yellow pow-
Intrix; Rocephin; Socef; Starxon; Terfacef; Termicef; Tricefin; Trijec; Tyason; der. Freely soluble in water; very slightly soluble in alcohol, in The plasma half-life is about 70 minutes and is pro-
 Cefuroxime/Chloramphenicol 239
longed in patients with renal impairment and in ne- sites, has been used. A single 1-g oral dose of cefurox- Profile
onates. ime has been given for uncomplicated gonorrhoea. In Cethromycin is a ketolide antibacterial under investigation for
the treatment of susceptible respiratory-tract infections.
Cefuroxime is widely distributed in the body including each case an oral dose of probenecid 1 g may be given
with cefuroxime. ◊ References.
pleural fluid, sputum, bone, synovial fluid, and aque-
1. Dougherty TJ, Barrett JF. ABT-773: a new ketolide antibiotic.
ous humour, but only achieves therapeutic concentra- For surgical infection prophylaxis, the usual dose is Expert Opin Invest Drugs 2001; 10: 343–51.
tions in the CSF when the meninges are inflamed. It 1.5 g of cefuroxime intravenously before the proce- 2. Zhanel GG, et al. The ketolides: a critical review. Drugs 2002;
dure; this may be supplemented by 750 mg intramus- 62: 1771–1804.
crosses the placenta and has been detected in breast 3. Zhanel GG, et al. Ketolides: an emerging treatment for mac-
milk. cularly every 8 hours for up to 24 to 48 hours depend- rolide-resistant respiratory infections, focusing on S. pneumoni-
ing upon the procedure. For total joint replacement, ae. Expert Opin Emerg Drugs 2003; 8: 297–321.
Cefuroxime is excreted unchanged, by glomerular fil- 4. Reinert RR. Clinical efficacy of ketolides in the treatment of res-
tration and renal tubular secretion, and high concentra- 1.5 g of cefuroxime powder may be mixed with the piratory tract infections. J Antimicrob Chemother 2004; 53:
tions are achieved in the urine. On injection, most of a methylmethacrylate cement. 918–27.
5. Anonymous. Cethromycin: A-195773, A-195773-0, A-1957730,
dose of cefuroxime is excreted within 24 hours, the ◊ Reviews. Abbott-195773, ABT 773. Drugs R D 2007; 8: 95–102.
majority within 6 hours. Probenecid competes for renal 1. Perry CM, Brogden RN. Cefuroxime axetil: a review of its anti- 6. Hammerschlag MR, Sharma R. Use of cethromycin, a new ke-
bacterial activity, pharmacokinetic properties and therapeutic ef- tolide, for treatment of community-acquired respiratory infec-
tubular secretion with cefuroxime resulting in higher ficacy. Drugs 1996; 52: 125–58. tions. Expert Opin Invest Drugs 2008; 17: 387–400.
and more prolonged plasma concentrations of cefurox- 2. Scott LJ, et al. Cefuroxime axetil: an updated review of its use in
ime. Small amounts of cefuroxime are excreted in bile. the management of bacterial infections. Drugs 2001; 61:
1455–1500.
Plasma concentrations are reduced by dialysis. Administration in renal impairment. Parenteral doses of Chloramphenicol (BAN, rINN)
cefuroxime may need to be reduced in renal impairment. Li-
Uses and Administration censed product information suggests the following doses based Chloramfenikol; Chloramfenikolis; Chloramphénicol; Chloram-
Cefuroxime is a second-generation cephalosporin anti- on creatinine clearance (CC): phenicolum; Chloranfenicol; Cloranfenicol; Klóramfenikol; Klor-
bacterial used in the treatment of susceptible infec- • CC 10 to 20 mL/minute: 750 mg twice daily amfenikol; Kloramfenikoli; Laevomycetinum. 2,2-Dichloro-N-
tions. These have included bone and joint infections, • CC less than 10 mL/minute: 750 mg once daily [(αR,βR)-β-hydroxy-α-hydroxymethyl-4-nitrophenethyl]aceta-
Patients undergoing haemodialysis should receive an additional mide.
bronchitis (and other lower respiratory-tract infec-
750-mg dose following each dialysis; those undergoing continu- Хлорамфеникол
tions), gonorrhoea, meningitis (although treatment fail-
ous peritoneal dialysis may be given 750 mg twice daily. C 11 H 12 Cl 2 N 2 O 5 = 323.1.
ures have been reported in H. influenzae meningitis),
Preparations C AS — 56-75-7.
otitis media, peritonitis, pharyngitis, sinusitis, skin in-
BP 2008: Cefuroxime Axetil Tablets; Cefuroxime Injection; ATC — D06AX02; D10AF03; G01AA05; J01BA01;
fections (including soft-tissue infections), and urinary- S01AA01; S02AA01; S03AA08.
USP 31: Cefuroxime Axetil for Oral Suspension; Cefuroxime Axetil Tab-
tract infections. It is also used for surgical infection lets; Cefuroxime for Injection; Cefuroxime Injection. ATC Vet — QD06AX02; QD10AF03; QG01AA05;
prophylaxis. For details of these infections and their Proprietary Preparations (details are given in Part 3) QJ01BA01; QJ51BA01; QS01AA01; QS02AA01;
treatment, see under Choice of Antibacterial, p.162. Arg.: Ceflux†; Cefogram†; Cefurox; Deltrox†; Ligramex†; Austral.: Zinnat; QS03AA08.
Austria: Curocef; Furoxim; Zinnat; Belg.: Axetine; Cefurim; Doccefuro;
Administration and dosage. Cefuroxime is given orally Kefurox†; Zinacef; Zinnat; Braz.: Cefunorth†; Cefuran†; Medcef; Zinacef;
Zinnat; Canad.: Ceftin; Kefurox†; Zinacef; Chile: Curocef; Zinnat; Cz.: Ax-
as the acetoxyethyl ester, cefuroxime axetil, in the form etine; Lifurox†; Xorimax; Zinacef; Zinnat; Zinoxime; Denm.: Zinacef; Zin- OH Cl
of tablets or suspension with or after food, or by injec- nat; Fin.: Zinacef; Zinnat; Fr.: Cepazine; Zinnat; Ger.: Cefu; Cefudura; Ce- H
fuhexal; Cefurax; Cefuro-Puren; Cefurox-Wolff; Elobact; Zinacef†; Zinnat; N
tion as the sodium salt. Cefuroxime sodium may be Gr.: Anaptivan; Cefoprim†; Cefur; Cefuroprol; Cerofene; Ceruxim; Cupax; Cl
given by deep intramuscular injection, by slow intrave- Ecoline†; Feacef; Foucacillin; Fredyr; Furaxil; Galemin; Genephoxal; Gonif;
Interbion; Lyoprovir; Medoxem; Mevecan†; Mosalan; Nelabocin; Nipogalin;
nous injection over 3 to 5 minutes, or by intravenous Normafenac; Receant; Saxetil; Sedopan; Vekfazolin; Yokel; Zagorine; Zeta- O
infusion. Doses of cefuroxime axetil and cefuroxime gal; Zilisten; Zinacef; Zinadol; Hong Kong: Anikef; Axetine†; Zinacef; Zin- O2N OH
nat; Hung.: Cefurin; Ceroxim; Cexim†; Xorim; Xorimax; Zinacef; Zinnat;
sodium are expressed in terms of the equivalent India: Altacef; Cefasyn; Cefogen; Cefoxim; Forcef; Supacef; Indon.: An-
amount of cefuroxime; 1.20 g of cefuroxime axetil and bacim; Cefurox; Celocid; Cethixim; Kalcef; Kenacef; Oxtercid; Roxbi; Shar-
NOTE. CPL is a code approved by the BP 2008 for use on single
ox; Zinacef; Zinnat; Irl.: Ceftal; Zinacef; Zinnat; Israel: Cefurax; Kefurim; unit doses of eye drops containing chloramphenicol where the
1.05 g of cefuroxime sodium are each equivalent to Zinacef; Zinnat; Ital.: Biociclin; Biofurex†; Cefoprim; Cefumax†; Cefur†; individual container may be too small to bear all the appropriate
about 1 g of cefuroxime. Cefurex†; Cefurin; Colifossim†; Curoxim; Deltacef†; Duxima; Ipacef†; Ito- labelling information.
rex; Kefox†; Kesint; Lafurex; Oraxim; Supero; Tilexim; Zinnat; Zinocep;
Usual oral doses for adults are 125 mg twice daily for Zoref; Malaysia: Ceflour; Efurox; Furoxime; Zinacef; Zinnat; Zocef; Mex.: Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
uncomplicated urinary-tract infections and 250 to Cefagen; Cefuracet; Cetoxil; Froxal; Fucerox; Lemoxin†; Magnaspor; Nova- Viet.
dor; Ximaken; Xorufec; Zinnat; Neth.: Cefofix; Zinacef; Zinnat; Norw.: Zi- Ph. Eur. 6.2 (Chloramphenicol). A substance produced by the
500 mg twice daily for respiratory-tract infections. A nacef; NZ: Zinacef; Zinnat; Philipp.: Aeruginox; Cervin; Clovixime; Fubax- growth of certain strains of Streptomyces venezuelae, but now
dose for children more than 3 months of age is 125 mg yn; Furocef; Furocem; Furoxy; Infekor; Kefox; Keunzef; Laxinat; Loxatrel;
Panaxim; Profurex; Romicef; Ruxim; Sharox; Shincef; Unoximed; Xorimax; mainly prepared synthetically. A white, greyish-white or yellow-
twice daily or 10 mg/kg twice daily to a maximum of Zegen; Zinacef; Zinnat; Pol.: Biofuroksym; Bioracef; Ceroxim; Novocef; Of- ish-white, fine crystalline powder or fine crystals, needles, or
250 mg daily. Children over 2 years of age with otitis ramax; Plixym; Tarsime; Xorim; Xorimax; Zamur; Zinacef; Zinnat; Port.: elongated plates. Slightly soluble in water; freely soluble in alco-
Antibioxime; Cefaricida†; Cefofix; Cefrix†; Curoxime; Furaxetil†; Lusocef; hol and in propylene glycol. Protect from light.
media may be given 250 mg twice daily or 15 mg/kg Pluscef; Zipos; Zoref; Rus.: Axetine (Аксетин); Kefstar (Кефстар); Ketocef
(Кетоцеф); Zinacef (Зинацеф); Zinnat (Зиннат); S.Afr.: Cefasyn; Cefu- USP 31 (Chloramphenicol). Fine, white to greyish-white or yel-
twice daily to a maximum of 500 mg daily. lowish-white, needle-like crystals or elongated plates. Soluble 1
Hexal; Ceroxim; Cipofix†; Intracef; Lifurom†; Medaxime; Zefroxe; Zinacef;
By injection the usual adult dose is 750 mg of cefurox- Zinnat; Singapore: Bearcef; Ceftil; Shincef; Zinacef; Zinnat; Spain: Curoxi- in 400 of water; freely soluble in alcohol, in acetone, in ethyl ac-
ma; Lifurox†; Nivador; Selan; Zinnat; Swed.: Zinacef; Zinnat; Switz.: Ce- etate, and in propylene glycol. pH of a 2.5% suspension in water
ime every 8 hours but in more severe infections 1.5 g furim; Zinacef; Zinat; Thai.: Axetine†; Axurocef; Cefamar; Cefogen†; Ce-
may be given intravenously every 8, or in some cases furim; Farmacef; Furoxime; Magnaspor; Zinacef; Zinnat; Zonef; Turk.: is between 4.5 and 7.5. Its solutions are practically neutral to lit-
Aksef; Cefatin; Enfexia; Multisef; Oraceftin; Sefaktil; Sefuroks; Zinnat; UAE: mus. It is reasonably stable in neutral or moderately acid solu-
every 6, hours. Infants and children can be given 30 to Cefuzime; UK: Zinacef; Zinnat; USA: Ceftin; Zinacef; Venez.: Xorim; tions. Store in airtight containers.
60 mg/kg daily, increased to 100 mg/kg daily if neces- Zencef; Zinacef; Zinnat.
sary, given in 3 or 4 divided doses. Neonates may be Chloramphenicol Palmitate (BANM, rINNM)
given similar total daily doses but in 2 or 3 divided dos- Chloramfenikolio palmitatas; Chloramfenikol-palmitát; Chloram-
es. Cethromycin (USAN, rINN) fenikolu palmitynian; Chloramphenicol α-Palmitate; Chloram-
Adults with pneumonia or with acute exacerbations of A-195773; Abbott-195773; ABT-773; Céthromycine; Cethro- phénicol, palmitate de; Chloramphenicoli palmitas; Kloram-
chronic bronchitis may respond to sequential therapy mycinum; Cetromicina. (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4- fenikolipalmitaatti; Kloramfenikolpalmitat; Klóramfenikol-palmitát;
Ethyl-3a,7,9,11,13,15-hexamethyl-11-{[3-(quinolin-3-yl)prop-2- Palmitato de cloranfenicol; Palmitylchloramphenicol.
with parenteral cefuroxime 1.5 g twice daily or 750 mg enyl]oxy}-10-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hex-
twice daily respectively, followed by oral cefuroxime Хлорамфеникола Пальмитат
opyranosyl]oxy}octahydro-2H-oxacyclotetradecino[4,3-d]oxa-
500 mg twice daily in each case. C 27 H 42 Cl 2 N 2 O 6 = 561.5.
zole-2,6,8,14(1H,7H,9H)-tetrone.
C AS — 530-43-8.
For Lyme disease in adults, an oral dose of 500 mg is Цетромицин ATC — D06AX02; D10AF03; G01AA05; J01BA01;
given twice daily for 20 days. C 42 H 59 N 3 O 10 = 765.9. S01AA01; S02AA01; S03AA08.
For details of reduced dosage of cefuroxime in patients C AS — 205110-48-1. ATC Vet — QD06AX02; QD10AF03; QG01AA05;
QJ01BA01; QS01AA01; QS02AA01; QS03AA08.
with renal impairment, see below.
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
For the treatment of meningitis due to sensitive strains N O Viet.
of bacteria, cefuroxime is given intravenously in adult H CH3
H3C Ph. Eur. 6.2 (Chloramphenicol Palmitate). A fine, white or al-
doses of 3 g every 8 hours. Infants and children are giv- H most white, unctuous, powder. M.p. 87° to 95°. Chlorampheni-
en 200 to 240 mg/kg daily intravenously in 3 or 4 di- CH3 col palmitate shows polymorphism and the thermodynamically
O H stable form has low bioavailability following oral administra-
vided doses, which may be decreased to 100 mg/kg O
CH3 H 3C HN tion. Practically insoluble in water; sparingly soluble in alcohol;
daily after 3 days or when there is clinical improve- H freely soluble in acetone; very slightly soluble in hexane. Protect
ment. For neonates, a dose of 100 mg/kg daily, de- O O O O from light.
H 3C CH3 H CH3 H
creased to 50 mg/kg daily when indicated, may be N CH3 USP 31 (Chloramphenicol Palmitate). A fine, white, unctuous,
O O crystalline powder, having a faint odour. M.p. 87° to 95°. Insol-
used.
H CH3 uble in water; sparingly soluble in alcohol; freely soluble in ace-
In the treatment of gonorrhoea, a single dose of 1.5 g OH tone and in chloroform; soluble in ether; very slightly soluble in
by intramuscular injection, divided between 2 injection hexane. Store in airtight containers.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
240 Antibacterials
Chloramphenicol Sodium Succinate ducing the intestinal flora with consequent inhibition Ocular use. Ocular chloramphenicol is widely used in the UK
(BANM, rINNM) of vitamin K synthesis. Haemolytic anaemia has oc- for the treatment of superficial eye infections. In view of the po-
tential for serious toxicity, such as aplastic anaemia, after system-
Chloramfenikolio natrio sukcinatas; Chloramfenikol-sukcinát curred in some patients with the Mediterranean form of ic absorption some, particularly in the USA, have advised that its
sodná sůl; Chloramphenicol α-Sodium Succinate; Chloramphéni- glucose 6-phosphate dehydrogenase deficiency, but is ocular use should be restricted to situations where there is no al-
col, succinate sodique de; Chloramphenicoli natrii succinas; Klor- rare in patients with milder forms of the deficiency. ternative treatment.1 However, apart from patients with a person-
amfenikol Süksinat Sodyum; Klóramfenikol-hidrogénszukcinát- al or family history of blood dyscrasias, the use, particularly of
Peripheral as well as optic neuritis has been reported, short courses, was defended by several specialists in the UK,2-4
nátrium; Kloramfenikolinatriumsuksinaatti; Kloramfenikolnatrium-
succinat; Succinato sódico de cloranfenicol.
usually in patients treated over prolonged periods. Al- and the arguments have been the subject of several reviews.5-7
though ocular symptoms are often reversible if treat- Prospective case-control studies were considered necessary to
Хлорамфеникола Натрия Сукцинат clarify the risk.8 One such study,9 involving 145 patients with
ment is withdrawn early, permanent visual impairment
C 15 H 15 Cl 2 N 2 NaO 8 = 445.2. aplastic anaemia and 1226 controls, found that only 3 of the pa-
C AS — 982-57-0.
or blindness has occurred.
tients had been exposed to ocular chloramphenicol, and calculat-
ATC — D06AX02; D10AF03; G01AA05; J01BA01; Other neurological symptoms have included encepha- ed that the absolute risk was no more than 0.5 cases per million
S01AA01; S02AA01; S03AA08. lopathy with confusion and delirium, mental depres- treatment courses. Similarly, data10 from 2 other studies revealed
ATC Vet — QD06AX02; QD10AF03; QG01AA05; sion, and headache. Ototoxicity has also occurred, es- that none of 426 patients with aplastic anaemia and 7 of 3118
QJ01BA01; QS01AA01; QS02AA01; QS03AA08. controls had used chloramphenicol eye drops. In a survey11 of
pecially after the use of ear drops. patients who received prescriptions for chloramphenicol eye
Pharmacopoeias. In Eur. (see p.vii), Int., Jpn, US, and Viet.
Chin. includes Chloramphenicol Hydrogen Succinate. Hypersensitivity reactions including rashes, fever, and drops the risk of serious haematological toxicity was 3 per
Ph. Eur. 6.2 (Chloramphenicol Sodium Succinate). A white or angioedema may occur especially after topical use; an- 442 543 patients or 3 per 674 148 prescriptions.
yellowish-white hygroscopic powder. Very soluble in water; 1. Doona M, Walsh JB. Use of chloramphenicol as topical eye
aphylaxis has occurred but is rare. Jarisch-Herxheimer medication: time to cry halt? BMJ 1995; 310: 1217–18.
freely soluble in alcohol. A 25% solution in water has a pH of 6.4 reactions may also occur. Gastrointestinal symptoms 2. Mulla RJ, et al. Is it time to stop using chloramphenicol on the
to 7.0. Store in airtight containers. Protect from light. eye: fears are based on only six cases. BMJ 1995; 311: 450.
USP 31 (Chloramphenicol Sodium Succinate). A light yellow
including nausea, vomiting, and diarrhoea can follow 3. Buckley RJK, et al. Is it time to stop using chloramphenicol on
powder. Freely soluble in water and in alcohol. pH of a solution oral use. Disturbances of the oral and intestinal flora the eye: safe in patients with no history of blood dyscrasia. BMJ
may cause stomatitis, glossitis, and rectal irritation. Pa- 1995; 311: 450.
in water containing the equivalent of chloramphenicol 25% is 4. Hall AV, et al. Is it time to stop using chloramphenicol on the
between 6.4 and 7.0. Store in airtight containers. tients may experience an intensely bitter taste after rap- eye: risk is low in short courses. BMJ 1995; 311: 450–1.
id intravenous use of chloramphenicol sodium succi- 5. McGhee CNJ, Anastas CN. Widespread ocular use of topical
Incompatibility. Incompatibility or loss of activity has been re- chloramphenicol: is there justifiable concern regarding idiosyn-
ported between chloramphenicol and a wide variety of other sub- nate. cratic aplastic anaemia? Br J Ophthalmol 1996; 80: 182–4.
stances. Other factors, especially drug concentration, may play a 6. Rayner SA, Buckley RJ. Ocular chloramphenicol and aplastic
part and many incompatibilities are chiefly seen with concentrat- Aplastic anaemia. A review1 of the toxicity of chlorampheni- anaemia: is there a link? Drug Safety 1996; 14: 273–6.
ed solutions. col and related drugs, including the potential role of the p-nitro 7. Titcomb L. Ophthalmic chloramphenicol and blood dyscrasias:
group in producing aplastic anaemia, indicated that derivatives a review. Pharm J 1997; 258: 28–35.
such as thiamphenicol, which lack this grouping, are not associ- 8. Gordon-Smith EC, et al. Is it time to stop using chlorampheni-
Adverse Effects and Treatment ated with increased incidence of aplastic anaemia.
col on the eye: prospective study of aplastic anaemia should
give definitive answer. BMJ 1995; 311: 451.
Chloramphenicol may cause serious and sometimes 1. Yunis AA. Chloramphenicol: relation of structure to activity and 9. Laporte J-R, et al. Possible association between ocular chloram-
fatal adverse effects. Some of its toxicity is thought to toxicity. Ann Rev Pharmacol Toxicol 1988; 28: 83–100. phenicol and aplastic anaemia—the absolute risk is very low. Br
J Clin Pharmacol 1998; 46: 181–4.
be due to effects on mitochondrial protein synthesis. Overdosage. Charcoal haemoperfusion was found to be far su- 10. Wiholm B-E, et al. Relation of aplastic anaemia to use of chlo-
The most serious adverse effect of chloramphenicol is perior to exchange transfusion in the removal of chlorampheni- ramphenicol eye drops in two international case-control studies.
col from blood, although it did not prevent death in a 7-week-old BMJ 1998; 316: 666.
bone-marrow depression, which can take two different 11. Lancaster T, et al. Risk of serious haematological toxicity with
forms. The first is a fairly common dose-related revers- infant with the ‘grey syndrome’ after a dosage error.1 use of chloramphenicol eye drops in a British general practice
1. Freundlich M, et al. Management of chloramphenicol intoxica- database. BMJ 1998; 316: 667.
ible depression occurring usually when plasma- tion in infancy by charcoal hemoperfusion. J Pediatr 1983; 103:
chloramphenicol concentrations exceed 485–7. Porphyria. Chloramphenicol has been associated with acute at-
tacks of porphyria and is considered unsafe in porphyric patients.
25 micrograms/mL and is characterised by morpho-
logical changes in the bone marrow, decreased iron uti- Precautions Sodium content. Each g of chloramphenicol sodium succi-
Chloramphenicol is contra-indicated in patients with a nate represents about 2.2 mmol of sodium.
lisation, reticulocytopenia, anaemia, leucopenia, and
thrombocytopenia. This effect may be due to inhibition history of hypersensitivity or toxic reaction to the drug.
It should never be given systemically for minor infec-
Interactions
of protein synthesis in the mitochondria of bone mar- Chloramphenicol is inactivated in the liver and may,
row cells. tions or for prophylaxis. Repeated courses and pro-
therefore, interact with drugs that are metabolised by
The second and apparently unrelated form of bone- longed treatment should be avoided and it should not
hepatic microsomal enzymes. For example, chloram-
marrow toxicity is severe irreversible aplastic anaemia. be used in patients with pre-existing bone-marrow de-
phenicol enhances the effects of coumarin anticoagu-
This is fairly rare, with a suggested incidence of about pression or blood dyscrasias. Routine periodic blood
lants, such as dicoumarol and warfarin, some hypogly-
1:20 000 to 1:50 000, although the incidence varies examinations are advisable in all patients, but will not
caemics such as chlorpropamide and tolbutamide, and
throughout the world, and is not considered to be dose- warn of aplastic anaemia.
antiepileptics such as phenytoin. Conversely, the me-
related. The aplasia usually develops after a latent pe- Use of chloramphenicol with other drugs liable to de- tabolism of chloramphenicol may be increased by in-
riod of weeks or even months and has been suggested press bone-marrow function should be avoided. ducers of hepatic enzymes such as phenobarbital or ri-
to be the result of a nitrated benzene radical produced Reduced doses should be given to patients with hepatic fampicin. Some other interactions affecting the activity
in vivo. It is considered that there may be some genetic impairment. Excessive blood concentrations may also of chloramphenicol are discussed below.
or biochemical predisposition, but there is no way of occur after usual doses in patients with severe renal im- Chloramphenicol may decrease the effects of iron and
identifying susceptible patients. Although the majority pairment and in premature and full-term neonates who vitamin B12 in anaemic patients and has occasionally
of cases were after oral use, aplasia has also occurred have immature metabolic processes. Monitoring of impaired the action of oral contraceptives.
after intravenous and topical (eye drops) use of chlo- plasma-chloramphenicol concentrations may be desir- For the effects of chloramphenicol on the activity of
ramphenicol. Survival is most likely in those with early able in patients with risk factors. A suggested range other antibacterials, see Antimicrobial Action, below.
onset aplasia, but they may subsequently develop acute for peak plasma concentrations is 10 to
myeloid leukaemia. Antiepileptics. Serum concentrations of chloramphenicol are
25 micrograms/mL and for trough concentrations 5 to usually reduced by the hepatic enzyme induction that occurs
A toxic manifestation—the ‘grey syndrome’—charac- 15 micrograms/mL. with phenobarbital,1,2 and similar reductions have been reported
terised by abdominal distension, vomiting, ashen col- Neonates should never be given chloramphenicol sys- in a case study during phenytoin use.3 Conversely, elevated and
our, hypothermia, progressive pallid cyanosis, irregu- temically, unless it may be life-saving and there is no potentially toxic serum-chloramphenicol concentrations have re-
sulted during phenytoin use,2 apparently due to competition for
lar respiration, and circulatory collapse followed by alternative treatment, because of the risk of the ‘grey binding sites, although increased metabolism may alternatively
death in a few hours or days, has occurred in premature syndrome’. The use of chloramphenicol is probably lead to decreased serum-chloramphenicol concentrations.
and other newborn infants given large doses of chlo- best avoided during pregnancy. For reference to the effects of chloramphenicol on phenobarbital
ramphenicol. The syndrome is associated with high Chloramphenicol may interfere with the development and phenytoin, see p.493 and p.498, respectively.
plasma concentrations of chloramphenicol, due to re- of immunity and it should not be given during active
1. Bloxham RA, et al. Chloramphenicol and phenobarbitone—a
drug interaction. Arch Dis Child 1979: 54: 76–7.
duced capacity for glucuronidation and decreased immunisation. 2. Krasinski K, et al. Pharmacologic interactions among chloram-
glomerular filtration in children of this age, leading to phenicol, phenytoin and phenobarbital. Pediatr Infect Dis 1982;
drug accumulation. Recovery is usually complete if the Breast feeding. Chloramphenicol is distributed into breast 1: 232–5.
milk1 and the American Academy of Pediatrics2 considers that 3. Powell DA, et al. Interactions among chloramphenicol, pheny-
drug is withdrawn early enough after onset, but up to its use by mothers during breast feeding may be of concern, since toin, and phenobarbital in a pediatric patient. J Pediatr 1981; 98:
40% of infants with the full-blown syndrome may die. there have been reports of possible idiosyncratic bone-marrow 1001–3.
The syndrome has also been reported in infants born to suppression in the infant. Ciclosporin. For the effect of chloramphenicol on ciclosporin,
mothers given chloramphenicol in late pregnancy. A 1. Havelka J, et al. Excretion of chloramphenicol in human milk. see p.1825.
similar syndrome has been reported in adults and older Chemotherapy 1968; 13: 204–11. Cimetidine. Fatal aplastic anaemia of rapid onset has occurred
2. American Academy of Pediatrics. The transfer of drugs and oth- in 2 patients who received intravenous chloramphenicol and ci-
children given very high doses. er chemicals into human milk. Pediatrics 2001; 108: 776–89.
Correction. ibid.; 1029. Also available at: metidine.1,2 As there is usually a latent period of 2 weeks to 12
Prolonged oral use of chloramphenicol may induce h tt p : // a a p p o l ic y. a a p p u b li c a t i o ns . o rg / c g i /c on t e n t /f u l l / months before aplastic anaemia develops after chloramphenicol
bleeding, either by bone-marrow depression or by re- pediatrics%3b108/3/776 (accessed 25/05/04) therapy it is plausible that an additive or synergistic effect may
 Chloramphenicol 241
have occurred between the 2 drugs to cause bone-marrow toxic- ginosa is invariably resistant, although Burkholderia plasma protein. The half-life of chloramphenicol has
ity. (formerly Pseudomonas) spp. may be susceptible. been reported to range from 1.5 to 4 hours; the half-life
1. Farber BF, Brody JP. Rapid development of aplastic anemia after
intravenous chloramphenicol and cimetidine therapy. South Med Some Gram-negative anaerobes are susceptible, or is prolonged in patients with severe hepatic impair-
J 1981; 74: 1257–8. moderately so, including Bacteroides fragilis, Veillon- ment and is also much longer in neonates. Renal im-
2. West BC, et al. Aplastic anemia associated with parenteral chlo- pairment has relatively little effect on the half-life of
ramphenicol: review of 10 cases, including the second case of ella, and Fusobacterium spp.
possible increased risk with cimetidine. Rev Infect Dis 1988; 10: Other susceptible organisms include Actinomyces spp., the active drug, due to its extensive metabolism, but
1048–51.
Leptospira spp., spirochaetes such as Treponema palli- may lead to accumulation of the inactive metabolites.
Cyclophosphamide. For the effect of chloramphenicol on cy- dum, Chlamydiaceae, Mycoplasma spp., and Rickett- Chloramphenicol is excreted mainly in the urine but
clophosphamide, see p.703. only 5 to 10% of an oral dose appears unchanged; the
sia spp. Nocardia spp. are resistant. Chloramphenicol
Oral contraceptives. For the effect of chloramphenicol on is ineffective against fungi, protozoa, and viruses. remainder is inactivated in the liver, mostly by conju-
oral contraceptives, see Hormonal Contraceptives, p.2068. gation with glucuronic acid. About 3% is excreted in
Activity with other antimicrobials. As with other bacte-
Paracetamol. A report of an increase in chloramphenicol half- the bile. However, most is reabsorbed and only about
life from 3.25 to 15 hours when intravenous paracetamol was riostatic antimicrobials, the possibility exists of an an-
tagonistic effect if chloramphenicol is given with a 1%, mainly in the inactive form, is excreted in the fae-
given to 6 patients in intensive care 2 hours after intravenous
chloramphenicol1 has not been confirmed by subsequent studies bactericidal drug, and some antagonism has been dem- ces.
in patients receiving oral paracetamol. A study in 5 children onstrated in vitro between chloramphenicol and vari- The absorption, metabolism, and excretion of chloram-
found that the half-life of intravenous chloramphenicol was re- ous beta lactams and aminoglycosides, but the clinical phenicol are subject to considerable interindividual
duced from 3 to 1.2 hours, concomitant with an increase in clear- variation, especially in infants and children, making
ance, when oral paracetamol was given 30 minutes beforehand.2 significance of most of these interactions is usually
Furthermore, a study in 26 children found no evidence of altered held to be doubtful. Chloramphenicol may competi- monitoring of plasma concentrations necessary to de-
disposition when oral paracetamol was given to patients receiv- tively inhibit the effects of macrolides or lincosamides termine pharmacokinetics in a given patient.
ing intravenous chloramphenicol,3 and no significant change in such as clindamycin because of the adjacency of their
chloramphenicol pharmacokinetics was found in 5 patients given Uses and Administration
oral chloramphenicol and paracetamol.4
binding sites on the ribosome.
Resistance. Acquired resistance has been widely re- The risk of life-threatening adverse effects, particularly
1. Buchanan N, Moodley GP. Interaction between chloramphenicol
and paracetamol. BMJ 1979; 2: 307–8. ported, although the prevalence of resistance has tend- bone-marrow aplasia, has severely limited the clinical
2. Spika JS, et al. Interaction between chloramphenicol and aceta-
ed to decline where use of the drug has become less usefulness of chloramphenicol, although it is still wide-
minophen. Arch Dis Child 1986; 61: 1121–4. ly used in some countries. It should never be given sys-
3. Kearns GL, et al. Absence of a pharmacokinetic interaction be- frequent. The most commonly seen form of resistance
tween chloramphenicol and acetaminophen in children. J Pedi- has been the production of an acetyltransferase that in- temically for minor infections and regular blood counts
atr 1985; 107: 134–9. are usually advisable during treatment. The third-gen-
4. Stein CM, et al. Lack of effect of paracetamol on the pharmacok- activates the drug. Such resistance is usually plasmid-
inetics of chloramphenicol. Br J Clin Pharmacol 1989; 27: mediated and may be associated with resistance to oth- eration cephalosporins replaced chloramphenicol for
262–4.
er drugs such as the tetracyclines. Other mechanisms many of its former indications. There are consequently
Tacrolimus. For the effect of chloramphenicol on tacrolimus, that may reduce sensitivity to chloramphenicol include few unambiguous indications for the use of chloram-
see p.1845.
reduced permeability or uptake, and ribosomal muta- phenicol. It has been used in severe typhoid and other
tion. salmonellal infections, although it does not eliminate
Antimicrobial Action the carrier state. Chloramphenicol is an alternative to a
Chloramphenicol is a bacteriostatic antibiotic with a The actual incidence of resistance varies considerably third-generation cephalosporin in the treatment of bac-
broad spectrum of action against both Gram-positive in different countries and different centres. Epidemics terial meningitis, both empirically and against sensitive
and Gram-negative bacteria, as well as some other or- of chloramphenicol-resistant Salmonella and Shigella organisms such as Haemophilus influenzae. It may be
ganisms. spp. have occurred in the past, and although the preva- used as part of a multi-drug regimen for the treatment
Mechanism of action. Chloramphenicol is thought to lence of resistance in Salmonella spp. has been report- of inhalation and gastrointestinal anthrax. It has been
enter sensitive cells by an active transport process. ed to be negligible except in parts of South or South- used in the treatment of severe anaerobic infections,
Within the cell it binds to the 50S subunit of the bacte- east Asia, resistant salmonellal infections acquired in particularly in brain abscesses, and in infections below
rial ribosome at a site adjacent to the site of action of these regions are increasingly being seen elsewhere. the diaphragm where Bacteroides fragilis is often im-
the macrolides and clindamycin, and inhibits bacterial Resistance among Haemophilus and Neisseria spp. oc- plicated; however, other drugs are usually preferred.
protein synthesis by preventing attachment of amino- curs, and the latter may be problematic in developing Although the tetracyclines remain the treatment of
acyl transfer RNA to its acceptor site on the ribosome, countries, although it does not yet seem to be wide- choice in rickettsial infections such as typhus and the
thus preventing peptide bond formation by peptidyl spread. However, resistant strains of enterococci and spotted fevers, chloramphenicol is also used as an al-
transferase. The block in protein synthesis results in a pneumococci are reported to be relatively common in ternative where the tetracyclines cannot be given.
primarily bacteriostatic action, although it may be bac- some areas, and over 50% of staphylococcal strains
have been reported to show resistance in some hospi- Other bacterial infections in which chloramphenicol
tericidal to some organisms, including Haemophilus may be used as an alternative to other drugs include
influenzae, Neisseria meningitidis, and Streptococcus tals.
ehrlichiosis, severe gastro-enteritis (including Salmo-
pneumoniae, at higher concentrations. nella enteritis, cholera, and Yersinia enteritis), gas gan-
Pharmacokinetics
Spectrum of activity. Chloramphenicol has activity Chloramphenicol is readily absorbed when given by grene, granuloma inguinale, severe Haemophilus influ-
against many types of bacteria, although in most cases mouth. Blood concentrations of 10 micrograms/mL or enzae infections (for example in epiglottitis),
there are less toxic alternatives available. The follow- more may be reached about 1 or 2 hours after a single listeriosis, severe melioidosis, plague (especially if
ing pathogens are usually susceptible (but see also Re- oral dose of 1 g, and blood concentrations of about meningitis develops), pneumonia, psittacosis, Q fever,
sistance, below). 18.5 micrograms/mL have been reported after multiple tularaemia (especially when meningitis is suspected),
Gram-positive cocci including staphylococci such as 1-g doses. Chloramphenicol palmitate is hydrolysed to and Whipple’s disease. For details of these infections
Staph. epidermidis and some strains of Staph. aureus, chloramphenicol in the gastrointestinal tract prior to and their treatment, see under Choice of Antibacterial,
and streptococci such as Str., pneumoniae, Str. pyo- absorption, and the sodium succinate, which is given p.162.
genes, and the viridans streptococci. Meticillin-resist- parenterally, is probably hydrolysed to free drug main- Chloramphenicol is extensively used in the topical
ant staphylococci and Enterococcus faecalis are com- ly in the liver, lungs, kidneys, and plasma; such hydrol- treatment of ear and, in particular, eye infections, de-
monly found to be resistant. ysis may be incomplete in infants and neonates, con- spite the fact that many of these are mild and self-lim-
Other Gram-positive species including Bacillus an- tributing to the variable pharmacokinetics in this age iting. It is also used topically in the treatment of skin
thracis, Corynebacterium diphtheriae, and anaerobes group. Chloramphenicol sodium succinate is, even in infections.
such as Peptococcus and Peptostreptococcus spp. are adults, only partially and variably hydrolysed, so that When given orally, chloramphenicol is usually used as
usually susceptible. blood concentrations of chloramphenicol obtained af- capsules or as a suspension of chloramphenicol palmi-
Gram-negative cocci such as Neisseria meningitidis ter the sodium succinate parenterally are often lower tate. When oral use is not feasible, water-soluble chlor-
and N. gonorrhoeae are usually highly sensitive, as are than those obtained after oral chloramphenicol, with up amphenicol sodium succinate may be given intrave-
Haemophilus influenzae and a variety of other Gram- to 30% of a dose excreted unchanged in the urine be- nously, but oral therapy should be substituted as soon
negative bacteria including Bordetella pertussis, Bru- fore hydrolysis can take place (but see under Adminis- as possible; an intravenous dose should be injected
cella abortus, Campylobacter spp., Legionella pneu- tration, below). over at least 1 minute. Intramuscular injection is con-
mophila, Pasteurella, and Vibrio spp. The Enterobacte- Chloramphenicol is widely distributed in body tissues troversial because of doubts whether absorption is ad-
riaceae vary in their susceptibility, and many strains and fluids; it enters the CSF, giving concentrations of equate. In some countries chloramphenicol has been
have shown acquired resistance, but Escherichia coli, about 50% of those existing in the blood even in the given rectally.
and strains of Klebsiella spp., Proteus mirabilis, Sal- absence of inflamed meninges; it diffuses across the Doses are expressed in terms of chloramphenicol base
monella, Shigella, and Yersinia spp. have been reported placenta into the fetal circulation, into breast milk, and and are similar whether given orally or intravenously.
to be susceptible. Many strains of Enterobacter, in- into the aqueous and vitreous humours of the eye. It Chloramphenicol palmitate 1.7 g and chloramphenicol
dole-positive Proteus, and Serratia spp. are resistant, also enters the aqueous humour after topical applica- sodium succinate 1.4 g are each equivalent to about 1 g
or at best moderately susceptible. Pseudomonas aeru- tion. Up to about 60% in the circulation is bound to of chloramphenicol base.
The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
242 Antibacterials
For adults and children the usual dose is 50 mg/kg dai- for Injection; Chloramphenicol, Polymyxin B Sulfate, and Hydrocortisone and antifungal properties similar to those of clioquinol (p.254). It
Acetate Ophthalmic Ointment. is used topically in the treatment of dandruff and seborrhoeic der-
ly in divided doses every 6 hours; up to 100 mg/kg dai-
Proprietary Preparations (details are given in Part 3) matitis of the scalp. It has also been given orally in preparations
ly may be given in meningitis or severe infections due Arg.: A-Solmicina-C†; Anuar; Bio-Gelin†; Bioticaps; Chloromycetin; Farmi- for gastrointestinal disorders.
to moderately resistant organisms, although these high- cetina; Isopto Fenicol; Klonalfenicol; Pluscloran; Poenfenicol; Quemicetina;
Quotal NF†; Austral.: Chloromycetin; Chlorsig; Austria: Halomycetin; Choroxine is a component of halquinol (p.286).
er doses should be reduced as soon as possible. It has Kemicetin; Oleomycetin; Belg.: Isopto Fenicol; Kemicetina†; Braz.: Amplo-
been recommended that treatment should be continued biotic†; Arifenicol; Auridonal†; Clorafenil; Cloranfenil†; Farmicetina†; Feni- Preparations
after the patient’s temperature has returned to normal clor†; Fenicloran†; Neo Fenicol; Profenicol; Quemicetina; Sintomicetina; Uni
Fenicol; Visalmin; Vixmicina; Canad.: Chloromycetin; Diochloram†; Pen- Proprietary Preparations (details are given in Part 3)
for a further 4 days in rickettsial diseases, and for 8 to tamycetin; Chile: Chloromycetin; Clorampast; Gemitin; Quemicetina†; Cz.: Endiaron; USA: Capitrol.
10 days in typhoid fever, to minimise the risk of re- Fin.: Chloromycetin; Oftan Akvakol; Oftan Chlora; Fr.: Cebenicol†; Ger.:
Aquamycetin-N†; Chloramsaar N†; Oleomycetin†; Paraxin; Posifenicol C; Multi-ingredient: Cz.: Endiform†; Triaderm; Triamcinolon Composi-
lapse. Thilocanfol C; Gr.: Chloranic; Ursa-Fenol; Hong Kong: Aristophen; Chlo- tum†; Triamcinolon E; Triamcinolon-Galena†; Ital.: Beben Clorossina.
ment†; Chloroph; Chlorsig; Europhenicol; Kemicetine; Spersanicol†; Vista-
Where there is no alternative to the use of chloram- Phenicol†; Xepanicol; Hung.: Chlorocid†; India: Biophenicol; Chloraxin;
phenicol, premature and full-term neonates may be Chloromycetin; Kemicetine Otological†; Kemicetine†; Paraxin; Reclor; Van-
mycetin; Vitamycetin; Indon.: Chloramex; Chlorbiotic; Cloramidina; Colain;
given daily doses of 25 mg/kg, in 4 divided doses, and Colme; Combicetin; Empeecetin; Enkacetyn; Fenicol; Ikamicetin; Isotic Sal- Chlorquinaldol (BAN, rINN)
full-term infants over the age of 2 weeks may be given micol; Kalmicetine; Kemicetine; Lanacetine; Licoklor; Microtina; Neopheni-
col; Palmicol; RECO; Ribocine; Spersanicol; Suprachlor; Xepanicol; Irl.: Chlorochinaldol; Chlorquinaldolum; Clorquinaldol; Kloorikinal-
up to 50 mg/kg daily, in 4 divided doses. Monitoring of Chloromycetin; Israel: Chloroptic; Chlorphenicol; Phenicol; Synthomycine; doli; Klorkinaldol. 5,7-Dichloro-2-methylquinolin-8-ol.
plasma concentrations is essential to avoid toxicity. Ital.: Chemicetina; Cloramfen†; Mycetin; Sificetina; Vitamfenicolo; Malay-
sia: Beaphenicol; Nicol; Spersanicol†; Xepanicol†; Mex.: Abefen; Alcan†; Хлорхинальдол
In patients with hepatic impairment or severe renal im- Bariclor; Brocil; Chloromycetin; Clomicin; Clorafen; Cloramed; Cloramfeni;
Clorampler; Cloran; Cloranmicron; Clorazin; Clordil; Clorfenil; Clorofunon; C 10 H 7 Cl 2 NO = 228.1.
pairment, the dose of chloramphenicol may need to be Clorotan; Diarman; Dilclor; Estreptopal; Exacol; Fenicol; Fenisol; Fenizzard; C AS — 72-80-0.
reduced because of decreased metabolism or excretion. Lebrocetin; Leclor A; Naxo; Oftadil; Omycet; Palcol; Palmiclor; Palmifer;
Palmisol; Procloril; Pronicol; Quemicetina; Uniclor; Vixin†; Neth.: Globeni- ATC — D08AH02; G01AC03; P01AA04; R02AA11.
In the treatment of eye infections, chloramphenicol is col†; NZ: Chloromycetin; Chlorsig; Isopto Fenicol†; Philipp.: Anphechlor; ATC Vet — QD08AH02; QG01AC03; QR02AA11.
Aphrenil; Biomycetin; Chloro-S; Chloromycetin; Chlorsig; Clovicol; Esnicol;
usually applied as a 0.5% solution or as a 1% ointment. Fen-Alcon; Forastrol; Genphenil; Gerafen; Kemicetine; Klorfen; Medimyce-
tin; Metrophenicol; Oliphenicol; Optomycin; Pediachlor; Penachlor; Pol.:
For bacterial infections in otitis externa, chloramphen- Detreomycyna; Port.: Clorocil; Dermimade Cloranfenicol; Fenoptic†; Mi- OH
icol has been given as ear drops in a strength of 5 or cetinoftalmina; Rus.: Synthomycin (Синтомицин); S.Afr.: Chloramex;
Chlorcol; Chloromycetin; Chloroptic†; Chlorphen; Lennacol; Spersanicol;
10%. Singapore: Beaphenicol†; Isopto Fenicol; Kemicetine; Spersanicol†; Vanaf-
Cl N CH3
Chloramphenicol has also been used in the form of oth- en-S†; Spain: Chemicetina; Chloromycetin†; Cloranfenic†; Normofenicol†;
Swed.: Chloromycetin; Switz.: Septicol; Spersanicol†; Thai.: Antibi-Otic;
er derivatives including the arginine succinate, the cin- Archifen; Chloracil; Chloramno; Chloroph; Chlorosin; Cogenate; Cogetine;
namate, the glycinate, the glycinate sulfate, the palmi- Fenicol†; Genercin; Kemicetine†; Koro†; Levomycetin; Mycochlorin; Nicol-
mycetin†; Opsaram†; Pharmacetin; Silmycetin; Synchlolim; Unison Oint-
toylglycolate, the pantothenate, the steaglate, the ment; Vanafen; Turk.: Armisetin; Kemicetine; Klorasuksinat; UK: Brochlor; Cl
stearate, and the hydrogen succinate. Chloromycetin; Golden Eye; Kemicetine; Optrex Infected Eyes; USA: Ak-
Chlor†; Chloromycetin; Chloroptic†; Venez.: Chloromycetin†; Cloftal; Clo-
ramfesa†; Quemicetina†. Pharmacopoeias. In Pol.
Administration. When parenteral use of chloramphenicol is
necessary the intravenous route is generally preferred, although Multi-ingredient: Arg.: Acnoxin; Antiflogol; Bioftal; Clorfibrase; Colirio Profile
the intramuscular route has been advocated. Adequate serum Antibiotico CNH; Esodar; Eubetal Biotic†; Fluoropoen; Iruxol; Klonovan; Chlorquinaldol is a halogenated hydroxyquinoline with proper-
Neocortizul; Oftal; Oftalmoflogol†; Poenbioptal; Quemicetina con Hidro-
concentrations after intramuscular injection have been report- cortisona; Quemicetina Nasal Compuesta; Vistacloran†; Austria: Cortison ties similar to those of clioquinol (p.254). It is mainly applied
ed,1,2 although this is contrary to the widely held belief that chlor- Kemicetin; Oleomycetin-Prednison; Belg.: De Icol; Braz.: Dermofibrin C†; topically in infected skin conditions and in vaginal infections.
amphenicol sodium succinate is poorly absorbed by this route. Dexaclor†; Dexafenicol; Epitezan; Fenidex; Fibrase; Fibrinase c/Cloranfeni-
Pain on injection was also claimed to be minimal.1 After a study col; Gino-Fibrase; Gyno Iruxol; Iruxol; Kollagenase com cloranfenicol; Nax- Preparations
ogin Composto; Oto-Biotic†; Otofenicol-D†; Otomicina; Otopen†; Ouvi-
in children with bacterial meningitis,3 treatment with intramus- donal; Procutan†; Regencel; Regenom; Sulnil; Canad.: Pentamycetin-HC; Proprietary Preparations (details are given in Part 3)
cular chloramphenicol for 2 or 3 days followed by oral therapy Chile: Cortifenol H†; Gemitin con Prednisolona; Naxogin Compositum; Hung.: Chlorosan†; Venez.: Agel†.
has been suggested, although a later study2 found that the intra- Otandrol; Sintoftona; Spersadex Comp†; Cz.: Betabioptal†; Spersadex
muscular route produced therapeutic concentrations when the Compositum; Denm.: Spersadex Comp; Fin.: Iruxol; Oftan C-C; Oftan Multi-ingredient: Arg.: Nerisona C; Braz.: Bi-Nerisona; Chile: Bi-
Dexa-Chlora; Fr.: Cebedexacol; Ger.: Aquapred; Berlicetin; Ichthoseptal; Nerisona; Cz.: Colposeptine†; Proctospre†; Denm.: Locoidol; Fin.: Loco-
oral route did not. However, it has been said4 that children de- Oleomycetin-Prednison†; Spersadex Comp†; Spersadexolin†; Gr.: Chlo- idol†; Fr.: Nerisone C; Ger.: Nerisona C†; Proctospre†; Hong Kong: Col-
scribe intramuscular chloramphenicol as amongst the worst rapred; Cortiphenol H; Dexachlor; Dispersadron-C; Geypirina; Nezefib; poseptine; Nerisone C; Indon.: Nerisona Combi; Irl.: Locoid C; Israel:
treatments they ever receive, and certainly much worse than the Spersadexoline†; Sulfachloramphenicol; Sulfanicole; Hong Kong: Chlomy- Multiderm; Ital.: Impetex; Nerisona C; Mex.: Bi-Nerisona; Norw.: Loco-
insertion of intravenous cannulae. P†; Chloram-D; Cortiphenol H; Eurodron; Ginetris†; Neo-Dex (Improved); idol; NZ: Locoid C; Nerisone C; Philipp.: Nerisona Combi; Pol.: Chlorchi-
Sonexa-C; Spersadex Comp; Spersadexoline†; Hung.: Chlorocid-H†; naldin H; Gynalgin; Laticort-CH; Port.: Locoid C†; Nerisona C; Trophosep-
1. Shann F, et al. Absorption of chloramphenicol sodium succinate Spersadex Comp†; India: Belmycetin-C; Candibiotic; Chlormixin; Chloro- tine; Rus.: Gynalgin (Гиналгин); Singapore: Nerisone C†; Spain:
after intramuscular administration in children. N Engl J Med mycetin Ear Drops; Cortison Kemicetine†; Dexosyn-C; Kemicetine An- Amplidermis; Claral Plus; Quinortar†; Switz.: Anginazol; Turk.: Colposep-
1985; 313: 410–14. tiozena; Kemicetine Otological†; Ocupol; Ocupol-D; Otek-AC+; Otek- tine; Impetex; Nerisona C; UK: Locoid C; Venez.: Binerisona.
2. Weber MW, et al. Chloramphenicol pharmacokinetics in infants AC†; Paraxin Ear†; Perfocyn; Pyrimon; Indon.: Chloramphecort; Chloram-
less than three months of age in the Philippines and The Gambia. phecort-H; Colsancetine; Gynoxa; Indoson; Kemiderm; Kloramixin; Klor-
Pediatr Infect Dis J 1999; 18: 896–901. amixin D; Klorfeson; Naxogin Complex; Otolin; Particol; Ramicort; Spersa-
3. Shann F, et al. Chloramphenicol alone versus chloramphenicol dex Comp; Israel: Phenimixin; Tarocidin; Tarocidin D; Threolone; Ital.:
plus penicillin for bacterial meningitis in children. Lancet 1985; Antibioptal; Betabioptal; Cloradex; Colbiocin; Cortison Chemicetina; Cos- Chlortetracycline (BAN, rINN)
ii 681–3. miciclina; Dexoline; Eubetal Antibiotico; Idracemi; Iruxol; Vasofen; Vitecaf;
Xantervit Antibiotico; Malaysia: De Icol; Spersadex Comp†; Spersadexo- Chlortétracycline; Chlortetracyclinum; Clortetraciclina; Kloor-
4. Coulthard MG, Lamb WH. Antibiotics: intramuscular or intrave- line; Mex.: Cloran Otico; Cloxona-O; Fibrase; Levodexan; Levofenil; Nispil;
nous? Lancet 1985; ii: 1015.
itetrasykliini; Klortetracyclin. (4S,4aS,5aS,6S,12aS)-7-Chloro-4-
Ofodex; Otalgan; Otifar; Otolone†; Poral; Pre Clor; Soldrin; Solfranicol; Sul-
fa Cloran; Trecloran; Ulcoderma; Norw.: Spersadex med kloramfenikol; dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-
Enterococcal infections. Chloramphenicol has been reported Philipp.: Dexanicol; Spersadex Compound; Port.: Cloranpectina†; Clor- pentahydroxy-6-methyl-1,11-dioxonaphthacene-2-carboxam-
to be effective against vancomycin-resistant Enterococcus fae- cor ticil†; Medrivas Antibiotico; Predniftalmina; Rus.: Candibiotic ide; 7-Chlorotetracycline.
cium.1-3 Although no significant effect of chloramphenicol on (Кандибиотик); Colbiocin (Колбиоцин); Cortomycetin (Кортомицетин);
mortality was found in one small study,4 a retrospective analysis5 Iruxol (Ируксол); Levomecol (Левомеколь); Levosin (Левосин); S.Afr.: Хлортетрациклин
Covomycin; Covomycin-D; Covotop; Spersacet C†; Spersadex Comp;
of the outcomes of 6 patients with bacteraemia due to vancomy- Spersadexoline; Singapore: Spersadex Comp†; Spersadexoline†; Spain: C 22 H 23ClN 2O 8 = 478.9.
cin-resistant Enterococcus faecium concluded that chloramphen- Blefarida; Cloram Zinc; Cloran Hemidex; Cortison Chemicet Topica; Der- C AS — 57-62-5.
icol was effective and should be considered as a treatment op- misone Epitelizante; Dexam Constric†; Fluo Fenic; Icol; Medrivas Antib;
tion. Otosedol Biotico; Predni Azuleno; Switz.: Spersacet C†; Spersadex Comp; ATC — A01AB21; D06AA02; J01AA03; S01AA02.
Spersadexoline†; Thai.: Archifen; Chlorotracin; Dermasol; Levoptin; Sper-
1. Norris AH, et al. Chloramphenicol for the treatment of vanco- sadexoline; Vagicin; UK: Actinac; Venez.: Clorasona; Deicol†; Otandrol†. ATC Vet — QA01AB21; QD06AA02; QJ01AA03;
mycin-resistant enterococcal infections. Clin Infect Dis 1995; QJ51AA03; QS01AA02.
20: 1137–44.
2. Papanicolaou GA, et al. Nosocomial infections with vancomy-
cin-resistant Enterococcus faecium in liver transplant recipients: Chloroxine (USAN)
risk factors for acquisition and mortality. Clin Infect Dis 1996; H 3C CH3
23: 760–6. Cloroxinum; 5,7-Dichlorochinolin-8-ol; 5,7-Dichloroquinolin-8- Cl HO CH3 N
3. Mato SP, et al. Vancomycin-resistant Enterococcus faecium ol; Kloroxin. H H
meningitis successfully treated with chloramphenicol. Pediatr OH
Infect Dis J 1999; 18: 483–4. Хлороксин
4. Lautenbach E, et al. The role of chloramphenicol in the treatment C 9 H 5 Cl 2 NO = 214.0.
of bloodstream infection due to vancomycin-resistant Entero- C AS — 773-76-2. NH2
coccus. Clin Infect Dis 1998; 27: 1259–65.
5. Ricaurte JC, et al. Chloramphenicol treatment for vancomycin- OH
resistant Enterococcus faecium bacteremia. Clin Microbiol In- OH O OH O O
fect 2001; 7: 17–21. OH
Preparations Cl N
Chlortetracycline Bisulfate (rINNM)
BP 2008: Chloramphenicol Capsules; Chloramphenicol Ear Drops; Chlo-
ramphenicol Eye Drops; Chloramphenicol Eye Ointment; Chloramphenicol Bisulfato de clortetraciclina; Chlortétracycline, Bisulfate de; Chlo-
Sodium Succinate Injection; rtetracycline Bisulphate (BANM); Chlortetracyclini Bisulfas.
USP 31: Chloramphenicol and Hydrocortisone Acetate for Ophthalmic
Suspension; Chloramphenicol and Polymyxin B Sulfate Ophthalmic Oint- Хлортетрациклина Бисульфат
ment; Chloramphenicol and Prednisolone Ophthalmic Ointment; Chlo- Cl
ramphenicol Capsules; Chloramphenicol Cream; Chloramphenicol for Pharmacopoeias. In US for veterinary use only.
Ophthalmic Solution; Chloramphenicol Ophthalmic Ointment; Chloram-
phenicol Ophthalmic Solution; Chloramphenicol Otic Solution; Chloram- Profile USP 31 (Chlortetracycline Bisulfate). Store in airtight containers.
phenicol Palmitate Oral Suspension; Chloramphenicol Sodium Succinate Chloroxine is a halogenated hydroxyquinoline with antibacterial Protect from light.
 Chloroxine/Ciprofloxacin 243
Chlortetracycline Hydrochloride (BANM, rINNM) Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. urinary-tract infections the usual oral dose is 500 mg twice daily;
Chlorotetracykliny chlorowodorek; Chlortetraciklino hidrochlo- Ph. Eur. 6.2 (Cilastatin Sodium). A white or light yellow, hygro- for prophylaxis 500 mg is given at bedtime.
ridas; Chlortétracycline, chlorhydrate de; Chlortetracyclini hy- scopic, amorphous powder. Very soluble in water and in methyl For advice on use in renal impairment, see below.
alcohol; slightly soluble in dehydrated alcohol; practically insol-
drochloridum; Chlortetracyklin-hydrochlorid; Hidrocloruro de Administration in renal impairment. Cinoxacin should be
uble in acetone and in dichloromethane; very slightly soluble in
clortetraciclina; Klooritetrasykliinihydrokloridi; Klórtetraciklin- used in reduced dosage, or not used at all, in patients with renal
dimethyl sulfoxide. A 1% solution in water has a pH of 6.5 to 7.5. impairment.
hidroklorid; Klortetracyklinhydroklorid. Store at a temperature not exceeding 8° in airtight containers.
Хлортетрациклина Гидрохлорид USP 31 (Cilastatin Sodium). A white to tan-coloured powder. Preparations
C 22 H 23ClN 2 O 8 ,HCl = 515.3. Soluble in water and in methyl alcohol. pH of a 1% solution in USP 31: Cinoxacin Capsules.
C AS — 64-72-2. water is between 6.5 and 7.5. Store at a temperature less than 8°. Proprietary Preparations (details are given in Part 3)
ATC — A01AB21; D06AA02; J01AA03; S01AA02. Gr.: Cinobactin†; Ital.: Cinobac; Cinocil; Cinoxen; Nossacin; Noxigram†;
ATC Vet — QA01AB21; QD06AA02; QJ01AA03; Profile Uroc; Uronorm†; Uroxacin†; Mex.: Gugecin†; USA: Cinobac†.
QS01AA02. Cilastatin is an inhibitor of dehydropeptidase I, an enzyme found
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., and US. in the brush border of the renal tubules. It is given as the sodium
Ph. Eur. 6.2 (Chlortetracycline Hydrochloride). The hydrochlo- salt with the antibacterial imipenem (p.286) to prevent its renal
ride of a substance produced by the growth of certain strains of
metabolism to microbiologically inactive and potentially neph- Ciprofloxacin (BAN, USAN, rINN)
rotoxic products. This increases the concentrations of imipenem
Streptomyces aureofaciens or by any other means. A yellow Bay-q-3939; Ciprofloksacinas; Ciprofloxacine; Ciprofloxacino;
achieved in the urine and protects against any nephrotoxic ef-
powder. Slightly soluble in water and in alcohol; it dissolves in Ciprofloxacinum; Siprofloksasiini; Siprofloksasin; Siprofloxacin. 1-
fects, which were seen with high doses of imipenem given exper-
solutions of alkali hydroxides and carbonates. A 1% solution in Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazin-1-ylquino-
imentally to animals.
water has a pH of 2.3 to 3.3. Protect from light. line-3-carboxylic acid.
USP 31 (Chlortetracycline Hydrochloride). A yellow, odourless Cilastatin has no antibacterial activity itself, and does not affect
crystalline powder. Soluble 1 in 75 of water and 1 in 560 of alco- the antibacterial activity of imipenem. Ципрофлоксацин
hol; practically insoluble in acetone, in chloroform, in dioxan, Preparations C 17 H 18 FN 3 O 3 = 331.3.
and in ether; soluble in solutions of alkali hydroxides and carbon- USP 31: Imipenem and Cilastatin for Injectable Suspension; Imipenem and C AS — 85721-33-1.
ates. pH of a 1% solution in water is between 2.3 and 3.3. Store Cilastatin for Injection. ATC — J01MA02; S01AX13; S02AA15; S03AA07.
in airtight containers. Protect from light. Proprietary Preparations (details are given in Part 3) ATC Vet — QJ01MA02; QS01AX13; QS02AA15;
Profile Pol.: Tienam. QS03AA07.
Chlortetracycline is a tetracycline derivative with general prop- Multi-ingredient: Arg.: Dixabiox; Imipecil; Imistatin; Klonam†; Zienam;
Austral.: Primaxin; Austria: Zienam; Belg.: Tienam; Braz.: Penexil†; Tien-
erties similar to those of tetracycline (p.347) and is used as the am; Canad.: Primaxin; Chile: Inem; Tienam; Cz.: Tienam; Denm.: Tienam;
hydrochloride, more often topically than orally. It is used as a 1% Fin.: Tienam; Fr.: Tienam; Ger.: Zienam; Gr.: Primaxin; Hong Kong: Pre-
ophthalmic ointment and as a 3% ointment for application to the penem; Tienam; Hung.: Tienam; India: Cilanem; Indon.: Pelastin; Tienam; HN
skin. It is poorly absorbed from the gastrointestinal tract com- Israel: Tienam; Ital.: Imipem; Tenacid; Tienam; Malaysia: Bacqure; Tien-
pared with other tetracyclines but is sometimes given orally with am; Mex.: Arzomeba; Iminen; Tienam; Neth.: Tienam; Norw.: Tienam; N N
NZ: Primaxin; Philipp.: Anipen; Tienam; Port.: Tienam; Rus.: Tienam
other tetracycline derivatives. (Тиенам); S.Afr.: Tienam; Singapore: Tienam; Spain: Tienam; Swed.:
Preparations Tienam; Switz.: Tienam; Thai.: Tienam; Turk.: Tienam; UK: Primaxin;
USA: Primaxin; Venez.: Zienam. F COOH
BP 2008: Chlortetracycline Eye Ointment; Chlortetracycline Ointment;
USP 31: Chlortetracycline Hydrochloride Ointment; Chlortetracycline O
Hydrochloride Ophthalmic Ointment.
Proprietary Preparations (details are given in Part 3) Cinoxacin (BAN, USAN, rINN) Pharmacopoeias. In Chin., Eur. (see p.vii), Int., and US.
Austria: Aureomycin; Belg.: Aureomycin; Aureomycine; Fr.: Aureomy-
cine; Ger.: Aureomycin; Hong Kong: Aureomycin†; Chlortralim; Ital.: Au- 64716; Azolinic Acid; Cinoxacine; Cinoxacino; Cinoxacinum; Ph. Eur. 6.2 (Ciprofloxacin). An almost white or pale yellow,
reomicina; Malaysia: Chlortralim; Norw.: Aureomycin†; Pol.: Chlorocy- Compound 64716; Sinoksasiini. 1-Ethyl-1,4-dihydro-4-oxo-1,3- slightly hygroscopic, crystalline powder. Practically insoluble in
clinum; Port.: Aurecil†; Aureodermil†; Singapore: Chlortralim; Spain: dioxolo[4,5-g]cinnoline-3-carboxylic acid.
Aureomicina; Dermosa Aureomicina; Thai.: Aureomycin; Chlortralim. water; very slightly soluble in dehydrated alcohol and in dichlo-
Циноксацин romethane. Store in airtight containers. Protect from light.
Multi-ingredient: Austria: Aureocort; Braz.: Corciclen; Ger.: Aure-
odelf†; Aureomycin N†; Ital.: Aureocort; Aureomix; S.Afr.: Tritet; UK: C 12 H 10 N 2 O 5 = 262.2. USP 31 (Ciprofloxacin). Store in airtight containers at a temper-
Aureocort; Deteclo†. C AS — 28657-80-9. ature of 25°, excursions permitted between 15° and 30°. Avoid
ATC — J01MB06. temperatures above 40°. Protect from light.
ATC Vet — QJ01MB06.
Ciclacillin (BAN, rINN) Ciprofloxacin Hydrochloride (BANM, USAN, rINNM)
Ciclacilina; Ciclacilline; Ciclacillinum; Ciklacillin; Cyclacillin (USAN); Bay-o-9867; Ciprofloksacino hidrochloridas; Ciprofloxacine,
Siklasilliini; Wy-4508. (6R)-6-(1-Aminocyclohexanecarboxami- H3C chlorhydrate de; Ciprofloxacin-hidroklorid; Ciprofloxacin-hydro-
do)penicillanic acid. chlorid; Ciprofloxacinhydroklorid; Ciprofloxacini hydrochlori-
Циклациллин N dum; Cyprofloksacyny chlorowodorek; Hidrocloruro de cipro-
O floxacino; Siprofloksasiinihydrokloridi; Siprofloksasin Hidroklorür.
C 15 H 23N 3 O 4 S = 341.4. N
C AS — 3485-14-1. Ciprofloxacin hydrochloride monohydrate.
HO
Pharmacopoeias. In Jpn. O Ципрофлоксацина Гидрохлорид
C 17 H 18 FN 3 O 3 ,HCl,H 2 O = 385.8.
Profile O O C AS — 86483-48-9 (anhydrous ciprofloxacin hydrochlo-
Ciclacillin is an aminopenicillin with properties similar to those ride); 86393-32-0 (ciprofloxacin hydrochloride monohy-
of ampicillin (p.204), although it is generally less active in vitro. Pharmacopoeias. In US. drate).
Preparations USP 31 (Cinoxacin). A white to yellowish-white, odourless ATC — S02AA15.
Proprietary Preparations (details are given in Part 3) crystalline solid. Insoluble in water and in most common organic ATC Vet — QS02AA15.
Braz.: Cilinase†. solvents; soluble in alkaline solution. Store in airtight containers. Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet.
Ph. Eur. 6.2 (Ciprofloxacin Hydrochloride). A pale yellow,
Adverse Effects and Precautions slightly hygroscopic, crystalline powder. Soluble in water; very
As for Nalidixic Acid, p.304. slightly soluble in dehydrated alcohol; practically insoluble in
Cilastatin Sodium (BANM, USAN, rINNM) Cinoxacin should be used in reduced dosage, or not at all, in pa- acetone, in dichloromethane, and in ethyl acetate; slightly solu-
Cilastatin sodná sůl; Cilastatina sódica; Cilastatine sodique; Cilas- tients with renal impairment. ble in methyl alcohol. A 2.5% solution in water has a pH of 3.5
tatinnatrium; Cilastatino natrio druska; Cilastatinum natricum; ◊ References. to 4.5. Store in airtight containers. Protect from light.
Cilasztatin-nátrium; L-642957; MK-791; Natrii Cilastatinas; Natrii 1. Stricker BHC, et al. Anaphylactic reactions to cinoxacin. BMJ USP 31 (Ciprofloxacin Hydrochloride). Faintly yellowish to
Cilastatinum; Natriumsilastatinaatti; Natriumsilastatinat; Silastati- 1988; 297: 1434–5. light yellow crystals. Sparingly soluble in water; very slightly
ininatrium; Silastatin Sodyum. (Z)-(S)-6-Carboxy-6-[(S)-2,2- soluble in dehydrated alcohol; slightly soluble in acetic acid and
Interactions
dimethylcyclopropanecarboxamido]hex-5-enyl-L-cysteine, As for Nalidixic Acid, p.304. in methyl alcohol; practically insoluble in acetone, in ace-
monosodium salt. tonitrile, in dichloromethane, in ethyl acetate, and in hexane. pH
Натрий Циластатин Antimicrobial Action of a 2.5% solution in water is between 3.0 and 4.5. Store in air-
As for Nalidixic Acid, p.304. Cross-resistance with nalidixic tight containers at a temperature of 25°, excursions permitted be-
C 16 H 25N 2 NaO 5 S = 380.4.
acid has been shown. tween 15° and 30°. Protect from light.
C AS — 82009-34-5 (cilastatin); 81129-83-1 (cilastatin
sodium). Pharmacokinetics
Cinoxacin is rapidly and almost completely absorbed after oral Ciprofloxacin Lactate (BANM, rINNM)
doses. Peak serum concentrations of about 15 micrograms/mL Ciprofloxacine, Lactate de; Ciprofloxacini Lactas; Lactato de cip-
H 3C occur 2 to 3 hours after a 500-mg dose. The plasma half-life is rofloxacino.
about 1 to 2 hours. Cinoxacin is more than 60% bound to plasma
Ципрофлоксацина Лактат
H 3C proteins.
C 17 H 18 FN 3 O 3 ,C 3 H 6 O 3 = 421.4.
Cinoxacin appears to be metabolised in the liver and is excreted C AS — 97867-33-9.
via the kidney. Over 95% of a dose appears in the urine within 24 ATC — S02AA15.
hours, over half as unaltered drug and the remainder as inactive ATC Vet — QS02AA15.
NH2 O NH
metabolites. Mean urinary concentrations of about
300 micrograms/mL have been achieved during the first 4 hours Incompatibility. Ciprofloxacin infusion is stated in UK li-
HO S OH censed product information to have a pH of 3.9 to 4.5 and to be
after a 500-mg oral dose. Urinary excretion is reduced by
probenecid and in patients with renal impairment. incompatible with injections chemically or physically unstable at
O O this pH range. Incompatibility has been reported between cipro-
Uses and Administration floxacin and other drugs including some antibacterials.1-5
(cilastatin) Cinoxacin is a 4-quinolone antibacterial with actions and uses 1. Lyall D, Blythe J. Ciprofloxacin lactate infusion. Pharm J 1987;
similar to those of nalidixic acid (p.304). In the treatment of 238: 290.

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
244 Antibacterials
2. Janknegt R, et al. Quinolones and penicillins incompatibility. 4. Leone R, et al. Adverse drug reactions related to the use of fluo- 9. Gaynes R, et al. Outbreak of Clostridium difficile infection in a
DICP Ann Pharmacother 1989; 23: 91–2. roquinolone antimicrobials: an analysis of spontaneous reports long-term care facility: association with gatifloxacin use. Clin
3. Goodwin SD, et al. Compatibility of ciprofloxacin injection with and fluoroquinolone consumption data from three Italian re- Infect Dis 2004; 38: 640–5.
selected drugs and solutions. Am J Hosp Pharm 1991; 48: gions. Drug Safety 2003; 26: 109–20. 10. Pépin J, et al. Emergence of fluoroquinolones as the predomi-
2166–71. 5. Stahlmann R, Lode H. Fluoroquinolones in the elderly: safety nant risk factor for Clostridium difficile-associated diarrhea: a
considerations. Drugs Aging 2003; 20: 289–302. cohort study during an epidemic in Quebec. Clin Infect Dis
4. Jim LK. Physical and chemical compatibility of intravenous cip- 2005; 41: 1254–60.
rofloxacin with other drugs. Ann Pharmacother 1993; 27: 6. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoro-
704–7. quinolones. Clin Infect Dis 2005; 41 (suppl 2): S144–S157. Effects on glucose metabolism. For the effects of fluoroqui-
5. Elmore RL, et al. Stability and compatibility of admixtures of 7. Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolo- nolones, and in particular gatifloxacin, on blood glucose see un-
intravenous ciprofloxacin and selected drugs. Clin Ther 1996; nes. Ann Pharmacother 2007; 41: 1859–66.
der Gatifloxacin, p.281.
18: 246–55. 8. Segev S, et al. Safety of long-term therapy with ciprofloxacin:
data analysis of controlled clinical trials and review. Clin Infect Effects on the kidneys. A review1 of case reports of renal tox-
Stability. For mention of loss of activity in ciprofloxacin solu- Dis 1999; 28: 299–308. icity (including interstitial nephritis, acute renal failure, acute tu-
tions exposed to ultraviolet light see under Precautions, below. 9. Heyd A, Haverstock D. Retrospective analysis of the safety pro- bular necrosis, and crystalluria) associated with ciprofloxacin
file of oral and intravenous ciprofloxacin in a geriatric popula-
tion. Clin Ther 2000; 22: 1239–50. and other fluoroquinolones indicated that such toxicity, although
Adverse Effects potentially serious, was rare. It was also noted that nearly all pa-
Effects on the blood. Haematological disturbances including tients developing acute renal failure were over 50 years of age.
Ciprofloxacin is generally well tolerated. The range of thrombocytopenia,1 eosinophilia,2 leucopenia, and, very rarely, Another review,2 confirming that the problem remained rare,
adverse effects associated with ciprofloxacin and the pancytopenia,3 haemolytic anaemia,4 or agranulocytosis have noted that risk factors for quinolone-induced nephrotoxicity
other fluoroquinolones is broadly similar to that of ear- been reported with ciprofloxacin and some other fluoroquinolo- seemed to include the particular quinolone chosen, with cipro-
lier quinolones such as nalidixic acid (p.304). They nes. There has also been a case report5 of haemolytic-uraemic floxacin the most often involved, as well as the use of high doses,
syndrome associated with ciprofloxacin therapy; the patient re- patient age, inadequate hydration, and use of other nephrotoxic
most often involve the gastrointestinal tract, CNS, or covered with routine supportive treatment (haemodialysis and
skin. drugs or the presence of other processes likely to contribute to
plasma exchange) after the drug was stopped. In addition, tran- renal damage such as diabetes.
Gastrointestinal disturbances include nausea, vomit- sient reductions in factor VIII and von Willebrand’s factor lead- 1. Lomaestro BM. Fluoroquinolone-induced renal failure. Drug
ing, diarrhoea, abdominal pain, and dyspepsia and are ing to bleeding in 2 patients receiving ciprofloxacin has been re- Safety 2000; 22: 479–85.
ported.6 Neutropenia that developed in an elderly patient a few 2. Montagnac R, et al. Les insuffisances rénales aiguës aux qui-
the most frequent adverse effects. Pseudomembranous days after starting treatment with intravenous moxifloxacin re- nolones: revue générale à propos d’une observation avec cristal-
colitis, pancreatitis, and dysphagia have been reported solved on stopping the drug.7 lisation liée à la ciprofloxacine. Nephrol Ther 2005; 1: 44–51.
rarely. 1. Starr JA, Ragucci KR. Thrombocytopenia associated with intra- Effects on the liver. Fluoroquinolones, including cipro-
venous ciprofloxacin. Pharmacotherapy 2005; 25: 1030–4. floxacin, may cause elevated liver enzyme values. In most pa-
Headache, dizziness, confusion, insomnia, and rest- 2. Mofredj A, et al. Norfloxacin-induced eosinophilia in a cirrhotic tients this effect is transient and reversible without stopping the
lessness are among the commonest effects on the CNS. patient. Ann Pharmacother 2002; 36: 1107–8. drug.
3. Deng JY, Tovar JM. Pancytopenia with levofloxacin therapy for
Others include tremor, drowsiness, nightmares, visual pelvic inflammatory disease in an otherwise healthy young pa- More serious cases of hepatotoxicity, including fatalities, have
and other sensory disturbances, hallucinations, psy- tient. Ann Pharmacother 2006; 40: 1692–3. been reported both with ciprofloxacin 1-5 and with other
chotic reactions, depression, convulsions, and intracra- 4. Oh YR, et al. Levofloxacin-induced autoimmune hemolytic ane- fluoroquinolones4,6-14 but they are rare. In many cases the pa-
mia. Ann Pharmacother 2003; 37: 1010–13. tients were elderly and had co-morbid conditions.
nial hypertension. Paraesthesia and peripheral neurop- 5. Allan DS, et al. Ciprofloxacin-associated hemolytic-uremic syn- 1. Grassmick BK, et al. Fulminant hepatic failure possibly related
athy have also been reported. drome. Ann Pharmacother 2002; 36: 1000–1002. to ciprofloxacin. Ann Pharmacother 1992; 26: 636–9.
6. Castaman G, Rodeghiero F. Acquired transitory von Willebrand 2. Sherman O, Beizer JL. Possible ciprofloxacin-induced acute
In addition to rash and pruritus, hypersensitivity-type syndrome with ciprofloxacin. Lancet 1994; 343: 492. cholestatic jaundice. Ann Pharmacother 1994; 28: 1162–4.
reactions affecting the skin have included, rarely, vas- 7. Chang C-M, et al. Moxifloxacin-associated neutropenia in a cir- 3. Villeneuve J-P, et al. Suspected ciprofloxacin-induced hepato-
rhotic elderly woman with lower extremity cellulitis. Ann Phar- toxicity. Ann Pharmacother 1995; 29: 257–9.
culitis, erythema multiforme, Stevens-Johnson syn- macother 2008; 42: 580–3. 4. Jones SE, Smith RH. Quinolones may induce hepatitis. BMJ
drome, and toxic epidermal necrolysis. Photosensitivi- Effects on the cardiovascular system. Prolongation of the
1997; 314: 869.
5. Contreras MÁ, et al. Severe ciprofloxacin-induced acute hepa-
ty has occurred, although it may be more frequent with QT interval,1,2 sometimes progressing to torsade de pointes,3-8 titis. Eur J Clin Microbiol Infect Dis 2001; 20: 434–5.
some other fluoroquinolones such as lomefloxacin and has been associated with ciprofloxacin and other fluoroquinolo- 6. González Carro P, et al. Fatal subfulminant hepatic failure with
sparfloxacin. Anaphylaxis has been associated with nes although a review9 considered that ciprofloxacin was least ofloxacin. Am J Gastroenterol 2000; 95: 1606.
likely to produce this effect. Licensed product information rec- 7. Björnsson E, et al. Norfloxacin-induced eosinophilic necrotiz-
ciprofloxacin and some other quinolones. As with oth- ing granulomatous hepatitis. Am J Gastroenterol 2000; 95:
ommends that gatifloxacin, gemifloxacin, levofloxacin, lome- 3662–4.
er quinolones, reversible arthralgia or myalgia has floxacin, moxifloxacin, ofloxacin, and sparfloxacin should be 8. Spahr L, et al. Acute fatal hepatitis related to levofloxacin. J
sometimes occurred and joint erosions have been doc- avoided in patients with predisposing factors or who are also re- Hepatol 2001; 35: 308–9.
umented in immature animals. Tendon damage has ceiving other drugs that are known to cause this effect and that 9. Karim A, et al. Possible levofloxacin-induced acute hepatocel-
lular injury in a patient with chronic obstructive lung disease.
also been reported. norfloxacin should be used with caution in such situations. Clin Infect Dis 2001; 33: 2088–90.
1. Noel GJ, et al. Effects of three fluoroquinolones on QT interval 10. Soto S, et al. Moxifloxacin-induced acute liver injury. Am J
Other adverse effects reported with ciprofloxacin in- in healthy adults after single doses. Clin Pharmacol Ther 2003; Gastroenterol 2002; 97: 1853–4.
clude crystalluria, transient increases in serum creati- 73: 292–303. 11. Coleman CI, et al. Possible gatifloxacin-induced fulminant he-
2. Nykamp DL, et al. QTc prolongation associated with combina- patic failure. Ann Pharmacother 2002; 36: 1162–7.
nine or blood urea nitrogen and, rarely, acute renal fail- tion therapy of levofloxacin, imipramine, and fluoxetine. Ann 12. Schwalm J-D, Lee CH. Acute hepatitis associated with oral lev-
ure secondary to interstitial nephritis. Elevated liver Pharmacother 2005; 39: 543–6. ofloxacin therapy in a hemodialysis patient. CMAJ 2003; 168:
3. Frothingham R. Rates of torsades de pointes associated with cip- 847–8.
enzyme values, jaundice, and hepatitis have occurred, rofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxi- 13. Cheung O, et al. Gatifloxacin-induced hepatotoxicity and acute
as have haematological disturbances including eosi- floxacin. Pharmacotherapy 2001; 21: 1468–72. pancreatitis. Ann Intern Med 2004; 140: 73–4.
14. Çoban Ş, et al. Levofloxacin-induced acute fulminant hepatic
nophilia, leucopenia, thrombocytopenia and, very rare- 4. Owens RC, Ambrose PG. Torsades de pointes associated with
failure in a patient with chronic hepatitis B infection. Ann Phar-
fluoroquinolones. Pharmacotherapy 2002; 22: 663–8.
ly, pancytopenia, haemolytic anaemia or agranulocyto- 5. Bertino JS, et al. Gatifloxacin-associated corrected QT interval
macother 2005; 39: 1737–40.
sis. Cardiovascular adverse effects include prolongation, torsades de pointes, and ventricular fibrillation in Effects on the musculoskeletal system. Reversible arthral-
tachycardia, hypotension, oedema, syncope, hot flush- patients with known risk factors. Clin Infect Dis 2002; 34: gia has sometimes occurred with the fluoroquinolones;1 joint
861–3. erosions have been documented in immature animals. In a re-
es, and sweating. Some fluoroquinolones may rarely 6. Amankwa K, et al. Torsades de pointes associated with fluoro-
port,2 treatment with pefloxacin may have contributed to the de-
cause prolongation of the QT interval and ventricular quinolones: importance of concomitant risk factors. Clin Phar-
structive arthropathy that occurred in a 17-year-old youth. For a
macol Ther 2004; 75: 242–7.
arrhythmias, including torsade de pointes (see below). 7. Dale KM, et al. Moxifloxacin and torsade de pointes. Ann Phar- discussion of the use of fluoroquinolones in children and adoles-
As with other antibacterials, superinfection with organ- macother 2007; 41: 336–40. cents, see Administration in Children, under Precautions, below.
8. Knorr JP, et al. Ciprofloxacin-induced Q-T interval prolonga- There have been reports3-7 of tendinitis and tendon rupture asso-
isms not very susceptible to ciprofloxacin is possible. tion. Am J Health-Syst Pharm 2008; 65: 547–51. ciated with fluoroquinolones. By July 1995, the UK CSM5 had
Such organisms include Candida, Clostridium diffi- 9. Owens RC. QT prolongation with antimicrobial agents: under-
received 21 reports of tendon damage, often of the Achilles ten-
cile, and Streptococcus pneumoniae. There is some ev- standing the significance. Drugs 2004; 64: 1091–1124.
don, associated with these antibacterials—11 with ciprofloxacin
idence that fluoroquinolone use may be associated Effects on the gastrointestinal tract. There have been case and 10 with ofloxacin. In a later case-control study8 of a cohort
with an increased risk of colonisation by MRSA. reports and studies of pseudomembranous colitis or superinfec- of 46 776 users of fluoroquinolones between July 1992 to June
tion with Clostridium difficile in patients given ciprofloxacin1-6 1998, 704 had Achilles tendinitis and 38 had Achilles tendon
Pain and irritation may occur at the site of infusion ac- and other fluoroquinolones7-10 although some commentators rupture; the adjusted relative risk of Achilles tendon disorders
companied rarely by phlebitis or thrombophlebitis. have questioned this association and pointed out that other cir- with current use was 1.9. The risk of tendon damage is increased
cumstances, such as poor infection control, may be significant by use with corticosteroids and is more common with increasing
Adverse effects reported after ocular use of cipro- contributory factors. age:5 the case-control study8 found that the relative risk for cur-
floxacin include local burning or discomfort, keratopa- 1. Cain DB, O’Connor ME. Pseudomembranous colitis associated rent users rose to 3.2 among those aged 60 and over, and to 6.2
thy, corneal staining, corneal precipitates or infiltrates, with ciprofloxacin. Lancet 1990; 336: 946. in those in this age group also using corticosteroids. Another
2. Bates CJ, et al. Ciprofloxacin and Clostridium difficile infec- case-control study9 using data from 1988 to 1998 held on a dif-
and photophobia. tion. Lancet 1990; 336: 1193.
3. Low N, Harries A. Ciprofloxacin and pseudomembranous coli- ferent UK general practice database reported similar findings
Local discomfort, pain, or pruritus have occurred after tis. Lancet 1990; 336: 1510. and concluded that ofloxacin was associated with a higher risk of
use of ear drops containing ciprofloxacin. 4. Hillman RJ, et al. Ciprofloxacin as a cause of Clostridium diff- tendon damage than other fluoroquinolones. A review10 of the
icile-associated diarrhoea in an HIV antibody-positive patient. J literature between 1966 and 2001 revealed 98 case reports of
◊ General reviews of the adverse effects of fluoroquinolones1-7 Infect 1990; 21: 205–7. fluoroquinolone-associated tendon damage. Of these, 36 were
and ciprofloxacin specifically.8,9 5. McFarland LV, et al. Ciprofloxacin-associated Clostridium dif-
associated with pefloxacin therapy and 25 with ciprofloxacin;
ficile disease. Lancet 1995; 346: 977–8.
1. Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a re- 6. Angel CA, et al. Severe ciprofloxacin-associated pseudomem- ofloxacin was associated with 6 cases. Renal disease or impair-
view focusing on newer agents. Clin Infect Dis 1999; 28: branous colitis in an eight-year-old child. J Pediatr Surg 2004; ment was also considered as a risk factor.
352–64. 39: 1590–2.
2. Ball P, et al. Comparative tolerability of the newer fluoroqui- Onset may be rapid: rupture has occurred within 48 hours of
7. Dan M, Samra Z. Clostridium difficile colitis associated with
nolone antibacterials. Drug Safety 1999; 21: 407–21. ofloxacin therapy. Am J Med 1989; 87: 479. starting therapy.11 The CSM5 warned that at the first sign of pain
3. Rubinstein E. History of quinolones and their side effects. Chem- 8. Ortiz-de-Saracho J, et al. Moxifloxacin-induced Clostridium or inflammation the fluoroquinolone should be withdrawn and
otherapy 2001; 47 (suppl 3): 3–8. difficile diarrhea. Ann Pharmacother 2003; 37: 452–3. the affected limb rested until the tendon symptoms had resolved.
 Ciprofloxacin 245
Similar warnings have been issued in other countries, but some 11. Zehnder D, et al. Painful dysaesthesia with ciprofloxacin. BMJ has been suggested that these drugs should not gener-
cases have continued to be reported.12 In the USA the FDA has 1995; 311: 1204.
12. Akhtar S, Ahmad H. Ciprofloxacin-induced catatonia. J Clin ally be used in patients aged under 18 years (see also
required a warning to be added to prescribing information for the Psychiatry 1993; 54: 115–16.
fluoroquinolones stating that there is an increased risk in patients below), pregnant women, or breast-feeding mothers
13. Rosolen A, et al. Acute hemiparesis associated with cipro-
over 60, in kidney, heart, and lung transplant recipients, and with floxacin. BMJ 1994; 309: 1411. (but see also below) unless the benefits outweigh the
use of concomitant corticosteroid therapy.13 14. Paul J, Brown NM. Tinnitus and ciprofloxacin. BMJ 1995; 311: risks. Tendon damage may occur rarely with fluoroqui-
232.
There have been reports14,15 of rhabdomyolysis in patients given 15. Tripathi A, et al. Acute psychosis following the use of topical nolones (see Effects on the Musculoskeletal System,
fluoroquinolones, including one fatality associated with levo- ciprofloxacin. Arch Ophthalmol 2002; 120: 665–6. above) and treatment should be stopped if patients ex-
floxacin therapy.14 16. Abouesh A, et al. Antimicrobial-induced mania (antibiomania):
a review of spontaneous reports. J Clin Psychopharmacol 2002; perience tendon pain, inflammation, or rupture; subse-
1. Alfaham M, et al. Arthropathy in a patient with cystic fibrosis
taking ciprofloxacin. BMJ 1987; 295: 699. 22: 71–81. quent use of fluoroquinolones is contra-indicated in
2. Chevalier X, et al. A case of destructive polyarthropathy in a 17- 17. Upton C. Sleep disturbance in children treated with ofloxacin.
BMJ 1994; 309: 1411. these patients.
year-old youth following pefloxacin treatment. Drug Safety
18. Thomas RJ, Reagan DR. Association of a Tourette-like syn-
1992; 7: 310–14.
drome with ofloxacin. Ann Pharmacother 1996; 30: 138–41. Exposure to strong sunlight or sunlamps should be
3. Huston KA. Achilles tendinitis and tendon rupture due to fluor-
oquinolone antibiotics. N Engl J Med 1994; 331: 748. 19. Mohan N, et al. Oral gatifloxacin-induced ataxia. Am J Health- avoided during treatment with ciprofloxacin. The abil-
Syst Pharm 2002; 59: 1894.
4. Szarfman A, et al. More on fluoroquinolone antibiotics and ten-
20. Adams M, Tavakoli H. Gatifloxacin-induced hallucinations in a ity to drive or operate machinery may be impaired, es-
don rupture. N Engl J Med 1995; 332: 193.
5. Committee on Safety of Medicines/Medicines Control Agency.
19-year-old man. Psychosomatics 2006; 47: 360. pecially when alcohol is also taken.
Tendon damage associated with quinolone antibiotics. Current Hypersensitivity. Hypersensitivity and skin reactions have Some fluoroquinolones have the potential to prolong
Problems 1995; 21: 8. Also available at: http://www.mhra.gov.uk/ been associated with ciprofloxacin and other fluoroquinolones.
home/idcplg?IdcService=GET_FILE&dDocName= the QT interval (see Effects on the Cardiovascular Sys-
CON2015619&RevisionSelectionMethod=LatestReleased (ac- Reports have included anaphylaxis (which has sometimes been
cessed 12/07/06) fatal, and may occur after the first dose),1-7 serum sickness,8 Ste- tem, above) and should be avoided or used with cau-
6. Carrasco JM, et al. Tendinitis associated with ciprofloxacin. vens-Johnson syndrome,9 toxic epidermal necrolysis (some- tion in patients with QT prolongation or relevant risk
Ann Pharmacother 1997; 31: 120. times fatal),10-17 laryngeal oedema,18 and vasculitis.19-21 Fatal factors such as uncorrected electrolyte disturbances,
7. Mathis AS, et al. Levofloxacin-associated Achilles tendon rup- vasculitis has been reported with ofloxacin.22
ture. Ann Pharmacother 2003; 37: 1014–17. bradycardia, or pre-existing cardiac disease. Certain
8. van der Linden PD, et al. Fluoroquinolones and risk of Achilles 1. Davis H, et al. Anaphylactoid reactions reported after treatment
with ciprofloxacin. Ann Intern Med 1989; 111: 1041–3. drugs may also increase the risk (see Interactions, be-
tendon disorders: case-control study. BMJ 2002; 324: 1306–7.
9. van der Linden PD, et al. Increased risk of Achilles tendon rup- 2. Peters B, Pinching AJ. Fatal anaphylaxis associated with cipro- low).
ture with quinolone antibacterial use, especially in elderly pa- floxacin in a patient with AIDS related complex. BMJ 1989;
tients taking oral corticosteroids. Arch Intern Med 2003; 163: 298: 605. Ciprofloxacin and other fluoroquinolones should be
1801–7. 3. Wurtz RM, et al. Anaphylactoid drug reactions to ciprofloxacin avoided in MRSA infections because of the high level
10. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopa- and rifampicin in HIV-infected patients. Lancet 1989; i: 955–6.
thy: a critical review of the literature. Clin Infect Dis 2003; 36: 4. Assouad M, et al. Anaphylactoid reactions to ciprofloxacin. Ann of resistance.
1404–10. Intern Med 1995; 122: 396–7.
11. Committee on Safety of Medicines/Medicines Control Agency. 5. Smythe MA, Cappelletty DM. Anaphylactoid reaction to levo- Administration in children. Since ciprofloxacin and other
Reminder: fluoroquinolone antibiotics and tendon disorders. floxacin. Pharmacotherapy 2000; 20: 1520–3. fluoroquinolones can cause degenerative changes in weight-
Current Problems 2002; 28: 3–4. Also available at: http:// 6. Ho DY, et al. Anaphylactoid reaction to ciprofloxacin. Ann bearing joints of young animals they should only be used in chil-
www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& Pharmacother 2003; 37: 1018–23.
7. Sachs B, et al. Fluoroquinolone-associated anaphylaxis in spon- dren and adolescents where their use may be justified if the ben-
dDocName=CON007454& RevisionSelectionMethod= efits outweigh the risks.1-3 For example, ciprofloxacin is licensed
LatestReleased (accessed 12/07/06) taneous adverse drug reaction reports in Germany: differences
12. Adverse Drug Reactions Advisory Committee (ADRAC). Fluor- in reporting rates between individual fluoroquinolones and oc- in some countries for use in the prophylaxis and treatment of in-
oquinolone antibiotics: remember tendon disorders. Aust Adverse currence after first-ever use. Drug Safety 2006; 29: 1087–1100. halational anthrax and also in the treatment of certain infections
Drug React Bull 2006; 25: 3. Also available at: http:// 8. Slama TG. Serum sickness-like illness associated with cipro- in those under 18 years of age (see under Uses and Administra-
www.tga.health.gov.au/adr/aadrb/aadr0602.pdf (accessed floxacin. Antimicrob Agents Chemother 1990; 34: 904–5.
9. Hällgren J, et al. Stevens-Johnson syndrome associated with tion, below).
12/07/06)
13. FDA. Fluoroquinolone Antimicrobial Drugs [ciprofloxacin (mar- ciprofloxacin: a review of adverse cutaneous events reported in A comparative cohort study2 involving about 500 children and
keted as Cipro and generic ciprofloxacin), ciprofloxacin extended Sweden as associated with this drug. J Am Acad Dermatol 2003; adolescents found that the incidence of musculoskeletal adverse
release (marketed as Cipro XR and Proquin XR), gemifloxacin 49 (suppl): S267–S269.
10. Tham TCK, et al. Possible association between toxic epidermal effects was higher (10 cases out of 264 patients) in those taking
(marketed as Factive), levofloxacin (marketed as Levaquin), moxi-
floxacin (marketed as Avelox), norfloxacin (marketed as Noroxin), necrolysis and ciprofloxacin. Lancet 1991; 338: 522. fluoroquinolones (ciprofloxacin, ofloxacin, or pefloxacin) than
and ofloxacin (marketed as Floxin and generic ofloxacin)] (issued 11. Moshfeghi M, Mandler HD. Ciprofloxacin-induced toxic epi- in those taking other antibacterials (1 out of 237). In the former
8th July, 2008). Available at: http://www.fda.gov/cder/drug/ dermal necrolysis. Ann Pharmacother 1993; 27: 1467–9. group of patients, these adverse effects, mainly arthralgias, were
InfoSheets/HCP/fluoroquinolonesHCP.htm (accessed 12/08/08) 12. Yerasi AB, Oertel MD. Ciprofloxacin-induced toxic epidermal
necrolysis. Ann Pharmacother 1996; 30: 297. reversible and were most frequent with pefloxacin therapy.
14. Petitjeans F, et al. A case of rhabdomyolysis with fatal outcome
after a treatment with levofloxacin. Eur J Clin Pharmacol 2003; 13. Livasy CA, Kaplan AM. Ciprofloxacin-induced toxic epidermal 1. Burstein GR, et al. Ciprofloxacin for the treatment of uncompli-
59: 779–80. necrolysis: a case report. Dermatology 1997; 195: 173–5. cated gonorrhea infection in adolescents: does the benefit out-
15. Hsiao S-H, et al. Acute rhabdomyolysis associated with 14. Melde SL. Ofloxacin: a probable cause of toxic epidermal weigh the risk? Clin Infect Dis 2002; 35 (suppl 2): S191–S199.
ofloxacin/levofloxacin therapy. Ann Pharmacother 2005; 39: necrolysis. Ann Pharmacother 2001; 35: 1388–90. 2. Chalumeau M, et al. Fluoroquinolone safety in pediatric pa-
146–9. 15. Sahin MT, et al. Norfloxacin-induced toxic epidermal necroly- tients: a prospective, multicenter, comparative cohort study in
sis. Ann Pharmacother 2005; 39: 768–70. France. Abstract: Pediatrics 2003; 111: 1427–8. Full version:
Effects on the nervous system. By 1991 the UK CSM1 had 16. Christie MJ, et al. Generalized seizure and toxic epidermal http://pediatrics.aappublications.org/cgi/reprint/111/6/e714 (ac-
received 26 reports of convulsions associated with ciprofloxacin, necrolysis following levofloxacin exposure. Ann Pharmacother cessed 01/11/06)
1 with norfloxacin, and 1 with ofloxacin. It was noted that con- 2005; 39: 953–5.
17. Islam AFMS, Rahman MS. Levofloxacin-induced fatal toxic 3. American Academy of Pediatrics Committee on Infectious Dis-
vulsions could occur both in patients with epilepsy and in those epidermal necrolysis. Ann Pharmacother 2005; 39: 1136–7. eases. The use of systemic fluoroquinolones. Pediatrics 2006;
with no history of convulsions. Generalised seizures have been 18. Baciewicz AM, et al. Laryngeal edema related to ciprofloxacin 118: 1287–92.
reported in patients given gatifloxacin2 and levofloxacin.3,4 Sei- therapy. Ann Pharmacother 1992; 26: 1456. Breast feeding. Ciprofloxacin was found to be undetectable in
zures have also been associated with the use of ear drops contain- 19. Choe U, et al. Ciprofloxacin-induced vasculitis. N Engl J Med
1989; 320: 257–8. the serum of a breast-fed infant whose mother took ciprofloxacin
ing ciprofloxacin.5 All 5 case reports2-5 involved patients aged 65 20. Stubbings J, et al. Cutaneous vasculitis due to ciprofloxacin. 500 mg daily for 10 days.1 In another study2 involving 30 wom-
years and over; of these, 1 had a history (although unclear) of BMJ 1992; 305: 29. en who underwent termination of pregnancy, 10 each were given
seizures,2 3 had chronic renal impairment,3-5 and 1 had neither.3 21. Drago F, et al. Henoch-Schönlein purpura induced by fluoroqui- ciprofloxacin, ofloxacin, or pefloxacin respectively, and all 3
nolones. Br J Dermatol 1994; 131: 448.
Other reports of CNS toxicity associated with ciprofloxacin have 22. Pace JL, Gatt P. Fatal vasculitis associated with ofloxacin. BMJ drugs were found to be highly concentrated in breast milk with
included eosinophilic meningitis,6 delirium,7 and acute psycho- 1989; 299: 658. ratios exceeding 75% of the simultaneous serum concentrations
ses.8,9 Peripheral neuropathy,10 dysaesthesia,11 catatonia,12 hemi- 2 hours after a dose. It was concluded that, because fluoroqui-
Superinfection. Superinfection with Streptococcus pneumoni-
paresis,13 and tinnitus14 have also been reported. Acute psychosis nolones had been shown to cause arthropathy in young animals,
ae has been reported in patients receiving ciprofloxacin.1-3 For
occurred15 in a patient using ciprofloxacin eye drops. A review16 their potential benefits should be weighed against the risk to the
references to superinfection with Clostridium difficile and asso-
of published and spontaneous reports found an association be- infant before they were considered for use in breast-feeding
ciated pseudomembranous colitis, see under Effects on the Gas-
tween adverse manic reactions and the use of certain antibacteri-
trointestinal Tract, above. women. The American Academy of Pediatrics3 considers that
als including ciprofloxacin and ofloxacin. the use of ciprofloxacin is usually compatible with breast feed-
Fungal otitis externa is also associated with the use of ear drops
There have also been reports of sleep disturbances17 and of a ing.
containing fluoroquinolones.4
Tourette-like syndrome18 associated with ofloxacin. Ataxia19 1. Gardner DK, et al. Simultaneous concentrations of ciprofloxacin
1. Righter J. Pneumococcal meningitis during intravenous cipro-
and hallucinations20 have been reported with the use of gati- floxacin therapy. Am J Med 1990; 88: 548.
in breast milk and in serum in mother and breast-fed infant. Clin
floxacin. Pharm 1992; 11: 352–4.
2. Gordon JJ, Kauffman CA. Superinfection with Streptococcus
1. Committee on Safety of Medicines. Convulsions due to qui- pneumoniae during therapy with ciprofloxacin. Am J Med 1990; 2. Giamarellou H, et al. Pharmacokinetics of three newer quinolo-
nolone antimicrobial agents. Current Problems 32 1991. Also 89: 383–4. nes in pregnant and lactating women. Am J Med 1989; 87 (suppl
a v a i l a b l e a t : h t t p : / / w w w. m h r a . g o v.u k/ ho m e / i d c p l g ? 3. Lee BL, et al. Infectious complications with respiratory patho- 5A): 49S–51S.
I d c S e r v i c e = G ET _ F I LE & d D oc N a m e = C O N 2 0 2 44 5 0 & gens despite ciprofloxacin therapy. N Engl J Med 1991; 325: 3. American Academy of Pediatrics. The transfer of drugs and oth-
RevisionSelectionMethod=LatestReleased (accessed 02/03/07) 520–1. er chemicals into human milk. Pediatrics 2001; 108: 776–89.
2. Quigley CA, Lederman JR. Possible gatifloxacin-induced sei- 4. Schrader N, Isaacson G. Fungal otitis externa: its association Correction. ibid.; 1029. Also available at:
zure. Ann Pharmacother 2004; 38: 235–7. with fluoroquinolone eardrops. Pediatrics 2003; 111: 1123. h t tp : / /a a p po l i c y. a a pp u b l ica ti o n s .o rg/ c g i / c o nt e n t / f u ll /
3. Kushner JM, et al. Seizures associated with fluoroquinolones. pediatrics%3b108/3/776 (accessed 25/05/04)
Ann Pharmacother 2001; 35: 1194–8.
4. Christie MJ, et al. Generalized seizure and toxic epidermal Precautions Exposure to UV light. Loss of antibacterial activity has been
necrolysis following levofloxacin exposure. Ann Pharmacother Ciprofloxacin should be used with caution in patients reported after irradiation of ciprofloxacin solutions by UV light.1
2005; 39: 953–5. In addition to the possible hazard of photosensitivity reactions, a
5. Orr CF, Rowe DB. Eardrop attacks: seizures triggered by cipro- with epilepsy or a history of CNS disorders. Care is reduction in both cutaneous and circulating levels of cipro-
floxacin eardrops. Med J Aust 2003; 178: 343. also necessary in those with renal impairment, G6PD
6. Asperilla MO, et al. Eosinophilic meningitis associated with floxacin was predicted in patients exposed to sunlight through
ciprofloxacin. Am J Med 1989; 87: 589–90. deficiency, or myasthenia gravis. An adequate fluid in- window glass or the longer wavelength UVA radiation from
7. Ja